David Schneider

All Publications

• How Many Parameters Does It Take to Describe Disease Tolerance? PLOS BIOLOGY Louie, A., Song, K. H., Hotson, A., Tate, A. T., Schneider, D. S. 2016; 14 (4)

  Abstract

  The study of infectious disease has been aided by model organisms, which have helped to elucidate molecular mechanisms and contributed to the development of new treatments; however, the lack of a conceptual framework for unifying findings across models, combined with host variability, has impeded progress and translation. Here, we fill this gap with a simple graphical and mathematical framework to study disease tolerance, the dose response curve relating health to microbe load; this approach helped uncover parameters that were previously overlooked. Using a model experimental system in which we challenged Drosophila melanogaster with the pathogen Listeria monocytogenes, we tested this framework, finding that microbe growth, the immune response, and disease tolerance were all well represented by sigmoid models. As we altered the system by varying host or pathogen genetics, disease tolerance varied, as we would expect if it was indeed governed by parameters controlling the sensitivity of the system (the number of bacteria required to trigger a response) and maximal effect size according to a logistic equation. Though either the pathogen or host immune response or both together could theoretically be the proximal cause of pathology that killed the flies, we found that the pathogen, but not the immune response, drove damage in this model. With this new understanding of the circuitry controlling disease tolerance, we can now propose better ways of choosing, combining, and developing treatments.

  View details for DOI 10.1371/journal.pbio.1002435

  View details for Web of Science ID 000375094800006

  View details for PubMedID 27088212

• Tracking Resilience to Infections by Mapping Disease Space. PLoS biology Torres, B. Y., Oliveira, J. H., Thomas Tate, A., Rath, P., Cumnock, K., Schneider, D. S. 2016; 14 (4)

  Abstract

  Infected hosts differ in their responses to pathogens; some hosts are resilient and recover their original health, whereas others follow a divergent path and die. To quantitate these differences, we propose mapping the routes infected individuals take through "disease space." We find that when plotting physiological parameters against each other, many pairs have hysteretic relationships that identify the current location of the host and predict the future route of the infection. These maps can readily be constructed from experimental longitudinal data, and we provide two methods to generate the maps from the cross-sectional data that is commonly gathered in field trials. We hypothesize that resilient hosts tend to take small loops through disease space, whereas nonresilient individuals take large loops. We support this hypothesis with experimental data in mice infected with Plasmodium chabaudi, finding that dying mice trace a large arc in red blood cells (RBCs) by reticulocyte space as compared to surviving mice. We find that human malaria patients who are heterozygous for sickle cell hemoglobin occupy a small area of RBCs by reticulocyte space, suggesting this approach can be used to distinguish resilience in human populations. This technique should be broadly useful in describing the in-host dynamics of infections in both model hosts and patients at both population and individual levels.

  View details for DOI 10.1371/journal.pbio.1002436

  View details for PubMedID 27088359

  View details for PubMedCentralID PMC4835107

• Tracing Personalized Health Curves during Infections PLOS BIOLOGY Schneider, D. S. 2011; 9 (9)

  Abstract

  It is difficult to describe host-microbe interactions in a manner that deals well with both pathogens and mutualists. Perhaps a way can be found using an ecological definition of tolerance, where tolerance is defined as the dose response curve of health versus parasite load. To plot tolerance, individual infections are summarized by reporting the maximum parasite load and the minimum health for a population of infected individuals and the slope of the resulting curve defines the tolerance of the population. We can borrow this method of plotting health versus microbe load in a population and make it apply to individuals; instead of plotting just one point that summarizes an infection in an individual, we can plot the values at many time points over the course of an infection for one individual. This produces curves that trace the course of an infection through phase space rather than over a more typical timeline. These curves highlight relationships like recovery and point out bifurcations that are difficult to visualize with standard plotting techniques. Only nine archetypical curves are needed to describe most pathogenic and mutualistic host-microbe interactions. The technique holds promise as both a qualitative and quantitative approach to dissect host-microbe interactions of all kinds.

  View details for DOI 10.1371/journal.pbio.1001158

  View details for PubMedID 21957398

• The Role of Anorexia in Resistance and Tolerance to Infections in Drosophila PLOS BIOLOGY Ayres, J. S., Schneider, D. S. 2009; 7 (7)

  Abstract

  Most infections induce anorexia but its function, if any, remains unclear. Because this response is common among animals, we hypothesized that infection-induced diet restriction might be an adaptive trait that modulates the host's ability to fight infection. Two defense strategies protect hosts against infections: resistance, which is the ability to control pathogen levels, and tolerance, which helps the host endure infection-induced pathology. Here we show that infected fruit flies become anorexic and that diet restriction alters defenses, increasing the fly's tolerance to Salmonella typhimurium infections while decreasing resistance to Listeria monocytogenes. This suggests that attempts to extend lifespan through diet restriction or the manipulation of pathways mimicking this process will have complicated effects on a host's ability to fight infections.

  View details for DOI 10.1371/journal.pbio.1000150

  View details for Web of Science ID 000268405700004

  View details for PubMedID 19597539

  View details for PubMedCentralID PMC2701602

• Resilience integrates concepts in aging research. iScience Promislow, D., Anderson, R. M., Scheffer, M., Crespi, B., DeGregori, J., Harris, K., Horowitz, B. N., Levine, M. E., Riolo, M. A., Schneider, D. S., Spencer, S. L., Valenzano, D. R., Hochberg, M. E. 2022; 25 (5): 104199

  Abstract

  Aging research is unparalleled in the breadth of disciplines it encompasses, from evolutionary studies examining the forces that shape aging to molecular studies uncovering the underlying mechanisms of age-related functional decline. Despite a common focus to advance our understanding of aging, these disciplines have proceeded along distinct paths with little cross-talk. We propose that the concept of resilience can bridge this gap. Resilience describes the ability of a system to respond to perturbations by returning to its original state. Although resilience has been applied in a few individual disciplines in aging research such as frailty and cognitive decline, it has not been explored as a unifying conceptual framework that is able to connect distinct research fields. We argue that because a resilience-based framework can cross broad physiological levels and time scales it can provide the missing links that connect these diverse disciplines. The resulting framework will facilitate predictive modeling and validation and influence targets and directions in research on the biology of aging.

  View details for DOI 10.1016/j.isci.2022.104199

  View details for PubMedID 35494229

• Linking functional and molecular mechanisms of host resilience to malaria infection ELIFE Kamiya, T., Davis, N. M., Greischar, M. A., Schneider, D., Mideo, N. 2021; 10

  View details for DOI 10.7554/eLife.65846.sa2

  View details for Web of Science ID 000708931800001

• Linking functional and molecular mechanisms of host resilience to malaria infection. eLife Kamiya, T., Davis, N. M., Greischar, M. A., Schneider, D., Mideo, N. 2021; 10

  Abstract

  It remains challenging to understand why some hosts suffer severe illnesses, while others are unscathed by the same infection. We fitted a mathematical model to longitudinal measurements of parasite and red blood cell density in murine hosts from diverse genetic backgrounds to identify aspects of within-host interactions that explain variation in host resilience and survival during acute malaria infection. Among eight mouse strains that collectively span 90% of the common genetic diversity of laboratory mice, we found that high host mortality was associated with either weak parasite clearance, or a strong, yet imprecise response that inadvertently removes uninfected cells in excess. Subsequent cross-sectional cytokine assays revealed that the two distinct functional mechanisms of poor survival were underpinned by low expression of either pro- or anti-inflammatory cytokines, respectively. By combining mathematical modelling and molecular immunology assays, our study uncovered proximate mechanisms of diverse infection outcomes across multiple host strains and biological scales.

  View details for DOI 10.7554/eLife.65846

  View details for PubMedID 34636723

• Metabolomic Analysis of Diverse Mice Reveals Hepatic Arginase-1 as Source of Plasma Arginase in Plasmodium chabaudi Infection. mBio Davis, N. M., Lissner, M. M., Richards, C. L., Chevee, V., Gupta, A. S., Gherardini, F. C., Schneider, D. S. 2021: e0242421

  Abstract

  Infections disrupt host metabolism, but the factors that dictate the nature and magnitude of metabolic change are incompletely characterized. To determine how host metabolism changes in relation to disease severity in murine malaria, we performed plasma metabolomics on eight Plasmodium chabaudi-infected mouse strains with diverse disease phenotypes. We identified plasma metabolic biomarkers for both the nature and severity of different malarial pathologies. A subset of metabolic changes, including plasma arginine depletion, match the plasma metabolomes of human malaria patients, suggesting new connections between pathology and metabolism in human malaria. In our malarial mice, liver damage, which releases hepatic arginase-1 (Arg1) into circulation, correlated with plasma arginine depletion. We confirmed that hepatic Arg1 was the primary source of increased plasma arginase activity in our model, which motivates further investigation of liver damage in human malaria patients. More broadly, our approach shows how leveraging phenotypic diversity can identify and validate relationships between metabolism and the pathophysiology of infectious disease. IMPORTANCE Malaria is a severe and sometimes fatal infectious disease endemic to tropical and subtropical regions. Effective vaccines against malaria-causing Plasmodium parasites remain elusive, and malaria treatments often fail to prevent severe disease. Small molecules that target host metabolism have recently emerged as candidates for therapeutics in malaria and other diseases. However, our limited understanding of how metabolites affect pathophysiology limits our ability to develop new metabolite therapies. By providing a rich data set of metabolite-pathology correlations and by validating one of those correlations, our work is an important step toward harnessing metabolism to mitigate disease. Specifically, we showed that liver damage in P. chabaudi-infected mice releases hepatic arginase-1 into circulation, where it may deplete plasma arginine, a candidate malaria therapeutic that mitigates vascular stress. Our data suggest that liver damage may confound efforts to increase levels of arginine in human malaria patients.

