I am very interested in the host-pathogen interface from the time that the body first recognizes an infection through the co-evolution arms race between the pathogen and host as they struggle between colonization and clearance respectively. My PhD research focused on how cellular processes impact immune recognition of invading viruses. In my postdoctoral research I am currently investigating mechanisms of immune regulation that rein in the immune response and can be targeted to enable clearance of chronic infection. I am most excited about the notion of applying immunology to real world applications.
I currently lead the infectious disease team within the laboratory of Irving Weissman where I study the immumodulatory mechanisms by which the CD47-SIRPa axis impacts immune clearance of infectious disease. I'm also fascinated with the impact of temperature (local, systemic, and external) on the host immune response and the implications that this has for how we monitor and treat immune responses as well as how climate change will impact invertebrate host responses and the spread of disease. In general I think that we should be tracking infectious disease and immune responses more closely and accurately. I am passionate about developing highly accurate and accessible diagnostics that integrate big data to strive towards precision medicine in infectious disease.
Our immune system has the most sophisticated diagnostics capability known to man, with a pathogen recognition system that has been refined under tremendous selective pressure for millions of years. I would like to develop tools that allow us to tap into our own immune diagnostics and learn from them.
Honors & Awards
Inaugural Early Career Janeway Symposium, Yale University (2019)
Emerging Leader Award, Bay Area Lyme Foundation (2018-2019)
NIH NRSA F32 Postdoctoral Training Grant, NIAID (2016-2017)
NIH T32 Stanford Immunology Training Grant, NIH (2014-2016)
NIH NRSA F31 Predoctoral Training Grant, National Institute on Aging (2010-2012)
Gershon Fellowship, Immunobiology department at Yale University (2009-2010)
Boards, Advisory Committees, Professional Organizations
Postdoctoral committee, Immunology Department (2015 - Present)
Current Research and Scholarly Interests
Investigating how the CD47-SIRPa axis modulates multiple facets of immunity
Upregulation of CD47 Is a Host Checkpoint Response to Pathogen Recognition.
2020; 11 (3)
It is well understood that the adaptive immune response to infectious agents includes a modulating suppressive component as well as an activating component. We now show that the very early innate response also has an immunosuppressive component. Infected cells upregulate the CD47 "don't eat me" signal, which slows the phagocytic uptake of dying and viable cells as well as downstream antigen-presenting cell (APC) functions. A CD47 mimic that acts as an essential virulence factor is encoded by all poxviruses, but CD47 expression on infected cells was found to be upregulated even by pathogens, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), that encode no mimic. CD47 upregulation was revealed to be a host response induced by the stimulation of both endosomal and cytosolic pathogen recognition receptors (PRRs). Furthermore, proinflammatory cytokines, including those found in the plasma of hepatitis C patients, upregulated CD47 on uninfected dendritic cells, thereby linking innate modulation with downstream adaptive immune responses. Indeed, results from antibody-mediated CD47 blockade experiments as well as CD47 knockout mice revealed an immunosuppressive role for CD47 during infections with lymphocytic choriomeningitis virus and Mycobacterium tuberculosis Since CD47 blockade operates at the level of pattern recognition receptors rather than at a pathogen or antigen-specific level, these findings identify CD47 as a novel potential immunotherapeutic target for the enhancement of immune responses to a broad range of infectious agents.IMPORTANCE Immune responses to infectious agents are initiated when a pathogen or its components bind to pattern recognition receptors (PRRs). PRR binding sets off a cascade of events that activates immune responses. We now show that, in addition to activating immune responses, PRR signaling also initiates an immunosuppressive response, probably to limit inflammation. The importance of the current findings is that blockade of immunomodulatory signaling, which is mediated by the upregulation of the CD47 molecule, can lead to enhanced immune responses to any pathogen that triggers PRR signaling. Since most or all pathogens trigger PRRs, CD47 blockade could be used to speed up and strengthen both innate and adaptive immune responses when medically indicated. Such immunotherapy could be done without a requirement for knowing the HLA type of the individual, the specific antigens of the pathogen, or, in the case of bacterial infections, the antimicrobial resistance profile.
