Malaria-specific Type 1 regulatory T cells are more abundant in first pregnancies and associated with placental malaria.
2023; 95: 104772
Malaria in pregnancy (MIP) causes higher morbidity in primigravid compared to multigravid women; however, the correlates and mechanisms underlying this gravidity-dependent protection remain incompletely understood. We aimed to compare the cellular immune response between primigravid and multigravid women living in a malaria-endemic region and assess for correlates of protection against MIP.We characterised the second trimester cellular immune response among 203 primigravid and multigravid pregnant women enrolled in two clinical trials of chemoprevention in eastern Uganda, utilizing RNA sequencing, flow cytometry, and functional assays. We compared responses across gravidity and determined associations with parasitaemia during pregnancy and placental malaria.Using whole blood RNA sequencing, no significant differentially expressed genes were identified between primigravid (n = 12) and multigravid (n = 11) women overall (log 2(FC) > 2, FDR < 0.1). However, primigravid (n = 49) women had higher percentages of malaria-specific, non-naïve CD4+ T cells that co-expressed IL-10 and IFNγ compared with multigravid (n = 85) women (p = 0.000023), and higher percentages of these CD4+ T cells were associated with greater risks of parasitaemia in pregnancy (Rs = 0.49, p = 0.001) and placental malaria (p = 0.0073). These IL-10 and IFNγ co-producing CD4+ T cells had a genomic signature of Tr1 cells, including expression of transcription factors cMAF and BATF and cell surface makers CTLA4 and LAG-3.Malaria-specific Tr1 cells were highly prevalent in primigravid Ugandan women, and their presence correlated with a higher risk of malaria in pregnancy. Understanding whether suppression of Tr1 cells plays a role in naturally acquired gravidity-dependent immunity may aid the development of new vaccines or treatments for MIP.This work was funded by NIH (PO1 HD059454, U01 AI141308, U19 AI089674, U01 AI155325, U01 AI150741), the March of Dimes (Basil O'Connor award), and the Bill and Melinda Gates Foundation (OPP 1113682).
View details for DOI 10.1016/j.ebiom.2023.104772
View details for PubMedID 37634385
Malaria-driven expansion of adaptive-like functional CD56-negative NK cells correlates with clinical immunity to malaria.
Science translational medicine
2023; 15 (680): eadd9012
Natural killer (NK) cells likely play an important role in immunity to malaria, but the effect of repeated malaria on NK cell responses remains unclear. Here, we comprehensively profiled the NK cell response in a cohort of 264 Ugandan children. Repeated malaria exposure was associated with expansion of an atypical, CD56neg population of NK cells that differed transcriptionally, epigenetically, and phenotypically from CD56dim NK cells, including decreased expression of PLZF and the Fc receptor γ-chain, increased histone methylation, and increased protein expression of LAG-3, KIR, and LILRB1. CD56neg NK cells were highly functional and displayed greater antibody-dependent cellular cytotoxicity than CD56dim NK cells. Higher frequencies of CD56neg NK cells were associated with protection against symptomatic malaria and high parasite densities. After marked reductions in malaria transmission, frequencies of these cells rapidly declined, suggesting that continuous exposure to Plasmodium falciparum is required to maintain this modified, adaptive-like NK cell subset.
View details for DOI 10.1126/scitranslmed.add9012
View details for PubMedID 36696483
Early immune markers of clinical, virological, and immunological outcomes in patients with COVID-19: a multi-omics study.
The great majority of severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) infections are mild and uncomplicated, but some individuals with initially mild COVID-19 progressively develop more severe symptoms. Furthermore, there is substantial heterogeneity in SARS-CoV-2-specific memory immune responses following infection. There remains a critical need to identify host immune biomarkers predictive of clinical and immunological outcomes in SARS-CoV-2-infected patients.Leveraging longitudinal samples and data from a clinical trial (N=108) in SARS-CoV-2-infected outpatients, we used host proteomics and transcriptomics to characterize the trajectory of the immune response in COVID-19 patients. We characterized the association between early immune markers and subsequent disease progression, control of viral shedding, and SARS-CoV-2-specific T cell and antibody responses measured up to 7 months after enrollment. We further compared associations between early immune markers and subsequent T cell and antibody responses following natural infection with those following mRNA vaccination. We developed machine-learning models to predict patient outcomes and validated the predictive model using data from 54 individuals enrolled in an independent clinical trial.We identify early immune signatures, including plasma RIG-I levels, early IFN signaling, and related cytokines (CXCL10, MCP1, MCP-2, and MCP-3) associated with subsequent disease progression, control of viral shedding, and the SARS-CoV-2-specific T cell and antibody response measured up to 7 months after enrollment. We found that several biomarkers for immunological outcomes are shared between individuals receiving BNT162b2 (Pfizer-BioNTech) vaccine and COVID-19 patients. Finally, we demonstrate that machine-learning models using 2-7 plasma protein markers measured early within the course of infection are able to accurately predict disease progression, T cell memory, and the antibody response post-infection in a second, independent dataset.Early immune signatures following infection can accurately predict clinical and immunological outcomes in outpatients with COVID-19 using validated machine-learning models.Support for the study was provided from National Institute of Health/National Institute of Allergy and Infectious Diseases (NIH/NIAID) (U01 AI150741-01S1 and T32-AI052073), the Stanford's Innovative Medicines Accelerator, National Institutes of Health/National Institute on Drug Abuse (NIH/NIDA) DP1DA046089, and anonymous donors to Stanford University. Peginterferon lambda provided by Eiger BioPharmaceuticals.