  View details for DOI 10.1128/mBio.02424-21

  View details for PubMedID 34607466

• Immunology's intolerance of disease tolerance. Nature reviews. Immunology Schneider, D. S. 2021; 21 (10): 624-625

  View details for DOI 10.1038/s41577-021-00619-7

  View details for PubMedID 34580465

• Metabolic profiling during malaria reveals the role of the aryl hydrocarbon receptor in regulating kidney injury. eLife Lissner, M. M., Cumnock, K., Davis, N. M., Vilches-Moure, J. G., Basak, P., Navarrete, D. J., Allen, J. A., Schneider, D. 2020; 9

  Abstract

  Systemic metabolic reprogramming induced by infection exerts profound, pathogen-specific effects on infection outcome. Here, we detail the host immune and metabolic response during sickness and recovery in a mouse model of malaria. We describe extensive alterations in metabolism during acute infection, and identify increases in host-derived metabolites that signal through the aryl hydrocarbon receptor (AHR), a transcription factor with immunomodulatory functions. We find that Ahr-/- mice are more susceptible to malaria and develop high plasma heme and acute kidney injury. This phenotype is dependent on AHR in Tek-expressing radioresistant cells. Our findings identify a role for AHR in limiting tissue damage during malaria. Furthermore, this work demonstrates the critical role of host metabolism in surviving infection.

  View details for DOI 10.7554/eLife.60165

  View details for PubMedID 33021470

• Uncovering drivers of dose-dependence and individual variation in malaria infection outcomes. PLoS computational biology Kamiya, T. n., Greischar, M. A., Schneider, D. S., Mideo, N. n. 2020; 16 (10): e1008211

  Abstract

  To understand why some hosts get sicker than others from the same type of infection, it is essential to explain how key processes, such as host responses to infection and parasite growth, are influenced by various biotic and abiotic factors. In many disease systems, the initial infection dose impacts host morbidity and mortality. To explore drivers of dose-dependence and individual variation in infection outcomes, we devised a mathematical model of malaria infection that allowed host and parasite traits to be linear functions (reaction norms) of the initial dose. We fitted the model, using a hierarchical Bayesian approach, to experimental time-series data of acute Plasmodium chabaudi infection across doses spanning seven orders of magnitude. We found evidence for both dose-dependent facilitation and debilitation of host responses. Most importantly, increasing dose reduced the strength of activation of indiscriminate host clearance of red blood cells while increasing the half-life of that response, leading to the maximal response at an intermediate dose. We also explored the causes of diverse infection outcomes across replicate mice receiving the same dose. Besides random noise in the injected dose, we found variation in peak parasite load was due to unobserved individual variation in host responses to clear infected cells. Individual variation in anaemia was likely driven by random variation in parasite burst size, which is linked to the rate of host cells lost to malaria infection. General host vigour in the absence of infection was also correlated with host health during malaria infection. Our work demonstrates that the reaction norm approach provides a useful quantitative framework for examining the impact of a continuous external factor on within-host infection processes.

  View details for DOI 10.1371/journal.pcbi.1008211

  View details for PubMedID 33031367

• Western diet regulates immune status and the response to LPS-driven sepsis independent of diet-associated microbiome. Proceedings of the National Academy of Sciences of the United States of America Napier, B. A., Andres-Terre, M., Massis, L. M., Hryckowian, A. J., Higginbottom, S. K., Cumnock, K., Casey, K. M., Haileselassie, B., Lugo, K. A., Schneider, D. S., Sonnenburg, J. L., Monack, D. M. 2019; 116 (9): 3688–94

  Abstract

  Sepsis is a deleterious immune response to infection that leads to organ failure and is the 11th most common cause of death worldwide. Despite plaguing humanity for thousands of years, the host factors that regulate this immunological response and subsequent sepsis severity and outcome are not fully understood. Here we describe how the Western diet (WD), a diet high in fat and sucrose and low in fiber, found rampant in industrialized countries, leads to worse disease and poorer outcomes in an LPS-driven sepsis model in WD-fed mice compared with mice fed standard fiber-rich chow (SC). We find that WD-fed mice have higher baseline inflammation (metaflammation) and signs of sepsis-associated immunoparalysis compared with SC-fed mice. WD mice also have an increased frequency of neutrophils, some with an "aged" phenotype, in the blood during sepsis compared with SC mice. Importantly, we found that the WD-dependent increase in sepsis severity and higher mortality is independent of the microbiome, suggesting that the diet may be directly regulating the innate immune system through an unknown mechanism. Strikingly, we could predict LPS-driven sepsis outcome by tracking specific WD-dependent disease factors (e.g., hypothermia and frequency of neutrophils in the blood) during disease progression and recovery. We conclude that the WD is reprogramming the basal immune status and acute response to LPS-driven sepsis and that this correlates with alternative disease paths that lead to more severe disease and poorer outcomes.

  View details for PubMedID 30808756

• Western diet regulates immune status and the response to LPS-driven sepsis independent of diet-associated microbiome PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Napier, B. A., Andres-Terre, M., Massis, L. M., Hryckowian, A. J., Higginbottom, S. K., Cumnock, K., Casey, K. M., Haileselassie, B., Lugo, K. A., Schneider, D. S., Sonnenburg, J. L., Monack, D. M. 2019; 116 (9): 3688–94

  View details for DOI 10.1073/pnas.1814273116

  View details for Web of Science ID 000459694400055

• Vector Immunity and Evolutionary Ecology: The Harmonious Dissonance. Trends in immunology Shaw, D. K., Tate, A. T., Schneider, D. S., Levashina, E. A., Kagan, J. C., Pal, U., Fikrig, E., Pedra, J. H. 2018

  Abstract

  Recent scientific breakthroughs have significantly expanded our understanding of arthropod vector immunity. Insights in the laboratory have demonstrated how the immune system provides resistance to infection, and in what manner innate defenses protect against a microbial assault. Less understood, however, is the effect of biotic and abiotic factors on microbial-vector interactions and the impact of the immune system on arthropod populations in nature. Furthermore, the influence of genetic plasticity on the immune response against vector-borne pathogens remains mostly elusive. Herein, we discuss evolutionary forces that shape arthropod vector immunity. We focus on resistance, pathogenicity and tolerance to infection. We posit that novel scientific paradigms should emerge when molecular immunologists and evolutionary ecologists work together.

  View details for PubMedID 30301592

• The physiological basis of disease tolerance in insects. Current opinion in insect science Lissner, M. M., Schneider, D. S. 2018; 29: 133–36

  Abstract

  Immunology textbooks teach us about the ways hosts can recognize and kill microbes but leave out something important: the mechanisms used to survive infections. Survival depends on more than simply detecting and eliminating microbes; it requires that we prevent and repair the damage caused by pathogens and the immune response. Recent work in insects is helping to build our understanding of this aspect of pathology, called disease tolerance. Here we discuss papers that explore disease tolerance using theoretical, population genetics, and mechanistic approaches.

  View details for PubMedID 30551820

• Going to Bat(s) for Studies of Disease Tolerance FRONTIERS IN IMMUNOLOGY Mandl, J. N., Schneider, C., Schneider, D. S., Baker, M. L. 2018; 9

  View details for DOI 10.3389/fimmu.2018.02112

  View details for Web of Science ID 000445106400001

• Going to Bat(s) for Studies of Disease Tolerance. Frontiers in immunology Mandl, J. N., Schneider, C., Schneider, D. S., Baker, M. L. 2018; 9: 2112

  Abstract

  A majority of viruses that have caused recent epidemics with high lethality rates in people, are zoonoses originating from wildlife. Among them are filoviruses (e.g., Marburg, Ebola), coronaviruses (e.g., SARS, MERS), henipaviruses (e.g., Hendra, Nipah) which share the common features that they are all RNA viruses, and that a dysregulated immune response is an important contributor to the tissue damage and hence pathogenicity that results from infection in humans. Intriguingly, these viruses also all originate from bat reservoirs. Bats have been shown to have a greater mean viral richness than predicted by their phylogenetic distance from humans, their geographic range, or their presence in urban areas, suggesting other traits must explain why bats harbor a greater number of zoonotic viruses than other mammals. Bats are highly unusual among mammals in other ways as well. Not only are they the only mammals capable of powered flight, they have extraordinarily long life spans, with little detectable increases in mortality or senescence until high ages. Their physiology likely impacted their history of pathogen exposure and necessitated adaptations that may have also affected immune signaling pathways. Do our life history traits make us susceptible to generating damaging immune responses to RNA viruses or does the physiology of bats make them particularly tolerant or resistant? Understanding what immune mechanisms enable bats to coexist with RNA viruses may provide critical fundamental insights into how to achieve greater resilience in humans.

  View details for DOI 10.3389/fimmu.2018.02112

  View details for PubMedID 30294323

  View details for PubMedCentralID PMC6158362

• Host Energy Source Is Important for Disease Tolerance to Malaria CURRENT BIOLOGY Cumnock, K., Gupta, A. S., Lissner, M., Chevee, V., Davis, N. M., Schneider, D. S. 2018; 28 (10): 1635-+

  Abstract

  Pathologic infections are accompanied by a collection of short-term behavioral perturbations collectively termed sickness behaviors [1, 2]. These include changes in body temperature, reduced eating and drinking, and lethargy and mimic behaviors of animals in torpor and hibernation [1, 3-6]. Sickness behaviors are important, pathogen-specific components of the host response to infection [1, 3, 7-9]. In particular, host anorexia has been shown to be beneficial or detrimental depending on the infection [7, 8]. While these studies have illuminated the effects of anorexia on infection, they consider this behavior in isolation from other behaviors and from its effects on host metabolism and energy. Here, we explored the temporal dynamics of multiple sickness behaviors and their effect on host energy and metabolism throughout infection. We used the Plasmodium chabaudi AJ murine model of malaria as it causes severe pathology from which most animals recover. We found that infected animals did become anorexic, skewing their metabolism toward fatty acid oxidation and ketosis. Metabolism of fats requires oxygen for the production of ATP. In this model, animals also suffer severe anemia, limiting their ability to carry oxygen concurrent with their switch toward fatty acid metabolism. We reasoned that the combination of anorexia and anemia would increase pressure on glycolysis as a critical energy pathway because it does not require oxygen. Treating infected mice when anorexic with the glycolytic inhibitor 2-deoxyglucose (2DG) reduced survival; treating animals with glucose improved survival. Peak parasite loads were unchanged, demonstrating changes in disease tolerance. Parasite clearance was reduced with 2DG treatment, suggesting altered resistance.