View details for DOI 10.1128/mBio.01293-20
View details for PubMedID 32576678
A functional subset of CD8+ T cells during chronic exhaustion is defined by SIRPalpha expression.
2019; 10 (1): 794
Prolonged exposure of CD8+ T cells to antigenic stimulation, as in chronic viral infections, leads to a state of diminished function termed exhaustion. We now demonstrate that even during exhaustion there is a subset of functional CD8+ T cells defined by surface expression of SIRPalpha, a protein not previously reported on lymphocytes. On SIRPalpha+ CD8+ T cells, expression of co-inhibitory receptors is counterbalanced by expression of co-stimulatory receptors and it is only SIRPalpha+ cells that actively proliferate, transcribe IFNgamma and show cytolytic activity. Furthermore, target cells that express the ligand for SIRPalpha, CD47, are more susceptible to CD8+ T cell-killing in vivo. SIRPalpha+ CD8+ T cells are evident in mice infected with Friend retrovirus, LCMV Clone 13, and in patients with chronic HCV infections. Furthermore, therapeutic blockade of PD-L1 to reinvigorate CD8+ T cells during chronic infection expands the cytotoxic subset of SIRPalpha+ CD8+ T cells.
View details for PubMedID 30770827
Absence of autophagy results in reactive oxygen species-dependent amplification of RLR signaling
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2009; 106 (8): 2770-2775
Autophagy is a highly conserved process that maintains homeostasis by clearing damaged organelles and long-lived proteins. The consequences of deficiency in autophagy manifest in a variety of pathological states including neurodegenerative diseases, inflammatory disorders, and cancer. Here, we studied the role of autophagy in the homeostatic regulation of innate antiviral defense. Single-stranded RNA viruses are recognized by the members of the RIG-I-like receptors (RLRs) in the cytosol. RLRs signal through IPS-1, resulting in the production of the key antiviral cytokines, type I IFNs. Autophagy-defective Atg5(-/-) cells exhibited enhanced RLR signaling, increased IFN secretion, and resistance to infection by vesicular stomatitis virus. In the absence of autophagy, cells accumulated dysfunctional mitochondria, as well as mitochondria-associated IPS-1. Reactive oxygen species (ROS) associated with the dysfunctional mitochondria were largely responsible for the enhanced RLR signaling in Atg5(-/-) cells, as antioxidant treatment blocked the excess RLR signaling. In addition, autophagy-independent increase in mitochondrial ROS by treatment of cells with rotenone was sufficient to amplify RLR signaling in WT cells. These data indicate that autophagy contributes to homeostatic regulation of innate antiviral defense through the clearance of dysfunctional mitochondria, and revealed that ROS associated with mitochondria play a key role in potentiating RLR signaling.
View details for DOI 10.1073/pnas.0807694106
View details for Web of Science ID 000263652900055
View details for PubMedID 19196953
Functional cytotoxic T cells exhibit tissue-specific phenotypic differences during chronic Friend virus infection
AMER ASSOC IMMUNOLOGISTS. 2020
View details for Web of Science ID 000589972401051
Polymorphisms in SIRPA impact macrophage phagocytosis in response to therapeutic antibody blockade.
AMER ASSOC CANCER RESEARCH. 2020: 49
View details for Web of Science ID 000518188200069
Immunotherapeutic Blockade of CD47 Inhibitory Signaling Enhances Innate and Adaptive Immune Responses to Viral Infection.
2020; 31 (2): 107494
Paradoxically, early host responses to infection include the upregulation of the antiphagocytic molecule, CD47. This suggests that CD47 blockade could enhance antigen presentation and subsequent immune responses. Indeed, mice treated with anti-CD47 monoclonal antibody following lymphocytic choriomeningitis virus infections show increased activation of both macrophages and dendritic cells (DCs), enhancement of the kinetics and potency of CD8+ T cell responses, and significantly improved virus control. Treatment efficacy is critically dependent on both APCs and CD8+ T cells. In preliminary results from one of two cohorts of humanized mice infected with HIV-1 for 6 weeks, CD47 blockade reduces plasma p24 levels and restores CD4+ T cell counts. The results indicate that CD47 blockade not only enhances the function of innate immune cells but also links to adaptive immune responses through improved APC function. As such, immunotherapy by CD47 blockade may have broad applicability to treat a wide range of infectious diseases.
