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Principal Investigator: Thomas Nutman
Organization: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
Fiscal Year: 2023
Award: $1,250,220
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. Chitinase and indoleamine 2, 3-dioxygenase are prognostic biomarkers for unfavorable treatment outcomes in pulmonary tuberculosis
Chitinase, Indoleamine 2,3-dioxygenesae-1 (IDO-1) and heme oxygenase-1 (HO-1) are candidate diagnostic biomarkers for tuberculosis (TB). Whether these immune markers could also serve as predictive biomarkers of unfavorable treatment outcomes in pulmonary TB (PTB) is not known. A cohort of newly diagnosed, sputum culture-positive adults with drug-sensitive PTB were recruited. Plasma chitinase protein, IDO protein and HO-1 levels measured before treatment initiation were compared between 68 cases with unfavorable outcomes (treatment failure, death, or recurrence) and 108 control individuals who had recurrence-free cure. Plasma chitinase and IDO protein levels but not HO-1 levels were lower in cases compared to controls. The low chitinase and IDO protein levels were associated with increased risk of unfavorable outcomes in unadjusted and adjusted analyses. Receiver operating characteristic analysis revealed that chitinase and IDO proteins exhibited high sensitivity and specificity in differentiating cases vs controls as well as in differentiating treatment failure vs controls and recurrence vs controls, respectively. Classification and regression trees (CART) were used to determine threshold values for these two immune markers. Our study revealed a plasma chitinase and IDO protein signature that may be used as a tool for predicting adverse treatment outcomes in PTB.
B. Unique cellular immune signatures of multisystem inflammatory syndrome in children
The clinical presentation of MIS-C overlaps with other infectious/non-infectious diseases such as acute COVID-19, Kawasaki disease, acute dengue, enteric fever, and systemic lupus erythematosus. We examined the ex-vivo cellular parameters with the aim of distinguishing MIS-C from other syndromes with overlapping clinical presentations. MIS-C children differed from children with non-MIS-C conditions by having increased numbers of nave CD8+ T cells, nave, immature and atypical memory B cells and diminished numbers of transitional memory, stem cell memory, central and effector memory CD4+ and CD8+ T cells, classical, activated memory B and plasma cells and monocyte (intermediate and non-classical) and dendritic cell (plasmacytoid and myeloid) subsets. All of the above alterations were significantly reversed at 6-9 months post-recovery in MIS-C. Thus, MIS-C is characterized by a distinct cellular signature that distinguishes it from other syndromes with overlapping clinical presentations.
C. BCG vaccination induces enhanced humoral responses in elderly individuals
Studies have reported the beneficial effects of Bacillus Calmette Guerin (BCG) vaccination, including non-specific cross-protection against other infectious diseases. We investigated the impact of BCG vaccination on the frequencies of B cell subsets as well as total antibody levels in healthy elderly individuals at one month post vaccination. We also compared the above-mentioned parameters in post-vaccinated individuals to unvaccinated controls. Our results demonstrate that BCG vaccination induced enhanced frequencies of immature, classical and activated memory B cells and plasma cells and diminished frequencies of nave and atypical memory B cells. BCG vaccination induced significantly increased levels of total IgG subclass isotypes compared to baseline. Similarly, all of the above parameters were significantly higher in vaccinated individuals compared to unvaccinated controls. BCG vaccination was associated with enhanced B cell subsets, suggesting its potential utility by enhancing heterologous immunity.
D. Role of matrix metalloproteinases in multi-system inflammatory syndrome and acute COVID-19 in children
Multisystem Inflammatory Syndrome in children (MIS-C) is a serious inflammatory sequela of SARS-CoV2 infection. The pathogenesis of MIS-C is vague and matrix metalloproteinases (MMPs) may have an important role. Matrix metalloproteinases (MMPs) are known drivers of lung pathology in many diseases. To elucidate the role of MMPs in pathogenesis of pediatric COVID-19, we examined their plasma levels in MIS-C and acute COVID-19 children and compared them to convalescent COVID-19 and children with other common tropical diseases (with overlapping clinical manifestations). Children with MIS-C had elevated levels of MMPs (P < 0.005 statistically significant) in comparison to acute COVID-19, other tropical diseases (Dengue fever, typhoid fever, and scrub typhus fever) and convalescent COVID-19 children. PCA and ROC analysis (sensitivity 84-100% and specificity 80-100%) showed that MMP-8, 12, 13 could help distinguish MIS-C from acute COVID-19 and other tropical diseases with high sensitivity and specificity. Among MIS-C children, elevated levels of MMPs were seen in children requiring intensive care unit admission as compared to children not needing intensive care. Similar findings were noted when children with severe/moderate COVID-19 were compared to children with mild COVID-19. Finally, MMP levels exhibited significant correlation with laboratory parameters, including lymphocyte counts, CRP, D-dimer, Ferritin and Sodium levels. Our findings suggest that MMPs play a pivotal role in the pathogenesis of MIS-C and COVID-19 in children and may help distinguish MIS-C from other conditions with overlapping clinical presentation.