  View details for PubMedID 29754902

• Novel M-CSF-producing gamma delta T cells protect against recurrent malaria Mamedov, M. R., Scholzen, A., Nair, R. V., Cumnock, K., Kenkel, J. A., Oliveira, J. M., Trujillo, D. L., Saligrama, N., Zhang, Y., Rubelt, F., Schneider, D. S., Chien, Y., Sauerwein, R., Davis, M. M. AMER ASSOC IMMUNOLOGISTS. 2018

  View details for Web of Science ID 000459977700312

• Timing of host feeding drives rhythms in parasite replication PLOS PATHOGENS Prior, K. F., van der Veen, D. R., O'Donnell, A. J., Cumnock, K., Schneider, D., Pain, A., Subudhi, A., Ramaprasad, A., Rund, S. C., Savill, N. J., Reece, S. E. 2018; 14 (2): e1006900

  Abstract

  Circadian rhythms enable organisms to synchronise the processes underpinning survival and reproduction to anticipate daily changes in the external environment. Recent work shows that daily (circadian) rhythms also enable parasites to maximise fitness in the context of ecological interactions with their hosts. Because parasite rhythms matter for their fitness, understanding how they are regulated could lead to innovative ways to reduce the severity and spread of diseases. Here, we examine how host circadian rhythms influence rhythms in the asexual replication of malaria parasites. Asexual replication is responsible for the severity of malaria and fuels transmission of the disease, yet, how parasite rhythms are driven remains a mystery. We perturbed feeding rhythms of hosts by 12 hours (i.e. diurnal feeding in nocturnal mice) to desynchronise the host's peripheral oscillators from the central, light-entrained oscillator in the brain and their rhythmic outputs. We demonstrate that the rhythms of rodent malaria parasites in day-fed hosts become inverted relative to the rhythms of parasites in night-fed hosts. Our results reveal that the host's peripheral rhythms (associated with the timing of feeding and metabolism), but not rhythms driven by the central, light-entrained circadian oscillator in the brain, determine the timing (phase) of parasite rhythms. Further investigation reveals that parasite rhythms correlate closely with blood glucose rhythms. In addition, we show that parasite rhythms resynchronise to the altered host feeding rhythms when food availability is shifted, which is not mediated through rhythms in the host immune system. Our observations suggest that parasites actively control their developmental rhythms. Finally, counter to expectation, the severity of disease symptoms expressed by hosts was not affected by desynchronisation of their central and peripheral rhythms. Our study at the intersection of disease ecology and chronobiology opens up a new arena for studying host-parasite-vector coevolution and has broad implications for applied bioscience.

  View details for PubMedID 29481559

  View details for PubMedCentralID PMC5843352

• A Macrophage Colony-Stimulating-Factor-Producing γδ T Cell Subset Prevents Malarial Parasitemic Recurrence. Immunity Mamedov, M. R., Scholzen, A. n., Nair, R. V., Cumnock, K. n., Kenkel, J. A., Oliveira, J. H., Trujillo, D. L., Saligrama, N. n., Zhang, Y. n., Rubelt, F. n., Schneider, D. S., Chien, Y. H., Sauerwein, R. W., Davis, M. M. 2018; 48 (2): 350–63.e7

  Abstract

  Despite evidence that γδ T cells play an important role during malaria, their precise role remains unclear. During murine malaria induced by Plasmodium chabaudi infection and in human P. falciparum infection, we found that γδ T cells expanded rapidly after resolution of acute parasitemia, in contrast to αβ T cells that expanded at the acute stage and then declined. Single-cell sequencing showed that TRAV15N-1 (Vδ6.3) γδ T cells were clonally expanded in mice and had convergent complementarity-determining region 3 sequences. These γδ T cells expressed specific cytokines, M-CSF, CCL5, CCL3, which are known to act on myeloid cells, indicating that this γδ T cell subset might have distinct functions. Both γδ T cells and M-CSF were necessary for preventing parasitemic recurrence. These findings point to an M-CSF-producing γδ T cell subset that fulfills a specialized protective role in the later stage of malaria infection when αβ T cells have declined.

  View details for PubMedID 29426701

• Predicting position along a looping immune response trajectory. PloS one Rath, P., Allen, J. A., Schneider, D. S. 2018; 13 (10): e0200147

  Abstract

  When we get sick, we want to be resilient and recover our original health. To measure resilience, we need to quantify a host's position along its disease trajectory. Here we present Looper, a computational method to analyze longitudinally gathered datasets and identify gene pairs that form looping trajectories when plotted in the space described by these phases. These loops enable us to track where patients lie on a typical trajectory back to health. We analyzed two publicly available, longitudinal human microarray datasets that describe self-resolving immune responses. Looper identified looping gene pairs expressed by human donor monocytes stimulated by immune elicitors, and in YF17D-vaccinated individuals. Using loops derived from training data, we found that we could predict the time of perturbation in withheld test samples with accuracies of 94% in the human monocyte data, and 65-83% within the same cohort and in two independent cohorts of YF17D vaccinated individuals. We suggest that Looper will be useful in building maps of resilient immune processes across organisms.

  View details for PubMedID 30296270

• Innate Immune Memory: Activation of Macrophage Killing Ability by Developmental Duties. Current biology : CB Schneider, D., Tate, A. T. 2016; 26 (12): R503-R505

  Abstract

  Innate immune systems in many taxa exhibit hallmarks of memory in response to previous microbial exposure. A new study demonstrates that innate immune memory in Drosophila embryonic macrophages can also be induced by the successful engulfment of apoptotic cells, highlighting the importance of early exposure events for developing responsive immune systems.

  View details for DOI 10.1016/j.cub.2016.05.016

  View details for PubMedID 27326712

• What Can Vampires Teach Us about Immunology? Trends in immunology Schneider, D. S. 2016; 37 (4): 253-256

  Abstract

  Speculative fiction examines the leading edge of science and can be used to introduce ideas into the classroom. For example, most students are already familiar with the fictional infectious diseases responsible for vampire and zombie outbreaks. The disease dynamics of these imaginary ailments follow the same rules we see for real diseases and can be used to remind students that they already understand the basic rules of disease ecology and immunology. By engaging writers of this sort of fiction in an effort to solve problems in immunology we may be able to perform a directed evolution experiment where we follow the evolution of plots rather than genetic traits.

  View details for DOI 10.1016/j.it.2016.02.001

  View details for PubMedID 26968492

• Tracking Resilience to Infections by Mapping Disease Space PLOS BIOLOGY Torres, B. Y., Oliveira, J. H., Tate, A. T., Rath, P., Cumnock, K., Schneider, D. S. 2016; 14 (4)

  Abstract

  Infected hosts differ in their responses to pathogens; some hosts are resilient and recover their original health, whereas others follow a divergent path and die. To quantitate these differences, we propose mapping the routes infected individuals take through "disease space." We find that when plotting physiological parameters against each other, many pairs have hysteretic relationships that identify the current location of the host and predict the future route of the infection. These maps can readily be constructed from experimental longitudinal data, and we provide two methods to generate the maps from the cross-sectional data that is commonly gathered in field trials. We hypothesize that resilient hosts tend to take small loops through disease space, whereas nonresilient individuals take large loops. We support this hypothesis with experimental data in mice infected with Plasmodium chabaudi, finding that dying mice trace a large arc in red blood cells (RBCs) by reticulocyte space as compared to surviving mice. We find that human malaria patients who are heterozygous for sickle cell hemoglobin occupy a small area of RBCs by reticulocyte space, suggesting this approach can be used to distinguish resilience in human populations. This technique should be broadly useful in describing the in-host dynamics of infections in both model hosts and patients at both population and individual levels.

  View details for DOI 10.1371/journal.pbio.1002436

  View details for Web of Science ID 000375094800007

  View details for PubMedID 27088359

  View details for PubMedCentralID PMC4835107

• Drosophila melanogaster Natural Variation Affects Growth Dynamics of Infecting Listeria monocytogenes G3-GENES GENOMES GENETICS Hotson, A. G., Schneider, D. S. 2015; 5 (12): 2593-2600

  Abstract

  We find that in a Listeria monocytogenes/Drosophila melanogaster infection model, L. monocytogenes grows according to logistic kinetics, which means we can measure both a maximal growth rate and growth plateau for the microbe. Genetic variation of the host affects both of the pathogen growth parameters, and they can vary independently. Because growth rates and ceilings both correlate with host survival, both properties could drive evolution of the host. We find that growth rates and ceilings are sensitive to the initial infectious dose in a host-genotype-dependent manner, implying that experimental results differ as we change the original challenge dose within a single strain of host.

