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Principal Investigator: Thomas Nutman
Organization: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
Fiscal Year: 2022
Award: $917,866
Funding agency: National Institute of Allergy and Infectious Diseases
Our work focuses on the host response to helminth infection and pathogenesis of helminthic disease; immune responses in pulmonary and extrapulmonary tuberculosis; modulation of immune responses in tuberculosis by coinfections and comorbidities such as helminth infections, undernutrition, obesity, viral infections and type 2 diabetes mellitus; immune responses in and pathogenesis of SARS-CoV2 infection, adult and pediatric COVID-19 disease and Multi-System Inflammatory Syndrome in Children; and immune responses to vaccination in different populations including BCG and COVID-19 vaccination.
A. HEIGHTENED MICROBIAL TRANSLOCATION IS A PROGNOSTIC BIOMARKER OF RECURRENT TUBERCULOSIS
Microbial translocation is a known characteristic of pulmonary tuberculosis (PTB). Whether microbial translocation is also a biomarker of recurrence in PTB is not known. We examined the presence of microbial translocation in a cohort of newly diagnosed, sputum smear and culture positive individuals with drug-sensitive PTB. Participants were followed up for a year following the end of anti-tuberculosis treatment. They were classified as cases (in the event of recurrence, n=30) and compared to age and gender matched controls (in the event of successful, recurrence free cure; n=51). Plasma samples were used to measure the circulating microbial translocation markers. All the enrolled study participants were treatment nave, HIV negative and with or without diabetes mellitus. Baseline levels of lipopolysaccharide (LPS), sCD14 and LPS-binding protein (LBP) were significantly higher in recurrence than controls and were associated with increased risk for recurrence, while Intestinal fatty acid binding protein (I-FABP) and EndocAb showed no association. ROC curve analysis demonstrated the utility of these individual microbial markers in discriminating recurrence from cure with high sensitivity, specificity and AUC. Recurrence following microbiological cure in PTB is characterized by heightened baseline microbial translocation. These markers can be used as a rapid prognostic tool for predicting recurrence in PTB.
B. ENHANCED SEVERE ACUTE RESPIRATORY SYNDROME CORONAVIRUS 2 ANTIGEN-SPECIFIC IMMUNE RESPONSES IN MULTI-SYSTEM INFLAMMATORY SYNDROME IN CHILDREN AND REVERSAL AFTER RECOVERY
Multi-system inflammatory syndrome in children (MIS-C) presents with inflammation and pathology of multiple organs in the pediatric population in the weeks following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We characterized the SARS-CoV-2 antigen-specific cytokine and chemokine responses in children with MIS-C, coronavirus disease 2019 (COVID-19), and other infectious diseases. MIS-C is characterized by elevated levels of type 1 (interferon-, interleukin IL 2), type 2 (IL-4, IL-13), type 17 (IL-17), and other pro-inflammatory cytokines (IL-1, IL-6, IL-12p70, IL-18, and granulocyte-macrophage colony-stimulating factor) in comparison to COVID-19 and other infectious diseases following stimulation with SARS-CoV-2-specific antigens. Similarly, upon SARS-CoV-2 antigen stimulation, CCL2, CCL3, and CXCL10 chemokines were significantly elevated in children with MIS-C in comparison to the other 2 groups. Principal component analysis based on these cytokines and chemokines could clearly distinguish MIS-C from both COVID-19 and other infections. In addition, these responses were significantly diminished and normalized 6-9 months after recovery. Our data suggest that MIS-C is characterized by an enhanced production of cytokines and chemokines that may be associated with disease pathogenesis.
C. SEROPREVALENCE OF STRONGYLOIDES STERCORALIS INFECTION IN A SOUTH INDIAN ADULT POPULATION
The prevalence of Strongyloides stercoralis infection is estimated to be 30-100 million worldwide, although this an underestimate. Most cases remain undiagnosed due to the asymptomatic nature of the infection. We wanted to estimate the seroprevalence of S. stercoralis infection in a South Indian adult population. To this end, we performed community-based screening of 2351 individuals (aged 18-65) in Kanchipuram District of Tamil Nadu between 2013 and 2020. Serological testing for S. stercoralis was performed using the NIE ELISA.