View details for DOI 10.7554/eLife.77943
View details for PubMedID 36239699
The acquisition of humoral immune responses targeting Plasmodium falciparum sexual stages in controlled human malaria infections.
Frontiers in immunology
2022; 13: 930956
Individuals infected with P. falciparum develop antibody responses to intra-erythrocytic gametocyte proteins and exported gametocyte proteins present on the surface of infected erythrocytes. However, there is currently limited knowledge on the immunogenicity of gametocyte antigens and the specificity of gametocyte-induced antibody responses. In this study, we assessed antibody responses in participants of two controlled human malaria infection (CHMI) studies by ELISA, multiplexed bead-based antibody assays and protein microarray. By comparing antibody responses in participants with and without gametocyte exposure, we aimed to disentangle the antibody response induced by asexual and sexual stage parasites. We showed that after a single malaria infection, a significant anti-sexual stage humoral response is induced in malaria-naïve individuals, even after exposure to relatively low gametocyte densities (up to ~1,600 gametocytes/mL). In contrast to antibody responses to well-characterised asexual blood stage antigens that were detectable by day 21 after infection, responses to sexual stage antigens (including transmission blocking vaccine candidates Pfs48/45 and Pfs230) were only apparent at 51 days after infection. We found antigens previously associated with early gametocyte or anti-gamete immunity were highly represented among responses linked with gametocyte exposure. Our data provide detailed insights on the induction and kinetics of antibody responses to gametocytes and identify novel antigens that elicit antibody responses exclusively in individuals with gametocyte exposure. Our findings provide target identification for serological assays for surveillance of the malaria infectious reservoir, and support vaccine development by describing the antibody response to leading vaccine antigens after primary infection.
View details for DOI 10.3389/fimmu.2022.930956
View details for PubMedID 35924245
View details for PubMedCentralID PMC9339717
TNF-alpha+ CD4+ Tcells dominate the SARS-CoV-2 specific T cell response in COVID-19 outpatients and are associated with durable antibodies.
Cell reports. Medicine
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific CD4+ Tcells are likely important in immunity against coronavirus 2019 (COVID-19), but our understanding of CD4+ longitudinal dynamics following infection and of specific features that correlate with the maintenance of neutralizing antibodies remains limited. Here, we characterize SARS-CoV-2-specific CD4+ Tcells in a longitudinal cohort of 109 COVID-19 outpatients enrolled during acute infection. The quality of the SARS-CoV-2-specific CD4+ response shifts from cells producing interferon gamma (IFNgamma) to tumor necrosis factor alpha (TNF-alpha) from 5days to 4months post-enrollment, with IFNgamma-IL-21-TNF-alpha+ CD4+ Tcells the predominant population detected at later time points. Greater percentages of IFNgamma-IL-21-TNF-alpha+ CD4+ Tcells on day 28 correlate with SARS-CoV-2-neutralizing antibodies measured 7months post-infection (⍴= 0.4, p= 0.01). mRNA vaccination following SARS-CoV-2 infection boosts both IFNgamma- and TNF-alpha-producing, spike-protein-specific CD4+ Tcells. These data suggest that SARS-CoV-2-specific, TNF-alpha-producing CD4+ Tcells may play an important role in antibody maintenance following COVID-19.
View details for DOI 10.1016/j.xcrm.2022.100640
View details for PubMedID 35588734
Early immune responses have long-term associations with clinical, virologic, and immunologic outcomes in patients with COVID-19.