  View details for DOI 10.1534/g3.115.022558

  View details for Web of Science ID 000367257500009

• Defining Resistance and Tolerance to Cancer CELL REPORTS Dillman, A. R., Schneider, D. S. 2015; 13 (5): 884-887

  Abstract

  There are two ways to maintain fitness in the face of infection: resistance is a host's ability to reduce microbe load and disease tolerance is the ability of the host to endure the negative health effects of infection. Resistance and disease tolerance should be applicable to any insult to the host and have been explored in depth with regards to infection but have not been examined in the context of cancer. Here, we establish a framework for measuring and separating resistance and disease tolerance to cancer in Drosophila melanogaster. We plot a disease tolerance curve to cancer in wild-type flies and then compare this to natural variants, identifying a line with reduced cancer resistance. Quantitation of these two traits opens an additional dimension for analysis of cancer biology.

  View details for DOI 10.1016/j.celrep.2015.09.052

  View details for Web of Science ID 000363988100003

  View details for PubMedID 26565901

• Drosophila melanogaster Natural Variation Affects Growth Dynamics of Infecting Listeria monocytogenes. G3 (Bethesda, Md.) Hotson, A. G., Schneider, D. S. 2015

  Abstract

  We find that in a Listeria monocytogenes/Drosophila melanogaster infection model, L. monocytogenes grows according to logistic kinetics, which means we can measure both a maximal growth rate and growth plateau for the microbe. Genetic variation of the host affects both of the pathogen growth parameters, and they can vary independently. Because growth rates and ceilings both correlate with host survival, both properties could drive evolution of the host. We find that growth rates and ceilings are sensitive to the initial infectious dose in a host-genotype-dependent manner, implying that experimental results differ as we change the original challenge dose within a single strain of host.

  View details for DOI 10.1534/g3.115.022558

  View details for PubMedID 26438294

• The genetics of immunity. Genetics Lazzaro, B. P., Schneider, D. S. 2014; 197 (2): 467-70

  View details for DOI 10.1534/genetics.114.165449

  View details for PubMedID 24939992

  View details for PubMedCentralID PMC4063907

• The Drosophila Deubiquitinating Enzyme dUSP36 Acts in the Hemocytes for Tolerance to Listeria monocytogenes Infections JOURNAL OF INNATE IMMUNITY Taillebourgar, E., Schneider, D. S., Fauvarque, M. 2014; 6 (5): 632-638

  Abstract

  Listeria monocytogenes is a facultative intracellular pathogen which can infect Drosophila melanogaster. Upon infection, Drosophila mounts an immune response including antimicrobial peptide production and autophagy activation. A set of previously published results prompted us to study the role of the deubiquitinating enzyme dUSP36 in response to L. monocytogenes infections. We show in this report that flies with dUsp36-specific inactivation in hemocytes are susceptible to L. monocytogenes infections (as are flies with autophagy-deficient hemocytes) but are still able to control bacterial growth. Interestingly, flies with dUsp36-depleted hemocytes are not sensitized to infection by other pathogens. We conclude that dUsp36 plays a major role in hemocytes for tolerance to L. monocytogenes.

  View details for DOI 10.1159/000360293

  View details for Web of Science ID 000340345900008

  View details for PubMedID 24777180

• The ubiquitin ligase parkin mediates resistance to intracellular pathogens. Nature Manzanillo, P. S., Ayres, J. S., Watson, R. O., Collins, A. C., Souza, G., Rae, C. S., Schneider, D. S., Nakamura, K., Shiloh, M. U., Cox, J. S. 2013; 501 (7468): 512-516

  Abstract

  Ubiquitin-mediated targeting of intracellular bacteria to the autophagy pathway is a key innate defence mechanism against invading microbes, including the important human pathogen Mycobacterium tuberculosis. However, the ubiquitin ligases responsible for catalysing ubiquitin chains that surround intracellular bacteria are poorly understood. The parkin protein is a ubiquitin ligase with a well-established role in mitophagy, and mutations in the parkin gene (PARK2) lead to increased susceptibility to Parkinson's disease. Surprisingly, genetic polymorphisms in the PARK2 regulatory region are also associated with increased susceptibility to intracellular bacterial pathogens in humans, including Mycobacterium leprae and Salmonella enterica serovar Typhi, but the function of parkin in immunity has remained unexplored. Here we show that parkin has a role in ubiquitin-mediated autophagy of M. tuberculosis. Both parkin-deficient mice and flies are sensitive to various intracellular bacterial infections, indicating parkin has a conserved role in metazoan innate defence. Moreover, our work reveals an unexpected functional link between mitophagy and infectious disease.

  View details for DOI 10.1038/nature12566

  View details for PubMedID 24005326

• Listeria monocytogenes Infection Causes Metabolic Shifts in Drosophila melanogaster PLOS ONE Chambers, M. C., Song, K. H., Schneider, D. S. 2012; 7 (12)

  Abstract

  Immunity and metabolism are intimately linked; manipulating metabolism, either through diet or genetics, has the power to alter survival during infection. However, despite metabolism's powerful ability to alter the course of infections, little is known about what being "sick" means metabolically. Here we describe the metabolic changes occurring in a model system when Listeria monocytogenes causes a lethal infection in Drosophila melanogaster. L. monocytogenes infection alters energy metabolism; the flies gradually lose both of their energy stores, triglycerides and glycogen, and show decreases in both intermediate metabolites and enzyme message for the two main energy pathways, beta-oxidation and glycolysis. L. monocytogenes infection also causes enzymatic reduction in the anti-oxidant uric acid, and knocking out the enzyme uric oxidase has a complicated effect on immunity. Free amino acid levels also change during infection, including a drop in tyrosine levels which may be due to robust L. monocytogenes induced melanization.

  View details for DOI 10.1371/journal.pone.0050679

  View details for Web of Science ID 000312386600013

  View details for PubMedID 23272066

  View details for PubMedCentralID PMC3521769

• How the Fly Balances Its Ability to Combat Different Pathogens PLOS PATHOGENS Chambers, M. C., Lightfield, K. L., Schneider, D. S. 2012; 8 (12)

  Abstract

  Health is a multidimensional landscape. If we just consider the host, there are many outputs that interest us: evolutionary fitness determining parameters like fecundity, survival and pathogen clearance as well as medically important health parameters like sleep, energy stores and appetite. Hosts use a variety of effector pathways to fight infections and these effectors are brought to bear differentially. Each pathogen causes a different disease as they have distinct virulence factors and niches; they each warp the health landscape in unique ways. Therefore, mutations affecting immunity can have complex phenotypes and distinct effects on each pathogen. Here we describe how two components of the fly's immune response, melanization and phagocytosis, contribute to the health landscape generated by the transcription factor ets21c (CG2914) and its putative effector, the signaling molecule wntD (CG8458). To probe the landscape, we infect with two pathogens: Listeria monocytogenes, which primarily lives intracellularly, and Streptococcus pneumoniae, which is an extracellular pathogen. Using the diversity of phenotypes generated by these mutants, we propose that survival during a L. monocytogenes infection is mediated by a combination of two host mechanisms: phagocytic activity and melanization; while survival during a S. pneumoniae infection is determined by phagocytic activity. In addition, increased phagocytic activity is beneficial during S. pneumoniae infection but detrimental during L. monocytogenes infection, demonstrating an inherent trade-off in the immune response.

  View details for DOI 10.1371/journal.ppat.1002970

  View details for Web of Science ID 000312907100002

  View details for PubMedID 23271964

  View details for PubMedCentralID PMC3521699

• Where Does Innate Immunity Stop and Adaptive Immunity Begin? CELL HOST & MICROBE Ziauddin, J., Schneider, D. S. 2012; 12 (4): 394-395

  Abstract

  The regulation of alternative splicing in the immune effector Dscam reported by Dong et al. (2012) in this issue of Cell Host & Microbe raises important questions about the nature of immune responses. Can we clearly define "adaptive" as being different from "innate" immunity, or is it time for a more flexible description?

  View details for DOI 10.1016/j.chom.2012.10.004

  View details for Web of Science ID 000310719700003

  View details for PubMedID 23084909

• Infection-Related Declines in Chill Coma Recovery and Negative Geotaxis in Drosophila melanogaster PLOS ONE Linderman, J. A., Chambers, M. C., Gupta, A. S., Schneider, D. S. 2012; 7 (9)

  Abstract

  Studies of infection in Drosophila melanogaster provide insight into both mechanisms of host resistance and tolerance of pathogens. However, research into the pathways involved in these processes has been limited by the relatively few metrics that can be used to measure sickness and health throughout the course of infection. Here we report measurements of infection-related declines in flies' performance on two different behavioral assays. D. melanogaster are slower to recover from a chill-induced coma during infection with either Listeria monocytogenes or Streptococcus pneumoniae. L. monocytogenes infection also impacts flies' performance during a negative geotaxis assay, revealing a decline in their rate of climbing as part of their innate escape response after startle. In addition to providing new measures for assessing health, these assays also suggest pathological consequences of and metabolic shifts that may occur over the course of an infection.