Our data shows a seroprevalence of 33% (768/2351) for S. stercoralis infection which had a higher prevalence among males 36% (386/1069) than among females 29.8% (382/1282). Adults aged 55 (aOR = 1.65, 95% CI: 1.25-2.18) showed higher adjusted odds of association compared with other age groups. Eosinophil levels (39%) (aOR = 1.43, 95% CI: 1.19-1.74) and hemoglobin levels (24%) (aOR = 1.25, 95% CI: 1.11-1.53) were significantly associated with S. stercoralis infection. In contrast, low BMI (aOR = 1.15, 95% CI: 0.82-1.61) or the presence of diabetes mellitus (OR = 1.18, 95% CI: 0.83-1.69) was not associated with S. stercoralis seropositivity. Our study provides evidence for a very high baseline prevalence of S. stercoralis infection in South Indian communities and this information could provide realistic and concrete planning of control measures.
D. COVAXIN INDUCED ANTIBODY RESPONSES
Covaxin/BBV152 is one of the most widely used vaccines against SARS-CoV-2 infection and one of the few vaccines used extensively in low- and middle-income countries (LMIC). We investigated the effect of Covaxin on the SARS-CoV-2 specific IgG and IgA and neutralizing antibody (NAb) levels at baseline (M0) and at months 1 (M1), 2 (M2), 3 (M3), 4 (M4), 6 (M6) and 12 (M12) following vaccination in health care workers. In addition, we also examined the NAb levels against variant lineages of B.1.617.2 (Delta, India), B.1.617.2.1 (Delta Plus, India), B.1.351 (Beta, SA), B.1.1.7 (Alpha, UK) and B.1.1.529 (Omicron).Results: Covaxin induces enhanced SARS-CoV-2 binding antibodies of IgG and IgA responses against both spike (S) and nucleocapsid (N) antigens at M1, M2, M3, M4, M6 and M12 in comparison to M0. Our data also reveal that NAb levels against the ancestral strain (Wuhan, Wild type) are elevated and sustained at M1, M2, M3, M4, M6 and M12 in comparison to M0 and against variant lineages of B.1.617.2, B.1.617.2.1, B.1.351, B.1.1.7 are elevated at M3, M6 and M12 in comparison to M0. However, NAb levels against B.1.1.529 (Omicron) was consistently below the limit of detection except at M12. Thus, Covaxin induces an enhanced humoral immune response, with persistence till at least 12 months post-vaccination against most SARS-CoV-2 variants.
E. BCG VACCINATION INDUCES ENHANCED FREQUENCIES OF MEMORY T CELLS AND ALTERED PLASMA LEVELS OF COMMON CYTOKINES IN ELDERLY INDIVIDUALS
BCG vaccination is known to induce innate immune memory, which confers protection against heterologous infections. However, the effect of BCG vaccination on the conventional adaptive immune cells subsets is not well characterized. We investigated the impact of BCG vaccination on the frequencies of T cell subsets and common gamma c (c) cytokines in a group of healthy elderly individuals (age 60-80 years) at one month post vaccination. Our results demonstrate that BCG vaccination induced enhanced frequencies of central and effector memory CD4+ T cells and diminished frequencies of nave, transitional memory, stem cell memory CD4+ T cells and regulatory T cells. In addition, BCG vaccination induced enhanced frequencies of central, effector and terminal effector memory CD8+ T cells and diminished frequencies of nave, transitional memory and stem cell memory CD8+T cells. BCG vaccination also induced enhanced plasma levels of IL-7 and IL-15 but diminished levels of IL-2 and IL-21. Thus, BCG vaccination was associated with enhanced memory T cell subsets as well as memory enhancing c cytokines in elderly individuals, suggesting its ability to to induce non-specific adaptive immune responses.