E. Effect of prediabetes on tuberculosis treatment outcomes: A study from South India
The aim was to assess the effect of prediabetes on tuberculosis(TB) treatment outcomes. This is a prospective observational cohort study of 569 eligible new smear positive cases screened for DM between 2014 and 2018 in TB units in North Chennai, South India. Based on study criteria, a total of 187 subjects were included and categorised into two groups: TB with normoglycaemia (groupI) (HbA1c<5.7%) and TB with prediabetes (group II) (HbA1c = 5.7-6.4%) and followed them at 3rd and 6th month and treatment outcomes were assessed at the end of the TB treatment. Total cure rate was 72.7% with no significant difference between the groups. Higher proportion of deaths occurred in group II (6.3%) compared to group I (1.3%) (p = 0.09). At the end of intensive phase of directly observed therapy (DOTS) treatment, about 23.8% were observed to have positive sputum smear in group II compared to 8.6% in group I(p = 0.019). The estimated relative risk to remain as sputum smear positive among people with prediabetes at the end of intensive phase was 3.0(95% CI: 1.2-7.6). There was a significant association found with HbA1c at enrollment and unfavorable TB treatment outcomes ( = 1.38, odds ratio (95% CI) 3.98(1.65-9.64); p = 0.007. Death rate was high and there was a delay in sputum conversion among TB patients with prediabetes at the end of the intensive phase of TB treatment. HbA1c at the time of diagnosis of prediabetes was significantly associated with unfavorable TB treatment outcomes.
Terms: <0-11 years old><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><21+ years old><7S Gamma Globulin><AIDS Virus><Abdominal Typhus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Acute><Address><Admission><Admission activity><Adult><Adult Human><Adult-Onset Diabetes Mellitus><Ancylostomatidae><Antibodies><Area><B-Cell Subsets><B-Lymphocyte Subsets><BCG Live><BCG immunization><BCG vaccination><BCG-vaccinated><Bacille Calmette-Guerin vaccinated><Bacille Calmette-Guerin vaccination><Bacille Calmette-Guérin><Bacillus Calmette Guérin><Bacillus Calmette-Guerin vaccination><Bacillus Calmette-Guérin vaccination><Biotech><Biotechnology><Blood Plasma><Blood Plasma Cell><Blood monocyte><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><COVID-19><COVID-19 infection><COVID-19 vaccination><COVID-19 virus><COVID-19 virus infection><COVID19><COVID19 infection><COVID19 vaccination><COVID19 virus><CV-19><CV19><Categories><Cessation of life><Child><Child Youth><Childhood><Children (0-21)><Chitinase><Clinical><CoV-2><CoV2><Collaborations><Communicable Diseases><Country><Cross-Product Ratio><D-dimer><D-dimer fibrin><D-dimer fragments><Death><Death Rate><Dendritic Cells><Dengue><Dengue Fever><Dengue disease><Developing Countries><Developing Nations><Diabetes Mellitus><Diagnosis><Directly Observed Therapy><Disease><Disorder><Elderly><Eligibility><Eligibility Determination><Emerging Communicable Diseases><Emerging Infectious Diseases><Endemic Diseases><Enrollment><Enteric Fever><Epidemiology><Exhibits><Family><Ferritin><Fever><Fibrin fragment D><Filariasis><Filarioidea Infections><Fostering><Frequencies><Future><Glycohemoglobin A><Glycosylated hemoglobin A><Goals><HIV><HO-1 enzyme><HO1><HO2><HSP32><Hb A1><Hb A1a+b><Hb A1c><HbA1><HbA1c><Health><Healthcare><Helminths><Hemoglobin A(1)><Hookworms><Hospitals><Human Immunodeficiency Viruses><IDOase><IgG><Immune><Immune Markers><Immune response><Immunes><Immunity><Immunochemical Immunologic><Immunoglobulin G><Immunologic><Immunologic Markers><Immunological><Immunological response><Immunologically><Immunologics><Immunology><Immunomodulation><India><Individual><Indoleamine 2,3-Dioxygenase><Infection><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Inflammatory><Institution><Intensive Care><Intensive Care Units><International><Investigators><Kawasaki Disease><Ketosis-Resistant Diabetes Mellitus><LAV-HTLV-III><Laboratories><Less-Developed Countries><Less-Developed Nations><Link><Lung><Lung Respiratory System><Lung TB><Lung Tuberculosis><Lupus Erythematosus Disseminatus><Lymphadenopathy-Associated Virus><Lymphocyte Count><Lymphocyte Number><M tuberculosis infection><M. tb infection><M. tuberculosis infection><M.tb infection><M.tuberculosis infection><MIS-C><MMP-8><MMPs><MTB infection><Malaria><Malnutrition><Marrow monocyte><Matrix Metalloproteinase-8><Matrix Metalloproteinases><Maturity-Onset Diabetes Mellitus><Measures><Medical Research><Memory><Memory B Cell><Memory B-Lymphocyte><Metabolic Diseases><Metabolic Disorder><Mucocutaneous Lymph Node Syndrome><Multiorgan Inflammatory Syndrome in Children><Multisystem Inflammatory Syndrome in