  View details for DOI 10.1371/journal.pone.0041907

  View details for Web of Science ID 000308788700004

  View details for PubMedID 23028430

  View details for PubMedCentralID PMC3441536

• Balancing resistance and infection tolerance through metabolic means PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Chambers, M. C., Schneider, D. S. 2012; 109 (35): 13886-13887

  View details for DOI 10.1073/pnas.1211724109

  View details for Web of Science ID 000308565300013

  View details for PubMedID 22891309

  View details for PubMedCentralID PMC3435157

• Immunity in Society: Diverse Solutions to Common Problems PLOS BIOLOGY Babayan, S. A., Schneider, D. S. 2012; 10 (4)

  Abstract

  Understanding how organisms fight infection has been a central focus of scientific research and medicine for the past couple of centuries, and a perennial object of trial and error by humans trying to mitigate the burden of disease. Vaccination success relies upon the exposure of susceptible individuals to pathogen constituents that do not cause (excessive) pathology and that elicit specific immune memory. Mass vaccination allows us to study how immunity operates at the group level; denser populations are more prone to transmitting disease between individuals, but once a critical proportion of the population becomes immune, "herd immunity" emerges. In social species, the combination of behavioural control of infection--e.g., segregation of sick individuals, disposal of the dead, quality assessment of food and water--and aggregation of immune individuals can protect non-immune members from disease. While immune specificity and memory are well understood to underpin immunisation in vertebrates, it has been somewhat surprising to find similar phenomena in invertebrates, which lack the vertebrate molecular mechanisms deemed necessary for immunisation. Indeed, reports showing alternative forms of immune memory are accumulating in invertebrates. In this issue of PLoS Biology, Konrad et al. present an example of fungus-specific immune responses in social ants that lead to the active immunisation of nestmates by infected individuals. These findings join others in showing how organisms evolved diverse mechanisms that fulfil common functions, namely the discrimination between pathogens, the transfer of immunity between related individuals, and the group-level benefits of immunisation.

  View details for DOI 10.1371/journal.pbio

  View details for Web of Science ID 000303541800003

  View details for PubMedID 22509131

• Disease Tolerance as a Defense Strategy SCIENCE Medzhitov, R., Schneider, D. S., Soares, M. P. 2012; 335 (6071): 936-941

  Abstract

  The immune system protects from infections primarily by detecting and eliminating the invading pathogens; however, the host organism can also protect itself from infectious diseases by reducing the negative impact of infections on host fitness. This ability to tolerate a pathogen's presence is a distinct host defense strategy, which has been largely overlooked in animal and human studies. Introduction of the notion of "disease tolerance" into the conceptual tool kit of immunology will expand our understanding of infectious diseases and host pathogen interactions. Analysis of disease tolerance mechanisms should provide new approaches for the treatment of infections and other diseases.

  View details for DOI 10.1126/science.1214935

  View details for Web of Science ID 000300931800037

  View details for PubMedID 22363001

• Pioneering immunology: insect style CURRENT OPINION IN IMMUNOLOGY Chambers, M. C., Schneider, D. S. 2012; 24 (1): 10-14

  Abstract

  Insects are a powerful tool for discovering and then dissecting interesting new immunology. Recent insect research has made productive forays into non-classical immune areas including tolerance, immune priming (trained immunity), and environmental effects on immunity. Environments which affect immunity not only include diet and metabolism, but also social interactions and the animal's microbiota. We argue that every process that affects immunity should be considered as part of the immune response and that it is the broad phenomena discovered in insects that will be translated to other organisms rather than fine mechanistic details.

  View details for DOI 10.1016/j.coi.2011.11.003

  View details for Web of Science ID 000301560900003

  View details for PubMedID 22188798

• Tolerance of Infections ANNUAL REVIEW OF IMMUNOLOGY, VOL 30 Ayres, J. S., Schneider, D. S. 2012; 30: 271-294

  Abstract

  A host has two methods to defend against pathogens: It can clear the pathogens or reduce their impact on health in other ways. The first, resistance, is well studied. Study of the second, which ecologists call tolerance, is in its infancy. Tolerance measures the dose response curve of a host's health in reaction to a pathogen and can be studied in a simple quantitative manner. Such studies hold promise because they point to methods of treating infections that put evolutionary pressures on microbes different from antibiotics and vaccines. Studies of tolerance will provide an improved foundation to describe our interactions with all microbes: pathogenic, commensal, and mutualistic. One obvious mechanism affecting tolerance is the intensity of an immune response; an overly exuberant immune response can cause collateral damage through immune effectors and because of the energy allocated away from other physiological functions. There are potentially many other tolerance mechanisms, and here we systematically describe tolerance using a variety of animal systems.

  View details for DOI 10.1146/annurev-immunol-020711-075030

  View details for Web of Science ID 000304198100012

  View details for PubMedID 22224770

• Drosophila immunity research on the move. Fly Eleftherianos, I., Schneider, D. 2011; 5 (3): 247-254

  Abstract

  Drosophila has been established as useful model for infectious diseases because it allows large numbers of whole animals to be studied and provides powerful genetic tools and conservation with signaling and pathogenesis mechanisms in vertebrates. During the past twenty years, significant progress has been made on the characterization of innate immune responses against various pathogenic organisms in flies (Fig. 1). In this year's Drosophila Research Conference, which was held in San Diego (March 30-April 3) and sponsored by the Genetics Society of America, the immunity and pathogenesis session comprised seven platform presentations and 34 posters that highlighted the latest advances in Drosophila infection and immunity field. The presented work covered a wide range of studies from immune signaling pathways and the molecular basis of humoral and cellular immune mechanisms to the role of endosymbionts in fly immune function and effects of immune priming. Here, we give an overview of the presented work and we explain how these findings will open new avenues in Drosophila immunity research.

  View details for PubMedID 21738010

• Reciprocal Analysis of Francisella novicida Infections of a Drosophila melanogaster Model Reveal Host-Pathogen Conflicts Mediated by Reactive Oxygen and imd-Regulated Innate Immune Response PLOS PATHOGENS Moule, M. G., Monack, D. M., Schneider, D. S. 2010; 6 (8)

  Abstract

  The survival of a bacterial pathogen within a host depends upon its ability to outmaneuver the host immune response. Thus, mutant pathogens provide a useful tool for dissecting host-pathogen relationships, as the strategies the microbe has evolved to counteract immunity reveal a host's immune mechanisms. In this study, we examined the pathogen Francisella novicida and identified new bacterial virulence factors that interact with different parts of the Drosophila melanogaster innate immune system. We performed a genome-wide screen to identify F. novicida genes required for growth and survival within the fly and identified a set of 149 negatively selected mutants. Among these, we identified a class of genes including the transcription factor oxyR, and the DNA repair proteins uvrB, recB, and ruvC that help F. novicida resist oxidative stress. We determined that these bacterial genes are virulence factors that allow F. novicida to counteract the fly melanization immune response. We then performed a second in vivo screen to identify an additional subset of bacterial genes that interact specifically with the imd signaling pathway. Most of these mutants have decreased resistance to the antimicrobial peptide polymyxin B. Characterization of a mutation in the putative transglutaminase FTN_0869 produced a curious result that could not easily be explained using known Drosophila immune responses. By using an unbiased genetic screen, these studies provide a new view of the Drosophila immune response from the perspective of a pathogen. We show that two branches of the fly's immunity are important for fighting F. novicida infections in a model host: melanization and an imd-regulated immune response, and identify bacterial genes that specifically counteract these host responses. Our work suggests that there may be more to learn about the fly immune system, as not all of the phenotypes we observe can be readily explained by its interactions with known immune responses.

  View details for DOI 10.1371/journal.ppat.1001065

  View details for Web of Science ID 000281399900037

  View details for PubMedID 20865166

  View details for PubMedCentralID PMC2928790

• Relating immune and stress responses to infection resistance and tolerance BRAIN BEHAVIOR AND IMMUNITY Schneider, D. 2010; 24 (2): 193-193

  View details for DOI 10.1016/j.bbi.2009.10.012

  View details for Web of Science ID 000273507000005

  View details for PubMedID 19878717

• The Drosophila TNF Ortholog Eiger Is Required in the Fat Body for a Robust Immune Response JOURNAL OF INNATE IMMUNITY Mabery, E. M., Schneider, D. S. 2010; 2 (4): 371-378

  Abstract

  Eiger is the sole TNF family member found in Drosophila melanogaster. This signaling molecule is induced during infection and is required for an appropriate immune response to many microbes; however, little is known about where eiger is produced. Here, we show that eiger is made in the fly's fat body during a Salmonella typhimurium infection. Using tissue-specific knockdown, we found that eiger expression in the fat body is required for all of the phenotypes we observed in eiger null mutant flies. This includes reduced melanization, altered antimicrobial peptide expression and reduced feeding rates. The effect of eiger on feeding rates alone may account for the entire phenotype seen in eiger mutants infected with S. typhimurium.

  View details for DOI 10.1159/000315050

  View details for Web of Science ID 000279152200009

  View details for PubMedID 20505310

  View details for PubMedCentralID PMC2968759

• The Imd Pathway Is Involved in Antiviral Immune Responses in Drosophila PLOS ONE Costa, A., Jan, E., Sarnow, P., Schneider, D. 2009; 4 (10)

  Abstract

  Cricket Paralysis virus (CrPV) is a member of the Dicistroviridae family of RNA viruses, which infect a broad range of insect hosts, including the fruit fly Drosophila melanogaster. Drosophila has emerged as an effective system for studying innate immunity because of its powerful genetic techniques and the high degree of gene and pathway conservation. Intra-abdominal injection of CrPV into adult flies causes a lethal infection that provides a robust assay for the identification of mutants with altered sensitivity to viral infection. To gain insight into the interactions between viruses and the innate immune system, we injected wild type flies with CrPV and observed that antimicrobial peptides (AMPs) were not induced and hemocytes were depleted in the course of infection. To investigate the contribution of conserved immune signaling pathways to antiviral innate immune responses, CrPV was injected into isogenic mutants of the Immune Deficiency (Imd) pathway, which resembles the mammalian Tumor Necrosis Factor Receptor (TNFR) pathway. Loss-of-function mutations in several Imd pathway genes displayed increased sensitivity to CrPV infection and higher CrPV loads. Our data show that antiviral innate immune responses in flies infected with CrPV depend upon hemocytes and signaling through the Imd pathway.