Terms: <0-11 years old><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV vaccine><2019-nCoV variant><2019-nCoV variant forms><2019-nCoV variant strains><21+ years old><7S Gamma Globulin><AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Active Follow-up><Address><Adult><Adult Human><Adult-Onset Diabetes Mellitus><Age><Ancylostomatidae><Antibodies><Antibody Response><Antigens><Antitubercular Agents><Area><B cell differentiation factor><B cell growth factor><B cell stimulating factor 2><B-Cell Differentiation Factor><B-Cell Differentiation Factor-1><B-Cell Differentiation Factor-2><B-Cell Growth Factor-1><B-Cell Growth Factor-I><B-Cell Proliferating Factor><B-Cell Stimulating Factor><B-Cell Stimulating Factor-1><B-Cell Stimulation Factor-1><B-Cell Stimulatory Factor-1><B-Cell Stimulatory Factor-2><B.1.1.7><B.1.351><B.1.617.2><BCDF><BCDF-1><BCGF><BCGF-1><BCSF 1><BMI><BMI percentile><BMI z-score><BSF-1><BSF-2><BSF1><BSF2><Binding><Binetrakin><Biological Markers><Blood Eosinophil><Blood Plasma><Body mass index><CCL2><CCL2 gene><CCL3><CCL3 gene><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><COVID-19><COVID-19 antigen><COVID-19 infection><COVID-19 vaccination><COVID-19 vaccine><COVID-19 variant><COVID-19 variant forms><COVID-19 variant strains><COVID-19 virus><COVID19><COVID19 infection><COVID19 vaccination><COVID19 vaccine><COVID19 virus><CRG-2><CTLA-8><CTLA8><CV-19><CV19><CXCL10><CXCL10 gene><Cell Body><Cells><Characteristics><Chemokine (C-C motif) Ligand 3><Chemokine, CC Motif, Ligand 2><Chemotactic Cytokines><Child><Child Youth><Childhood><Children (0-21)><Clinical><Co-Stimulator><CoV-2><CoV2><Collaborations><Communicable Diseases><Communities><Costimulator><Country><Cytotoxic T-Lymphocyte-Associated Antigen 8><Cytotoxic T-Lymphocyte-Associated Serine Esterase 8><Data><Delta variant><Dengue><Developing Countries><Developing Nations><Diabetes Mellitus><Disease><Disorder><ELISA><Elderly><Emerging Communicable Diseases><Emerging Infectious Diseases><Endemic Diseases><Enrollment><Enzyme-Linked Immunosorbent Assay><Eosinophilic Granulocyte><Eosinophilic Leukocyte><Epidemiology><Epidermal Thymocyte Activating Factor><Event><Family><Female><Filariasis><Filarioidea Infections><Fostering><Frequencies><Future><G0S19-1><GM-CSF><Gender><Goals><Granulocyte-Macrophage Colony-Stimulating Factor><HIV><HIV Seronegativities><HIV Seronegativity><HIV negative><HPGF><HTLV-III Seronegativities><HTLV-III Seronegativity><Health><Health Care Providers><Health Personnel><Healthcare><Healthcare Providers><Healthcare worker><Helminths><Hemoglobin concentration result><Hepatocyte-Stimulating Factor><High Prevalence><Histamine-Producing Cell-Stimulating Factor><Homologous Chemotactic Cytokines><Hookworms><Hospitals><Human Immunodeficiency Viruses><Hybridoma Growth 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2><Interleukin 2 Precursor><Interleukin 7 Precursor><Interleukin 7 Precursor Gene><Interleukin I><Interleukin II><Interleukin-1><Interleukin-1 Gamma><Interleukin-13><Interleukin-15><Interleukin-15 Precursor><Interleukin-17><Interleukin-18><Interleukin-18 Precursor><Interleukin-2><Interleukin-4><Interleukin-4 Precursor><Interleukin-6><Interleukin-7><Interleukin-7 Gene><Interleukine 2><Interleukine 2 Precursor><Interleukine II><Interleukins><International><Ketosis-Resistant Diabetes Mellitus><LAV-HTLV-III><LD78ALPHA><LMIC><LPS-binding protein><Less-Developed Countries><Less-Developed Nations><Lipopolysaccharides><Lung><Lung Respiratory System><Lung TB><Lung Tuberculosis><Lymphadenopathy-Associated