View details for DOI 10.1016/j.celrep.2020.03.058
View details for PubMedID 32294445
Mx1 reveals innate pathways to antiviral resistance and lethal influenza disease
2016; 352 (6284): 463-466
Influenza A virus (IAV) causes up to half a million deaths worldwide annually, 90% of which occur in older adults. We show that IAV-infected monocytes from older humans have impaired antiviral interferon production but retain intact inflammasome responses. To understand the in vivo consequence, we used mice expressing a functional Mx gene encoding a major interferon-induced effector against IAV in humans. In Mx1-intact mice with weakened resistance due to deficiencies in Mavs and Tlr7, we found an elevated respiratory bacterial burden. Notably, mortality in the absence of Mavs and Tlr7 was independent of viral load or MyD88-dependent signaling but dependent on bacterial burden, caspase-1/11, and neutrophil-dependent tissue damage. Therefore, in the context of weakened antiviral resistance, vulnerability to IAV disease is a function of caspase-dependent pathology.
View details for DOI 10.1126/science.aaf3926
View details for Web of Science ID 000374479700048
View details for PubMedID 27102485
Mitochondrial DNA stress primes the antiviral innate immune response
2015; 520 (7548): 553-?
Mitochondrial DNA (mtDNA) is normally present at thousands of copies per cell and is packaged into several hundred higher-order structures termed nucleoids. The abundant mtDNA-binding protein TFAM (transcription factor A, mitochondrial) regulates nucleoid architecture, abundance and segregation. Complete mtDNA depletion profoundly impairs oxidative phosphorylation, triggering calcium-dependent stress signalling and adaptive metabolic responses. However, the cellular responses to mtDNA instability, a physiologically relevant stress observed in many human diseases and ageing, remain poorly defined. Here we show that moderate mtDNA stress elicited by TFAM deficiency engages cytosolic antiviral signalling to enhance the expression of a subset of interferon-stimulated genes. Mechanistically, we find that aberrant mtDNA packaging promotes escape of mtDNA into the cytosol, where it engages the DNA sensor cGAS (also known as MB21D1) and promotes STING (also known as TMEM173)-IRF3-dependent signalling to elevate interferon-stimulated gene expression, potentiate type I interferon responses and confer broad viral resistance. Furthermore, we demonstrate that herpesviruses induce mtDNA stress, which enhances antiviral signalling and type I interferon responses during infection. Our results further demonstrate that mitochondria are central participants in innate immunity, identify mtDNA stress as a cell-intrinsic trigger of antiviral signalling and suggest that cellular monitoring of mtDNA homeostasis cooperates with canonical virus sensing mechanisms to fully engage antiviral innate immunity.
View details for DOI 10.1038/nature14156
View details for Web of Science ID 000353334500046
View details for PubMedID 25642965
Autophagy and selective deployment of Atg proteins in antiviral defense
2013; 25 (1): 1-10
Autophagy is an evolutionarily ancient process eukaryotic cells utilize to remove and recycle intracellular material in order to maintain cellular homeostasis. In metazoans, the autophagy machinery not only functions in this capacity but also has evolved to perform a diverse repertoire of intracellular transport and regulatory functions. In response to virus infections, the autophagy machinery degrades viruses, shuttles viral pathogen-associated molecular patterns to endosomes containing Toll-like receptors, facilitates viral-antigen processing for major histocompatibility complex presentation and transports antiviral proteins to viral replication sites. This is accomplished through canonical autophagy or through processes involving distinct subsets of the autophagy-related genes (Atgs). Herein, we discuss how the variable components of the autophagy machinery contribute to antiviral defense and highlight three emerging themes: first, autophagy delivers viral cytosolic components to several distinct endolysosomal compartments; second, Atg proteins act alone, as subgroups or collectively; and third, the specificity of autophagy and the autophagy machinery is achieved by recognition of triggers and selective targeting by adaptors.