  View details for DOI 10.1371/journal.pone.0007436

  View details for Web of Science ID 000270847800002

  View details for PubMedID 19829691

  View details for PubMedCentralID PMC2758544

• A Signaling Protease Required for Melanization in Drosophila Affects Resistance and Tolerance of Infections PLOS BIOLOGY Ayres, J. S., Schneider, D. S. 2008; 6 (12): 2764-2773

  Abstract

  Organisms evolve two routes to surviving infections-they can resist pathogen growth (resistance) and they can endure the pathogenesis of infection (tolerance). The sum of these two properties together defines the defensive capabilities of the host. Typically, studies of animal defenses focus on either understanding resistance or, to a lesser extent, tolerance mechanisms, thus providing little understanding of the relationship between these two mechanisms. We suggest there are nine possible pairwise permutations of these traits, assuming they can increase, decrease, or remain unchanged in an independent manner. Here we show that by making a single mutation in the gene encoding a protease, CG3066, active in the melanization cascade in Drosophila melanogaster, we observe the full spectrum of changes; these mutant flies show increases and decreases in their resistance and tolerance properties when challenged with a variety of pathogens. This result implicates melanization in fighting microbial infections and shows that an immune response can affect both resistance and tolerance to infections in microbe-dependent ways. The fly is often described as having an unsophisticated and stereotypical immune response where single mutations cause simple binary changes in immunity. We report a level of complexity in the fly's immune response that has strong ecological implications. We suggest that immune responses are highly tuned by evolution, since selection for defenses that alter resistance against one pathogen may change both resistance and tolerance to other pathogens.

  View details for DOI 10.1371/journal.pbio.0060305

  View details for Web of Science ID 000261913700017

  View details for PubMedID 19071960

  View details for PubMedCentralID PMC2596860

• MICROBIOLOGY Rogue Insect Immunity SCIENCE Schneider, D. S., Chambers, M. C. 2008; 322 (5905): 1199-1200

  View details for DOI 10.1126/science.1167450

  View details for Web of Science ID 000261033400028

  View details for PubMedID 19023073

• Two ways to survive infection: what resistance and tolerance can teach us about treating infectious diseases NATURE REVIEWS IMMUNOLOGY Schneider, D. S., Ayres, J. S. 2008; 8 (11): 889-895

  Abstract

  A host can evolve two types of defence mechanism to increase its fitness when challenged with a pathogen: resistance and tolerance. Immunology is a well-defined field in which the mechanisms behind resistance to infection are dissected. By contrast, the mechanisms behind the ability to tolerate infections are studied in a less methodical manner. In this Opinion, we provide evidence that animals have specific tolerance mechanisms and discuss their potential clinical impact. It is important to distinguish between these two defence mechanisms because they have different pathological and epidemiological effects. An increased understanding of tolerance to pathogen infection could lead to more efficient treatments for infectious diseases and a better description of host-pathogen interactions.

  View details for DOI 10.1038/nri2432

  View details for Web of Science ID 000260313000013

  View details for PubMedID 18927577

• Use of a Drosophila Model to Identify Genes Regulating Plasmodium Growth in the Mosquito GENETICS Brandt, S. M., Jaramillo-Gutierrez, G., Kumar, S., Barillas-Mury, C., Schneider, D. S. 2008; 180 (3): 1671-1678

  Abstract

  We performed a forward genetic screen, using Drosophila as a surrogate mosquito, to identify host factors required for the growth of the avian malaria parasite, Plasmodium gallinaceum. We identified 18 presumed loss-of-function mutants that reduced the growth of the parasite in flies. Presumptive mutation sites were identified in 14 of the mutants on the basis of the insertion site of a transposable element. None of the identified genes have been previously implicated in innate immune responses or interactions with Plasmodium. The functions of five Anopheles gambiae homologs were tested by using RNAi to knock down gene function followed by measuring the growth of the rodent parasite, Plasmodium berghei. Loss of function of four of these genes in the mosquito affected Plasmodium growth, suggesting that Drosophila can be used effectively as a surrogate mosquito to identify relevant host factors in the mosquito.

  View details for DOI 10.1534/genetics.108.089748

  View details for Web of Science ID 000261036200034

  View details for PubMedID 18791251

  View details for PubMedCentralID PMC2581966

• Models of infectious diseases in the fruit fly Drosophila melanogaster DISEASE MODELS & MECHANISMS Dionne, M. S., Schneider, D. S. 2008; 1 (1): 43-49

  Abstract

  We examined the immune response of a fly as physicians might, by looking at the genesis of diseases caused by microorganisms. Fly infections are complex and there are few simple rules that can predict how an infected fly might fare. As we observed the finer details of the infections, we found that almost every microbe caused a different type of pathology in the fly. Two pattern recognition pathways, Toll and immune deficiency (Imd), were found to detect, and respond to, infections. The physiological response of the fly was modified further by Eiger, insulin, Wnt inhibitor of dorsal (WntD) and nitric oxide (NO) signaling. As in humans, some of the damage that occurred during the fly immune response was caused by an over-aggressive response rather than by the microbes themselves. When looking at the matrix of signaling pathways and the microbes being tested, it was immediately obvious that most of the pathways would need to be studied in more detail before defining the rules that govern their role in pathogenesis. This detailed analysis of signaling and pathogenesis has the potential to allow the fly to be used as a model patient instead of as simply an innate immune system model.

  View details for DOI 10.1242/dmm.000307

  View details for Web of Science ID 000268076900013

  View details for PubMedID 19048052

• Pathogenesis of Listeria-infected Drosophila wntD mutants is associated with elevated levels of the novel immunity gene edin PLOS PATHOGENS Gordon, M. D., Ayres, J. S., Schneider, D. S., Nusse, R. 2008; 4 (7)

  Abstract

  Drosophila melanogaster mount an effective innate immune response against invading microorganisms, but can eventually succumb to persistent pathogenic infections. Understanding of this pathogenesis is limited, but it appears that host factors, induced by microbes, can have a direct cost to the host organism. Mutations in wntD cause susceptibility to Listeria monocytogenes infection, apparently through the derepression of Toll-Dorsal target genes, some of which are deleterious to survival. Here, we use gene expression profiling to identify genes that may mediate the observed susceptibility of wntD mutants to lethal infection. These genes include the TNF family member eiger and the novel immunity gene edin (elevated during infection; synonym CG32185), both of which are more strongly induced by infection of wntD mutants compared to controls. edin is also expressed more highly during infection of wild-type flies with wild-type Salmonella typhimurium than with a less pathogenic mutant strain, and its expression is regulated in part by the Imd pathway. Furthermore, overexpression of edin can induce age-dependent lethality, while loss of function in edin renders flies more susceptible to Listeria infection. These results are consistent with a model in which the regulation of host factors, including edin, must be tightly controlled to avoid the detrimental consequences of having too much or too little activity.

  View details for DOI 10.1371/journal.ppat.1000111

  View details for Web of Science ID 000259783000017

  View details for PubMedID 18654628

  View details for PubMedCentralID PMC2453329

• Identification of drosophila mutants altering defense of and endurance to Listeria monocytogenes infection GENETICS Ayres, J. S., Freitag, N., Schneider, D. S. 2008; 178 (3): 1807-1815

  Abstract

  We extended the use of Drosophila beyond being a model for signaling pathways required for pattern recognition immune signaling and show that the fly can be used to identify genes required for pathogenesis and host-pathogen interactions. We performed a forward genetic screen to identify Drosophila mutations altering sensitivity to the intracellular pathogen Listeria monocytogenes. We recovered 18 mutants with increased susceptibility to infection, none of which were previously shown to function in a Drosophila immune response. Using secondary screens, we divided these mutants into two groups: In the first group, mutants have reduced endurance to infections but show no change in bacterial growth. This is a new fly immunity phenotype that is not commonly studied. In the second group, mutants have a typical defense defect in which bacterial growth is increased and survival is decreased. By further challenging mutant flies with L. monocytogenes mutants, we identified subgroups of fly mutants that affect specific stages of the L. monocytogenes life cycle, exit from the vacuole, or actin-based movement. There is no overlap between our genes and the hundreds of genes identified in Drosophila S2 cells fighting L. monocytogenes infection, using genomewide RNAi screens in vitro. By using a whole-animal model and screening for host survival, we revealed genes involved in physiologies different from those that were found in previous screens, which all had defects in defensive immune signaling.

  View details for DOI 10.1534/genetics.107.083782

  View details for Web of Science ID 000254921600059

  View details for PubMedID 18245331

• Confronting physiology: how do infected flies die? CELLULAR MICROBIOLOGY Shirasu-Hiza, M. M., Schneider, D. S. 2007; 9 (12): 2775-2783

  Abstract

  Fruit fly immunology is on the verge of an exciting new path. The fruit fly has served as a strong model for innate immune responses; the field is now expanding to use the fruit fly to study pathogenesis. We argue here that, to understand pathogenesis in the fly, we need to understand pathology - and to understand pathology, we need to confront physiology with molecular tools. When flies are infected with a pathogen, they get sick. We group the events following infection into three categories: innate immune responses (defence mechanisms by which the fly attempts to kill or neutralize the microbe, some of which can themselves cause harm to the fly); microbial virulence (mechanisms by which the microbe evades the immune response); and host pathology (physiologies adversely affected by either the immune response or microbial virulence). We divide this review into sections mirroring these categories. The molecular study of infection in the fruit fly has focused on the first category, has begun to explore the second, and has yet to tap the full potential of the fly regarding the third.