Virus><Lymphocyte Mitogenic Factor><Lymphocyte Stimulatory Factor 1><Lymphocyte-Stimulating Hormone><Lymphopoietin-1><M tuberculosis infection><M. tb infection><M. tuberculosis infection><M.tb infection><M.tuberculosis infection><MCAF><MCGF-2><MCP-1><MCP1><MGC12320><MGC9721><MGI-2><MIP 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Dependent Diabetes Mellitus><Nucleocapsid><Nutritional Deficiency><Obesity><Organ><Outcome><Paludism><Parasitic Worms><Participant><Pathogenesis><Pathology><Patient Recruitments><Physicians><Plasma><Plasma Enhancement><Plasma Serum><Plasmacytoma Growth Factor><Plasmodium Infections><Population><Prevalence><Principal Component Analyses><Principal Component Analysis><Production><Progenitor Cells><Prognostic Marker><Pulmonary TB><Pulmonary Tuberculosis><Quetelet index><ROC Analyses><ROC Curve><Recovery><Recurrence><Recurrent><Regulatory T-Lymphocyte><Research><Research Institute><Reticuloendothelial System, Serum, Plasma><Risk><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 B.1.1.7><SARS-CoV-2 B.1.351><SARS-CoV-2 B.1.617.2><SARS-CoV-2 alpha><SARS-CoV-2 antigen><SARS-CoV-2 beta><SARS-CoV-2 delta><SARS-CoV-2 infection><SARS-CoV-2 pathogenesis><SARS-CoV-2 vaccination><SARS-CoV-2 vaccine><SARS-CoV-2 variant><SARS-CoV-2 variant forms><SARS-CoV-2 variant 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infection><Severe acute respiratory syndrome coronavirus 2 vaccination><Severe acute respiratory syndrome coronavirus 2 vaccine><Severe acute respiratory syndrome related corona virus 2><Site><Slow-Onset Diabetes Mellitus><Small Inducible Cytokine A2><Small Inducible Cytokine A3><South Africa strain><South Africa variant><South African strain><South African variant><Sputum><Stable Diabetes Mellitus><Stem Cell Inhibitor><Strongyloides stercoralis><Strongyloidiasis><T Helper Factor><T cell growth factor><T memory cell><T-Cell Growth Factor><T-Cell Growth Factor 2><T-Cell Stimulating Factor><T-Cell Subsets><T-Lymphocyte Subsets><T2 DM><T2D><T2DM><T8 Cells><T8 Lymphocytes><TB immunity><TB infection><TB therapy><TB treatment><TC-GM-CSF><Thesaurismosis><Third-World Countries><Third-World Nations><Thymocyte Stimulating Factor><Training><Treg><Tuberculosis><Tuberculostatic Agents><Tumor-Cell Human GM Colony-Stimulating Factor><Type 2 Diabetes Mellitus><Type 2 diabetes><Type II Diabetes Mellitus><Type II diabetes><U.K. variant><UK strain><UK variant><Under-Developed Countries><Under-Developed Nations><Undernutrition><United Kingdom variant><Vaccination><Vaccines><Variant><Variation><Viral Diseases><Virus><Virus Diseases><Virus-HIV><Work><Wuhan coronavirus><active followup><adaptive immune response><adiposity><adult onset diabetes><adulthood><advanced age><age group><aged><ages><anamnestic reaction><anti-TB><anti-tuberculosis><antiTB><antituberculosis><base><bio-markers><biologic marker><biomarker><biomarker discovery><burden of disease><burden of illness><chemoattractant cytokine><chemokine><clinical research site><clinical site><co-infection><co-morbid><co-morbidity><cohort><coinfection><comorbidity><corona virus disease 2019><corona virus disease 2019 vaccine><coronavirus disease 2019><coronavirus disease 2019 antigen><coronavirus disease 2019 infection><coronavirus disease 2019 vaccination><coronavirus disease 2019 vaccine><coronavirus disease 2019 variant><coronavirus disease 2019 variant forms><coronavirus disease 2019 variant strains><coronavirus disease 2019 virus><coronavirus disease-19><coronavirus disease-19 vaccine><coronavirus disease-19 