The great majority of SARS-CoV-2 infections are mild and uncomplicated, but some individuals with initially mild COVID-19 progressively develop more severe symptoms. Furthermore, there is substantial heterogeneity in SARS-CoV-2-specific memory immune responses following infection. There remains a critical need to identify host immune biomarkers predictive of clinical and immunologic outcomes in SARS-CoV-2-infected patients. Leveraging longitudinal samples and data from a clinical trial in SARS-CoV-2 infected outpatients, we used host proteomics and transcriptomics to characterize the trajectory of the immune response in COVID-19 patients within the first 2 weeks of symptom onset. We identify early immune signatures, including plasma RIG-I levels, early interferon signaling, and related cytokines (CXCL10, MCP1, MCP-2 and MCP-3) associated with subsequent disease progression, control of viral shedding, and the SARS-CoV-2 specific T cell and antibody response measured up to 7 months after enrollment. We found that several biomarkers for immunological outcomes are shared between individuals receiving BNT162b2 (Pfizera"BioNTech) vaccine and COVID-19 patients. Finally, we demonstrate that machine learning models using 7-10 plasma protein markers measured early within the course of infection are able to accurately predict disease progression, T cell memory, and the antibody response post-infection in a second, independent dataset.
View details for DOI 10.21203/rs.3.rs-847082/v1
View details for PubMedID 35132407
DIMINISHED V delta 2+delta gamma T CELL CYTOKINE PRODUCTION AND DEGRANULATION FOLLOWING IN VITRO MALARIA EXPOSURE
AMER SOC TROP MED & HYGIENE. 2021: 16
View details for Web of Science ID 000778105601047
MALARIA-DRIVEN EXPANSION OF MATURE, SHORT-LIVED FUNCTIONAL CD56NEG NK CELLS CORRELATES WITH CLINICAL IMMUNITY TO MALARIA
AMER SOC TROP MED & HYGIENE. 2021: 16-17
View details for Web of Science ID 000778105601048
SARS-CoV-2 RNAemia predicts clinical deterioration and extrapulmonary complications from COVID-19.
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
The determinants of COVID-19 disease severity and extrapulmonary complications (EPCs) are poorly understood. We characterized relationships between SARS-CoV-2 RNAemia and disease severity, clinical deterioration, and specific EPCs.We used quantitative (qPCR) and digital (dPCR) PCR to quantify SARS-CoV-2 RNA from plasma in 191 patients presenting to the Emergency Department (ED) with COVID-19. We recorded patient symptoms, laboratory markers, and clinical outcomes, with a focus on oxygen requirements over time. We collected longitudinal plasma samples from a subset of patients. We characterized the role of RNAemia in predicting clinical severity and EPCs using elastic net regression.23.0% (44/191) of SARS-CoV-2 positive patients had viral RNA detected in plasma by dPCR, compared to 1.4% (2/147) by qPCR. Most patients with serial measurements had undetectable RNAemia within 10 days of symptom onset, reached maximum clinical severity within 16 days, and symptom resolution within 33 days. Initially RNAaemic patients were more likely to manifest severe disease (OR 6.72 [95% CI, 2.45 - 19.79]), worsening of disease severity (OR 2.43 [95% CI, 1.07 - 5.38]), and EPCs (OR 2.81 [95% CI, 1.26 - 6.36]). RNA load correlated with maximum severity (r = 0.47 [95% CI, 0.20 - 0.67]).dPCR is more sensitive than qPCR for the detection of SARS-CoV-2 RNAemia, which is a robust predictor of eventual COVID-19 severity and oxygen requirements, as well as EPCs. Since many COVID-19 therapies are initiated on the basis of oxygen requirements, RNAemia on presentation might serve to direct early initiation of appropriate therapies for the patients most likely to deteriorate.
View details for DOI 10.1093/cid/ciab394
View details for PubMedID 33949665
Naturally acquired immunity against immature Plasmodium falciparum gametocytes
SCIENCE TRANSLATIONAL MEDICINE
2019; 11 (495)
The recent decline in global malaria burden has stimulated efforts toward Plasmodium falciparum elimination. Understanding the biology of malaria transmission stages may provide opportunities to reduce or prevent onward transmission to mosquitoes. Immature P. falciparum transmission stages, termed stages I to IV gametocytes, sequester in human bone marrow before release into the circulation as mature stage V gametocytes. This process likely involves interactions between host receptors and potentially immunogenic adhesins on the infected red blood cell (iRBC) surface. Here, we developed a flow cytometry assay to examine immune recognition of live gametocytes of different developmental stages by naturally exposed Malawians. We identified strong antibody recognition of the earliest immature gametocyte-iRBCs (giRBCs) but not mature stage V giRBCs. Candidate surface antigens (n = 30), most of them shared between asexual- and gametocyte-iRBCs, were identified by mass spectrometry and mouse immunizations, as well as correlations between responses by protein microarray and flow cytometry. Naturally acquired responses to a subset of candidate antigens were associated with reduced asexual and gametocyte density, and plasma samples from malaria-infected individuals were able to induce immune clearance of giRBCs in vitro. Infected RBC surface expression of select candidate antigens was validated using specific antibodies, and genetic analysis revealed a subset with minimal variation across strains. Our data demonstrate that humoral immune responses to immature giRBCs and shared iRBC antigens are naturally acquired after malaria exposure. These humoral immune responses may have consequences for malaria transmission potential by clearing developing gametocytes, which could be leveraged for malaria intervention.