  View details for DOI 10.1111/j.1462-5822.2007.01042.x

  View details for Web of Science ID 000250761100003

  View details for PubMedID 17883424

• How and why does a fly turn its immune system off? PLOS BIOLOGY Schneider, D. S. 2007; 5 (9): 1847-1849

  View details for DOI 10.1371/journal.pbio.0050247

  View details for Web of Science ID 000249552300003

  View details for PubMedID 17880266

  View details for PubMedCentralID PMC1994275

• Interactions between circadian rhythm and immunity in Drosophila melanlogaster CURRENT BIOLOGY Shirasu-Hiza, M. M., Dionne, M. S., Pham, L. N., Ayres, J. S., Schneider, D. S. 2007; 17 (10): R353-R355

  View details for Web of Science ID 000246572900009

  View details for PubMedID 17502084

• A specific primed immune response in Drosophila is dependent on phagocytes PLOS PATHOGENS Pham, L. N., Dionne, M. S., Shirasu-Hiza, M., Schneider, D. S. 2007; 3 (3)

  Abstract

  Drosophila melanogaster, like other invertebrates, relies solely on its innate immune response to fight invading microbes; by definition, innate immunity lacks adaptive characteristics. However, we show here that priming Drosophila with a sublethal dose of Streptococcus pneumoniae protects against an otherwise-lethal second challenge of S. pneumoniae. This protective effect exhibits coarse specificity for S. pneumoniae and persists for the life of the fly. Although not all microbial challenges induced this specific primed response, we find that a similar specific protection can be elicited by Beauveria bassiana, a natural fly pathogen. To characterize this primed response, we focused on S. pneumoniae-induced protection. The mechanism underlying this protective effect requires phagocytes and the Toll pathway. However, activation of the Toll pathway is not sufficient for priming-induced protection. This work contradicts the paradigm that insect immune responses cannot adapt and will promote the search for similar responses overlooked in organisms with an adaptive immune response.

  View details for DOI 10.1371/journal.ppat.0030026

  View details for Web of Science ID 000248495200006

  View details for PubMedID 17352533

  View details for PubMedCentralID PMC1817657

• Drosophila eiger mutants are sensitive to extracellular pathogens PLOS PATHOGENS Schneider, D. S., Ayres, J. S., Brandt, S. M., Costa, A., Dionne, M. S., Gordon, M. D., Mabery, E. M., Moule, M. G., Pham, L. N., Shirasu-Hiza, M. M. 2007; 3 (3)

  Abstract

  We showed previously that eiger, the Drosophila tumor necrosis factor homolog, contributes to the pathology induced by infection with Salmonella typhimurium. We were curious whether eiger is always detrimental in the context of infection or if it plays a role in fighting some types of microbes. We challenged wild-type and eiger mutant flies with a collection of facultative intracellular and extracellular pathogens, including a fungus and Gram-positive and Gram-negative bacteria. The response of eiger mutants divided these microbes into two groups: eiger mutants are immunocompromised with respect to extracellular pathogens but show no change or reduced sensitivity to facultative intracellular pathogens. Hence, eiger helps fight infections but also can cause pathology. We propose that eiger activates the cellular immune response of the fly to aid clearance of extracellular pathogens. Intracellular pathogens, which can already defeat professional phagocytes, are unaffected by eiger.

  View details for DOI 10.1371/journal.ppat.0030041

  View details for Web of Science ID 000248495200015

  View details for PubMedID 17381241

  View details for PubMedCentralID PMC1829408

• Psidin is required in Drosophila blood cells for both phagocytic degradation and immune activation of the fat body CURRENT BIOLOGY Brennan, C. A., Delaney, J. R., Schneider, D. S., Anderson, K. V. 2007; 17 (1): 67-72

  Abstract

  Phagocytic blood cells are critical to innate immune defense: They internalize and destroy microbial invaders and produce signals that trigger other immune responses. Despite this central role, the in vivo contributions of phagocytosis to systemic immune activation are not well understood. Drosophila has proven a fruitful model for the investigation of evolutionarily conserved innate immune mechanisms, including NF-kappaB-dependent transcriptional induction, RNAi in antiviral responses, and phagocytosis. The phagocytes of Drosophila encounter bacterial invaders early in infection and contribute to survival of infection. Phagocytosis in flies and mammals is highly homologous: Both rely on scavenger receptors, opsonins, and actin rearrangements for engulfment; have phagosomal cysteine proteases active at low pH; and can be subverted by similar intracellular pathogens. Although the role of Drosophila phagocytes in the activation of other immune tissues has not been clear, we show that induction of the antibacterial-peptide gene Defensin in the fat body during infection requires blood-cell contributions. We identify a gene, psidin, that encodes a lysosomal protein required in the blood cells for both degradation of engulfed bacteria and activation of fat-body Defensin. These data establish a role for the phagocytic blood cells of Drosophila in detection of infection and activation of the humoral immune response.

  View details for DOI 10.1016/j.cub.2006.11.026

  View details for Web of Science ID 000243461300027

  View details for PubMedID 17208189

• Bacterial infection of fly ovaries reduces egg production and induces local hernocyte activation DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY Brandt, S. M., Schneider, D. S. 2007; 31 (11): 1121-1130

  Abstract

  Morbidity, the state of being diseased, is an important aspect of pathogenesis that has gone relatively unstudied in fruit flies. Our interest is in characterizing how bacterial pathogenesis affects various physiologies of the fly. We chose to examine the fly ovary because we found bacterial infection had a striking effect on fly reproduction. We observed decreased egg laying after bacterial infection that correlated with increased bacterial virulence. We also found that bacteria colonized the ovary in a previously undescribed manner; bacteria were found in the posterior of the ovary, adjacent to the lateral oviduct. This local infection in the ovary resulted in melanization and activation of the cellular immune response at the site of infection.

  View details for DOI 10.1016/j.dci.2007.02.003

  View details for Web of Science ID 000251077200005

  View details for PubMedID 17400292

  View details for PubMedCentralID PMC3109252

• Akt and foxo dysregulation contribute to infection-induced wasting in Drosophila CURRENT BIOLOGY Dionne, M. S., Pham, L. N., Shirasu-Hiza, M., Schneider, D. S. 2006; 16 (20): 1977-1985

  Abstract

  Studies in Drosophila have taught us a great deal about how animals regulate the immediate innate immune response, but we still know little about how infections cause pathology. Here, we examine the pathogenesis associated with Mycobacterium marinum infection in the fly. M. marinum is closely related to M. tuberculosis, which causes tuberculosis in people.A microarray analysis showed that metabolism is profoundly affected in M. marinum-infected flies. A genetic screen identified foxo mutants as slower-dying after infection than wild-type flies. FOXO activity is inhibited by the insulin effector kinase Akt; we show that Akt activation is systemically reduced as a result of M. marinum infection. Finally, we show that flies infected with Mycobacterium marinum undergo a process like wasting: They progressively lose metabolic stores, in the form of fat and glycogen. They also become hyperglycemic. In contrast, foxo mutants exhibit less wasting.In people, many infections--including tuberculosis--can cause wasting, much as we see in Drosophila. Our study is the first examination of the metabolic consequences of infection in a genetically tractable invertebrate and gives insight into the metabolic consequences of mycobacterial infection, implicating impaired insulin signaling as a key mediator of these events. These results suggest that the fly can be used to study more than the immediate innate immune response to infection; it can also be used to understand the physiological consequences of infection and the immune response.

  View details for DOI 10.1016/j.cub.2006.08.052

  View details for Web of Science ID 000241532000018

  View details for PubMedID 17055976

• Genomic dissection of microbial pathogenesis in cultured Drosophila cells TRENDS IN MICROBIOLOGY Ayres, J. S., Schneider, D. S. 2006; 14 (3): 101-104

  Abstract

  Recent RNA interference screens that were performed at a genome-wide level have identified host factors that are important for the growth of Listeria monocytogenes in cultured cells from the fruit fly Drosophila melanogaster. The screens identified genes that are involved in phagocytosis but did not detect genes known to be involved in immune signaling pathways. These studies provide a foundation for the identification of host factors and virulence mechanisms.

  View details for DOI 10.1016/j.tim.2006.01.008

  View details for Web of Science ID 000236650400002

  View details for PubMedID 16473012

• WntD is a feedback inhibitor of Dorsal/NF-kappa B in Drosophila development and immunity NATURE Gordon, M. D., Dionne, M. S., Schneider, D. S., Nusse, R. 2005; 437 (7059): 746-749

  Abstract

  Regulating the nuclear factor-kappaB (NF-kappaB) family of transcription factors is of critical importance to animals, with consequences of misregulation that include cancer, chronic inflammatory diseases and developmental defects. Studies in Drosophila melanogaster have proved fruitful in determining the signals used to control NF-kappaB proteins, beginning with the discovery that the Toll/NF-kappaB pathway, in addition to patterning the dorsal-ventral axis of the fly embryo, defines a major component of the innate immune response in both Drosophila and mammals. Here, we characterize the Drosophila wntD (Wnt inhibitor of Dorsal) gene. We show that WntD acts as a feedback inhibitor of the NF-kappaB homologue Dorsal during both embryonic patterning and the innate immune response to infection. wntD expression is under the control of Toll/Dorsal signalling, and increased levels of WntD block Dorsal nuclear accumulation, even in the absence of the IkappaB homologue Cactus. The WntD signal is independent of the common Wnt signalling component Armadillo (beta-catenin). By engineering a gene knockout, we show that wntD loss-of-function mutants have immune defects and exhibit increased levels of Toll/Dorsal signalling. Furthermore, the wntD mutant phenotype is suppressed by loss of zygotic dorsal. These results describe the first secreted feedback antagonist of Toll signalling, and demonstrate a novel Wnt activity in the fly.