View details for DOI 10.1093/intimm/dxs101
View details for Web of Science ID 000313127400001
View details for PubMedID 23042773
Mitoxosome: a mitochondrial platform for cross-talk between cellular stress and antiviral signaling
2011; 243: 215-234
Evidence is accumulating that the mitochondria form an integral platform from which innate signaling takes place. Recent studies revealed that the mitochondria are shaping the innate response to intracellular pathogens, and mitochondrial function is modulating and being modulated by innate immune signaling. Further, cell biologic analyses have uncovered the dynamic relocalization of key components involved in cytosolic viral recognition and signaling to the mitochondria, as well as the mobilization of mitochondria to the sites of viral replication. In this review, we provide an integrated view of how cellular stress and signals following cytosolic viral recognition are intimately linked and coordinated at the mitochondria. We incorporate recent findings into our current understanding of the role of mitochondrial function in antiviral immunity and suggest the existence of a 'mitoxosome', a mitochondrial oxidative signalosome where multiple pathways of viral recognition and cellular stress converge on the surface of the mitochondria to facilitate a coordinated antiviral response.
View details for DOI 10.1111/j.1600-065X.2011.01038.x
View details for Web of Science ID 000295016800017
View details for PubMedID 21884179
Autophagic control of RLR signaling
2009; 5 (5): 749-750
Innate immunity to viral infection is initiated within the infected cells through the recognition of unique viral signatures by pattern recognition receptors (PRRs) that mediate the induction of potent antiviral factor, type I interferons (IFNs). Infection with RNA viruses is recognized by the members of the retinoic acid inducible gene I (RIG-I)-like receptor (RLR) family in the cytosol. Our recent study demonstrates that IFN production in response to RNA viral ligands is increased in the absence of autophagy. The process of autophagy functions as an internal cleanup crew within the cell, shuttling damaged cellular organelles and long-lived proteins to the lysosomes for degradation. Our data show that the absence of autophagy leads to the amplification of RLR signaling in two ways. First, in the absence of autophagy, mitochondria accumulate within the cell leading to the buildup of mitochondrial associated protein, IPS-1, a key signaling protein for RLRs. Second, damaged mitochondria that are not degraded in the absence of autophagy provide a source of reactive oxygen species (ROS), which amplify RLR signaling in Atg5 knockout cells. Our study provides the first link between ROS and cytosolic signaling mediated by the RLRs, and suggests the importance of autophagy in the regulation of signaling emanating from mitochondria.
View details for DOI 10.1073/pnas.0807694106
View details for Web of Science ID 000268205300030
View details for PubMedID 19571662
Autophagy and Innate Recognition Systems
AUTOPHAGY IN INFECTION AND IMMUNITY
2009; 335: 107-121
Autophagy is an ancient, highly conserved pathway responsible for the lysosomal degradation of cytosolic constituents and organelles that is critical in maintaining cellular homeostasis. Recent studies have illustrated an important interplay between autophagy and the innate immune system. Signaling through innate pattern recognition receptors leads to the induction of autophagy. Autophagy is utilized by the innate immune cells to survey for virus infection through delivery of cytosolic viral replication complexes to the endosomal viral sensors. In another case, key molecules in the autophagy pathway were found to negatively regulate cytosolic sensors of RNA viruses. Moreover, it has recently become apparent that the autophagic machinery is utilized by phagocytic cells for efficient phagocytosis and clearance of extracellular pathogens. These studies shed light on the possibility that molecules classically thought to be dedicated to the process of autophagy may function in important physiological processes independent of autophagy, whereby the double-membrane structures form within the cytosol to enclose organelles and long-lived proteins. In this chapter, we will highlight key findings relevant to the role of the autophagic machinery in the innate immune system.
View details for DOI 10.1007/978-3-642-00302-8_5
View details for Web of Science ID 000273774900005
View details for PubMedID 19802562