View details for DOI 10.1126/scitranslmed.aav3963
View details for Web of Science ID 000470118600002
View details for PubMedID 31167926
View details for PubMedCentralID PMC6653583
Emerging role of gammadelta T cells in vaccine-mediated protection from infectious diseases.
Clinical & translational immunology
2019; 8 (8): e1072
gammadelta T cells are fascinating cells that bridge the innate and adaptive immune systems. They have long been known to proliferate rapidly following infection; however, the identity of the specific gammadelta T cell subsets proliferating and the role of this expansion in protection from disease have only been explored more recently. Several recent studies have investigated gammadelta T-cell responses to vaccines targeting infections such as Mycobacterium, Plasmodium and influenza, and studies in animal models have provided further insight into the association of these responses with improved clinical outcomes. In this review, we examine the evidence for a role for gammadelta T cells in vaccine-induced protection against various bacterial, protozoan and viral infections. We further discuss results suggesting potential mechanisms for protection, including cytokine-mediated direct and indirect killing of infected cells, and highlight remaining open questions in the field. Finally, building on current efforts to integrate strategies targeting gammadelta T cells into immunotherapies for cancer, we discuss potential approaches to improve vaccines for infectious diseases by inducing gammadelta T-cell activation and cytotoxicity.
View details for DOI 10.1002/cti2.1072
View details for PubMedID 31485329
MECHANISMS DRIVING ALTERED V Delta 2+Gamma Delta T CELL FUNCTION DURING RECURRENT MALARIA INFECTION
AMER SOC TROP MED & HYGIENE. 2019: 111
View details for Web of Science ID 000507364502362
γδ T Cells in Antimalarial Immunity: New Insights Into Their Diverse Functions in Protection and Tolerance.
Frontiers in immunology
2018; 9: 2445
Uniquely expressing diverse innate-like and adaptive-like functions, γδ T cells exist as specialized subsets, but are also able to adapt in response to environmental cues. These cells have long been known to rapidly proliferate following primary malaria infection in humans and mice, but exciting new work is shedding light into their diverse functions in protection and following repeated malaria infection. In this review, we examine the current knowledge of functional specialization of γδ T cells in malaria, and the mechanisms dictating recognition of malaria parasites and resulting proliferation. We discuss γδ T cell plasticity, including changing interactions with other immune cells during recurrent infection and potential for immunological memory in response to repeated stimulation. Building on recent insights from human and murine experimental studies and vaccine trials, we propose areas for future research, as well as applications for therapeutic development.
View details for DOI 10.3389/fimmu.2018.02445
View details for PubMedID 30405634
View details for PubMedCentralID PMC6206268
- gamma delta T Cells in Antimalarial Immunity: New Insights Into Their Diverse Functions in Protection and Tolerance FRONTIERS IN IMMUNOLOGY 2018; 9
IMPACT OF RECURRENT MALARIA ON V Delta 2 Gamma Delta T CELL <it>IN VITRO</it> ANTI-PARASITIC ACTIVITY
AMER SOC TROP MED & HYGIENE. 2018: 112
View details for Web of Science ID 000461386602361
Quantitative Proteomic Profiling Reveals Novel Plasmodium falciparum Surface Antigens and Possible Vaccine Candidates
MOLECULAR & CELLULAR PROTEOMICS
2018; 17 (1): 57-74
Despite recent efforts toward control and elimination, malaria remains a major public health problem worldwide. Plasmodium falciparum resistance against artemisinin, used in front line combination drugs, is on the rise, and the only approved vaccine shows limited efficacy. Combinations of novel and tailored drug and vaccine interventions are required to maintain the momentum of the current malaria elimination program. Current evidence suggests that strain-transcendent protection against malaria infection can be achieved using whole organism vaccination or with a polyvalent vaccine covering multiple antigens or epitopes. These approaches have been successfully applied to the human-infective sporozoite stage. Both systemic and tissue-specific pathology during infection with the human malaria parasite P. falciparum is caused by asexual blood stages. Tissue tropism and vascular sequestration are the result of specific binding interactions between antigens on the parasite-infected red blood cell (pRBC) surface and endothelial receptors. The major surface antigen and parasite ligand binding to endothelial receptors, PfEMP1 is encoded by about 60 variants per genome and shows high sequence diversity across strains. Apart from PfEMP1 and three additional variant surface antigen families RIFIN, STEVOR, and SURFIN, systematic analysis of the infected red blood cell surface is lacking. Here we present the most comprehensive proteomic investigation of the parasitized red blood cell surface so far. Apart from the known variant surface antigens, we identified a set of putative single copy surface antigens with low sequence diversity, several of which are validated in a series of complementary experiments. Further functional and immunological investigation is underway to test these novel P. falciparum blood stage proteins as possible vaccine candidates.