  View details for Web of Science ID 000232157900055

  View details for PubMedID 16107793

• Secreted bacterial effectors and host-produced eiger/TNF drive death in a Salmonella-infected fruit fly PLOS BIOLOGY Brandt, S. M., Dionne, M. S., Khush, R. S., Pham, L. N., Vigdal, T. J., Schneider, D. S. 2004; 2 (12): 2067-2075

  Abstract

  Death by infection is often as much due to the host's reaction as it is to the direct result of microbial action. Here we identify genes in both the host and microbe that are involved in the pathogenesis of infection and disease in Drosophila melanogaster challenged with Salmonella enterica serovartyphimurium (S. typhimurium). We demonstrate that wild-typeS. typhimurium causes a lethal systemic infection when injected into the hemocoel of D. melanogaster. Deletion of the gene encoding the secreted bacterial effect or Salmonella leucine-rich (PslrP)changes an acute and lethal infection to one that is persistent and less deadly. We propose a model in which Salmonella secreted effectors stimulate the fly and thus cause an immune response that is damaging both to the bacteria and, subsequently, to the host. In support of this model, we show that mutations in the fly gene eiger, a TNF homolog, delay the lethality of Salmonella infection. These results suggest that S. typhimurium-infected flies die from a condition that resembles TNF-induced metabolic collapse in vertebrates. This idea provides us with a new model to study shock-like biology in a genetically manipulable host. In addition, it allows us to study the difference in pathways followed by a microbe when producing an acute or persistent infection.

  View details for DOI 10.1371/journal.pbio.0020418

  View details for Web of Science ID 000226099600009

  View details for PubMedID 15562316

  View details for PubMedCentralID PMC532388

• Exploration of host-pathogen interactions using Listeria monocytogenes and Drosophila melanogaster CELLULAR MICROBIOLOGY Mansfield, B. E., Dionne, M. S., Schneider, D. S., Freitag, N. E. 2003; 5 (12): 901-911

  Abstract

  The facultative intracellular bacterial pathogen Listeria monocytogenes is capable of replicating within a broad range of host cell types and host species. We report here the establishment of the fruit fly Drosophila melanogaster as a new model host for the exploration of L. monocytogenes pathogenesis and host response to infection. Listeria monocytogenes was capable of establishing lethal infections in adult fruit flies and larvae with extensive bacterial replication occurring before host death. Bacteria were found in the cytosol of insect phagocytic cells, and were capable of directing host cell actin polymerization. Bacterial gene products necessary for intracellular replication and cell-to-cell spread within mammalian cells were similarly found to be required within insect cells, and although previous work has suggested that L. monocytogenes virulence gene expression requires temperatures above 30 degrees C, bacteria within insect cells were found to express virulence determinants at 25 degrees C. Mutant strains of Drosophila that were compromised for innate immune responses demonstrated increased susceptibility to L. monocytogenes infection. These data indicate L. monocytogenes infection of fruit flies shares numerous features of mammalian infection, and thus that Drosophila has the potential to serve as a genetically tractable host system that will facilitate the analysis of host cellular responses to L. monocytogenes infection.

  View details for DOI 10.1046/j.1462-5822.2003.00329.x

  View details for Web of Science ID 000186563600005

  View details for PubMedID 14641175

• Drosophila melanogaster is a genetically tractable model host for Mycobacterium marinum INFECTION AND IMMUNITY Dionne, M. S., Ghori, N., Schneider, D. S. 2003; 71 (6): 3540-3550

  Abstract

  Mycobacterium marinum is a pathogenic mycobacterial species that is closely related to Mycobacterium tuberculosis and causes tuberculosis-like disease in fish and frogs. We infected the fruit fly Drosophila melanogaster with M. marinum. This bacterium caused a lethal infection in the fly, with a 50% lethal dose (LD(50)) of 5 CFU. Death was accompanied by widespread tissue damage. M. marinum initially proliferated inside the phagocytes of the fly; later in infection, bacteria were found both inside and outside host cells. Intracellular M. marinum blocked vacuolar acidification and failed to colocalize with dead Escherichia coli, similar to infections of mouse macrophages. M. marinum lacking the mag24 gene were less virulent, as determined both by LD(50) and by death kinetics. Finally, in contrast to all other bacteria examined, mycobacteria failed to elicit the production of antimicrobial peptides in Drosophila.We believe that this system should be a useful genetically tractable model for mycobacterial infection.

  View details for DOI 10.1128/IAI.71.6.3540-3550.2003

  View details for Web of Science ID 000183116300067

  View details for PubMedID 12761139

  View details for PubMedCentralID PMC155752

• Plant immunity and film noir: What gumshoe detectives can teach us about plant-pathogen interactions CELL Schneider, D. S. 2002; 109 (5): 537-540

  Abstract

  Plant cells practice constant vigilance using resistance (R) proteins to monitor pathogenic processes. Three papers published recently in Cell and one in Science provide support for a model in which plant cells set up surveillance of signal transduction pathways, preparing to destroy the cell if any untoward fiddling with cellular physiology is detected. The demonstration of three separate examples of such a system suggests that it is broadly used and should provoke a reexamination of microbial pathogenesis in animal cells to look for similar mechanisms.

  View details for Web of Science ID 000175957900001

  View details for PubMedID 12062095

• Malaria parasite development in a Drosophila model SCIENCE Schneider, D., Shahabuddin, M. 2000; 288 (5475): 2376-2379

  Abstract

  Malaria is a devastating public health menace, killing over one million people every year and infecting about half a billion. Here it is shown that the protozoan Plasmodium gallinaceum, a close relative of the human malaria parasite Plasmodium falciparum, can develop in the fruit fly Drosophila melanogaster. Plasmodium gallinaceum ookinetes injected into the fly developed into sporozoites infectious to the vertebrate host with similar kinetics as seen in the mosquito host Aedes aegypti. In the fly, a component of the insect's innate immune system, the macrophage, can destroy Plasmodia. These experiments suggest that Drosophila can be used as a surrogate mosquito for defining the genetic pathways involved in both vector competence and part of the parasite sexual cycle.

  View details for Web of Science ID 000087913400043

  View details for PubMedID 10875925

• Interactions between the cellular and humoral immune responses in Drosophila CURRENT BIOLOGY Elrod-Erickson, M., Mishra, S., Schneider, D. 2000; 10 (13): 781-784

  Abstract

  Drosophila has highly efficient defenses against infection. These include both cellular immune responses, such as the phagocytosis of invading microorganisms, and humoral immune responses, such as the secretion of antimicrobial peptides into the hemolymph [1] [2]. These defense systems are thought to interact, but the nature and extent of these interactions is not known. Here we describe a method for inhibiting phagocytosis in Drosophila blood cells (hemocytes) by injecting polystyrene beads into the body cavity. This treatment does not in itself make a fly susceptible to Escherichia coli infection. However, when performed on flies carrying the mutation immune deficiency (imd), which affects the humoral immune response [3], the treatment results in a striking decrease in resistance to infection. We therefore carried out a sensitized genetic screen to identify immunocompromised mutants by co-injecting beads and E. coli. From this screen, we identified a new gene we have named red shirt and identified the caspase Dredd as a regulator of the Drosophila immune response. The observation that mutants with defects in the humoral immune response are further immunocompromised by blocking phagocytosis, and thus inhibiting the cellular immune response, shows that the Drosophila cellular and humoral immune responses act in concert to fight infection.

  View details for Web of Science ID 000088979000019

  View details for PubMedID 10898983

• Using Drosophila as a model insect Nature Reviews Genetics Schneider, D.S. 2000
• A PROCESSED FORM OF THE SPATZLE PROTEIN DEFINES DORSAL-VENTRAL POLARITY IN THE DROSOPHILA EMBRYO DEVELOPMENT Schneider, D. S., JIN, Y. S., Morisato, D., Anderson, K. V. 1994; 120 (5): 1243-1250

  Abstract

  Stein et al. (1991) identified a soluble, extracellular factor that induces ventral structures at the site where it is injected in the extracellular space of the early Drosophila embryo. This factor, called polarizing activity, has the properties predicted for a ligand for the transmembrane receptor encoded by the Toll gene. Using a bioassay to follow activity, we purified a 24 x 10(3) M(r) protein that has polarizing activity. The purified protein is recognized by antibodies to the C-terminal half of the Spätzle protein, indicating that this polarizing activity is a product of the spätzle gene. The purified protein is smaller than the primary translation product of spätzle, suggesting that proteolytic processing of Spätzle on the ventral side of the embryo is required to generate the localized, active form of the protein.

  View details for Web of Science ID A1994NM70200019

  View details for PubMedID 8026333

• DOMINANT AND RECESSIVE MUTATIONS DEFINE FUNCTIONAL DOMAINS OF TOLL, A TRANSMEMBRANE PROTEIN REQUIRED FOR DORSAL VENTRAL POLARITY IN THE DROSOPHILA EMBRYO GENES & DEVELOPMENT Schneider, D. S., Hudson, K. L., Lin, T. Y., Anderson, K. V. 1991; 5 (5): 797-807

  Abstract

  The asymmetry of the dorsal-ventral pattern of the Drosophila embryo appears to depend on the ventral activation of the transmembrane Toll protein. The Toll protein is found around the entire dorsal-ventral circumference of the embryo, and it appears to act as a receptor for a ventral, extracellular signal and to then relay that signal to the cytoplasm in ventral regions of the embryo. Three of five recessive loss-of-function alleles of Toll are caused by point mutations in the region of the cytoplasmic domain of Toll that is similar to the mammalian interleukin-1 receptor, supporting the hypothesis that Toll acts as a signal-transducing receptor. Nine dominant gain-of-function alleles that cause Toll to be active in dorsal, as well as ventral, regions of the embryo are caused by mutations in the extracellular domain. Three of the dominant alleles appear to cause the protein to be constitutively active and are caused by cysteine-to-tyrosine changes immediately outside the transmembrane domain. All six of the remaining dominant alleles require the presence of a wild-type transmembrane Toll protein for their ventralizing effect and all encode truncated proteins that lack the transmembrane and cytoplasmic domains.

  View details for Web of Science ID A1991FK81300009

  View details for PubMedID 1827421