Children><Mycobacterium tuberculosis (MTB) infection><Mycobacterium tuberculosis infection><Myelogenous><Myeloid><NIAID><NIDDM><NIH><Na element><National Institute of Allergy and Infectious Disease><National Institutes of Health><Neutrophil Collagenase><Newly Diagnosed><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Nutritional Deficiency><Obesity><Odds Ratio><Outcome><PMNL Collagenase><Paludism><Parasitic Worms><Pathogenesis><Patient Recruitments><Patients><Persons><Phase><Physicians><Plasma><Plasma Cells><Plasma Serum><Plasmacytes><Plasmodium Infections><Play><Population><Postdoc><Postdoctoral Fellow><Prediabetes><Prediabetes syndrome><Prediabetic State><Progenitor Cells><Prognostic Marker><Proteins><Protocol Screening><Pulmonary Pathology><Pulmonary TB><Pulmonary Tuberculosis><Pyrexia><ROC Analyses><ROC Curve><Recovery><Recurrence><Recurrent><Relative Odds><Relative Risks><Reporting><Research><Research Associate><Research Institute><Research Personnel><Research Resources><Researchers><Resources><Reticuloendothelial System, Serum, Plasma><Risk><Risk Ratio><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 infection><SARS-CoV-2 pathogenesis><SARS-CoV-2 vaccination><SARS-CoV2><SARS-CoV2 infection><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><SLE><Scientist><Scrub Typhus><Sensitivity and Specificity><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 vaccination><Severe acute respiratory syndrome related corona virus 2><Site><Slow-Onset Diabetes Mellitus><Sodium><Specificity><Sputum><Stable Diabetes Mellitus><Strongyloidiasis><Syndrome><System><Systemic Lupus Erythematosus><Systemic Lupus Erythematous><Systemic Lupus Erythmatosus><T2 DM><T2D><T2DM><T8 Cells><T8 Lymphocytes><TB immunity><TB infection><TB therapy><TB treatment><Thesaurismosis><Third-World Countries><Third-World Nations><Time><Total Lymphocyte Count><Training><Treatment Failure><Treatment outcome><Tropical Disease><Tryptophan 2,3 Dioxygenase><Tsutsugamushi Disease><Tsutsugamushi Fever><Tuberculosis><Type 2 Diabetes Mellitus><Type 2 diabetes><Type II Diabetes Mellitus><Type II diabetes><Typhoid><Typhoid Fever><Under-Developed Countries><Under-Developed Nations><Undernutrition><United States National Institutes of Health><Vaccination><Vaccinee><Veiled Cells><Viral Diseases><Virus><Virus Diseases><Virus-HIV><Work><Wuhan coronavirus><adiposity><adult onset diabetes><adulthood><advanced age><age group><biomarker discovery><breakbone fever><burden of disease><burden of illness><classification trees><clinical research site><clinical site><co-infection><co-morbid><co-morbidity><cohort><coinfection><comorbidity><compare to control><comparison control><corona virus disease 2019><coronavirus disease 2019><coronavirus disease 2019 infection><coronavirus disease 2019 vaccination><coronavirus disease 2019 virus><coronavirus disease-19><coronavirus disease-19 virus><coronavirus infectious disease-19><corpulence><cross immunity><cross protection><cyber infrastructure><cyberinfrastructure><developing country><developing nation><diabetes><diagnostic biomarker><diagnostic marker><dietary deficiency><disease burden><disseminated TB><disseminated lupus erythematosus><disseminated tuberculosis><drug-sensitive><elders><enroll><epidemiologic><epidemiological><febrile><febris><fibrin fragment D-dimer><fibrin fragment D1 dimer><fibrin fragment DD><filarial disease><filarial infection><geriatric><hCoV19><health care><helminth infection><helminthic infection><heme oxygenase-1><hemeoxygenase 1><hemoglobin A1c><host response><immune modulation><immune regulation><immune system response><immune-based biomarkers><immunity in tuberculosis><immunity to TB><immunity to tuberculosis><immunologic reactivity control><immunological biomarkers><immunological markers><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><indoleamine><infected with COVID-19><infected 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analyses><receiver operating characteristic curve><recruit><regression trees><research associates><response><senior citizen><severe acute respiratory syndrome coronavirus 2 pathogenesis><social role><stem cells><student mentoring><student-led learning><systemic lupus erythematosis><therapy failure><tryptamine 2,3 dioxygenase><tuberculosis immunity><tuberculosis infection><tuberculosis therapy><tuberculosis treatment><tuberculous spondyloarthropathy><type 2 DM><type II DM><type two diabetes><unvaccinated><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><vaccinated individual><vaccinated participant><vaccinated patient><vaccinated person><vaccinated subject><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><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>