View details for DOI 10.1074/mcp.RA117.000076
View details for Web of Science ID 000419169700006
View details for PubMedID 29162636
View details for PubMedCentralID PMC5750850
GAMETOCYTE-SPECIFIC IMMUNITY PROVIDES A RATIONALE FOR NOVEL TRANSMISSION BLOCKING INTERVENTIONS IN PLASMODIUM FALCIPARUM
AMER SOC TROP MED & HYGIENE. 2017: 414
View details for Web of Science ID 000412851502840
PLASMODIUM FALCIPARUM PHISTC PROTEINS ARE REQUIRED FOR ANTIGEN DELIVERY TO THE INFECTED ERYTHROCYTE SURFACE
AMER SOC TROP MED & HYGIENE. 2017: 13
View details for Web of Science ID 000412851501038
Naturally acquired immunity to sexual stage P. falciparum parasites
2016; 143 (2): 187-198
Gametocytes are the specialized form of Plasmodium parasites that are responsible for human-to-mosquito transmission of malaria. Transmission of gametocytes is highly effective, but represents a biomass bottleneck for the parasite that has stimulated interest in strategies targeting the transmission stages separately from those responsible for clinical disease. Studying targets of naturally acquired immunity against transmission-stage parasites may reveal opportunities for novel transmission reducing interventions, particularly the development of a transmission blocking vaccine (TBV). In this review, we summarize the current knowledge on immunity against the transmission stages of Plasmodium. This includes immune responses against epitopes on the gametocyte-infected erythrocyte surface during gametocyte development, as well as epitopes present upon gametocyte activation in the mosquito midgut. We present an analysis of historical data on transmission reducing immunity (TRI), as analysed in mosquito feeding assays, and its correlation with natural recognition of sexual stage specific proteins Pfs48/45 and Pfs230. Although high antibody titres towards either one of these proteins is associated with TRI, the presence of additional, novel targets is anticipated. In conclusion, the identification of novel gametocyte-specific targets of naturally acquired immunity against different gametocyte stages could aid in the development of potential TBV targets and ultimately an effective transmission blocking approach.
View details for DOI 10.1017/S0031182015001341
View details for Web of Science ID 000370042000006
View details for PubMedID 26743529
CHARACTERIZATION OF IMMUNE RESPONSES TO PLASMODIUM FALCIPARUM GAMETOCYTES
AMER SOC TROP MED & HYGIENE. 2015: 7
View details for Web of Science ID 000412844101018
Ensuring transmission through dynamic host environments: host-pathogen interactions in Plasmodium sexual development
CURRENT OPINION IN MICROBIOLOGY
2015; 26: 17-23
A renewed global commitment to malaria elimination lends urgency to understanding the biology of Plasmodium transmission stages. Recent progress toward uncovering the mechanisms underlying Plasmodium falciparum sexual differentiation and maturation reveals potential targets for transmission-blocking drugs and vaccines. The identification of parasite factors that alter sexual differentiation, including extracellular vesicles and a master transcriptional regulator, suggest that parasites make epigenetically controlled developmental decisions based on environmental cues. New insights into sexual development, especially host cell remodeling and sequestration in the bone marrow, highlight open questions regarding parasite homing to the tissue, transmigration across the vascular endothelium, and maturation in the parenchyma. Novel molecular and translational tools will provide further opportunities to define host-parasite interactions and design effective transmission-blocking therapeutics.
View details for DOI 10.1016/j.mib.2015.03.005
View details for Web of Science ID 000362132300005
View details for PubMedID 25867628
View details for PubMedCentralID PMC4577303