virus><coronavirus infectious disease-19><corpulence><cytokine><detection limit><developing country><developing nation><diabetes><dietary deficiency><disease burden><disseminated TB><disseminated tuberculosis><drug-sensitive><elders><enroll><enzyme linked immunoassay><eosinophil><epidemiologic><epidemiological><follow up><follow-up><followed up><followup><gIP-10><geriatric><granulocyte macrophage colony stimulating factor><hCoV19><health care><health care personnel><health care worker><health provider><health workforce><healthcare personnel><helminth infection><helminthic infection><hemoglobin level><host response><immune modulation><immune regulation><immune system response><immunity in tuberculosis><immunity to TB><immunity to tuberculosis><immunogen><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><infected with COVID-19><infected with COVID19><infected with SARS-CoV-2><infected with SARS-CoV2><infected with coronavirus disease 2019><infected with helminth><infected with severe acute respiratory syndrome coronavirus 2><infection due to Mycobacterium tuberculosis><interferon beta 2><international center><intestinal fatty acid binding protein><ketosis resistant diabetes><late life><later life><lipopolysaccharide-binding protein><low and middle-income countries><lymphocyte activating factor><male><malnourished><maturity onset diabetes><medical personnel><memory CD4 T cell><memory CD4 T lymphocyte><memory T lymphocyte><metabolism disorder><microbial><multisystem inflammatory syndrome of children><nCoV2><neutralizing antibody><nutrition deficiency><nutrition deficiency disorder><nutritional deficiency disorder><older adult><older person><participant recruitment><pediatric><pediatric inflammatory multisystem syndrome><predictive tools><prognostic biomarker><prognostic tool><programs><pulmonary><receiver operating characteristic analyses><receiver operating characteristic curve><regulatory T-cells><response><screening><secondary immune response><senior citizen><serology assay><seropositive><severe acute respiratory syndrome coronavirus 2 B.1.1.7><severe acute respiratory syndrome coronavirus 2 B.1.351><severe acute respiratory syndrome coronavirus 2 B.1.617.2><severe acute respiratory syndrome coronavirus 2 antigen><severe acute respiratory syndrome coronavirus 2 pathogenesis><severe acute respiratory syndrome coronavirus 2 variant><severe acute respiratory syndrome coronavirus 2 variant forms><severe acute respiratory syndrome coronavirus 2 variant strains><stem cells><treatment provider><tuberculosis immunity><tuberculosis infection><tuberculosis therapy><tuberculosis treatment><tuberculous spondyloarthropathy><type 2 DM><type II DM><type two diabetes><vaccinate against COVID-19><vaccinate against COVID19><vaccinate against SARS-CoV-2><vaccinate against coronavirus disease 2019><vaccinate against severe acute respiratory syndrome coronavirus 2><vaccination against COVID-19><vaccination against COVID19><vaccination against SARS-CoV-2><vaccination against Severe acute respiratory syndrome coronavirus 2><vaccination against coronavirus disease 2019><vaccine against 2019-nCov><vaccine against SARS-CoV-2><vaccine against SARS-CoV2><vaccine against SARS-coronavirus-2><vaccine against Severe Acute Respiratory Syndrome CoV 2><vaccine against Severe acute respiratory syndrome coronavirus 2><vaccine for novel coronavirus><viral infection><virus infection><virus-induced disease><welfare><work group><working group><years of life lost to disability><years of life lost to disease><youngster>