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Principal Investigator: Thomas Nutman
Organization: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
Fiscal Year: 2021
Award: $963,448
Funding agency: National Institute of Allergy and Infectious Diseases
A. Association of plasma matrix metalloproteinase and tissue inhibitors of matrix metalloproteinase levels with adverse treatment outcomes in patients with pulmonary tuberculosis
Identifying biomarkers of treatment response is an urgent need in the field of tuberculosis (TB). Matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) are potential diagnostic biomarkers in pulmonary tuberculosis (PTB). Our objective was to determine whether baseline plasma levels of MMPs and TIMPs are also prognostic biomarkers for adverse treatment outcomes in PTB. We followed two different cohorts (test and validation) of PTB individuals in Chennai, India for treatment outcomes and performed a nested case control study by matching the cases to controls in a 1:2 ratio for age, sex and body mass index. Two different sets of primary care centers in Chennai were used to recruit participants. Participants were newly diagnosed, sputum smear and culture positive individuals with drug-sensitive TB. We had 68 cases and 133 controls in the test cohort and 20 cases and 40 controls in the validation cohort. PTB individuals were treated with anti-tuberculosis chemotherapy (ATT) for six months and followed up for a year following the end of treatment. PTB individuals with adverse outcomes (treatment failure, all-cause mortality or recurrent TB) were defined as cases and those with favorable outcomes (recurrence free cure) were defined as controls. Plasma levels of MMPs and TIMPs before treatment were measured as potential biomarkers. We enrolled n=68 cases with matched n=133 controls which includes n=170 males and n=31 females in the test cohort and n=20 cases with matched n=40 controls which includes n=51 males and n=9 females in the validation cohort. Baseline plasma levels of five MMPs like MMP-1, MMP-2, MMP-7, MMP-8 and MMP-9 and two TIMP-1 and TIMP-2 in the test cohort and five MMPs like MMP-1, MMP-2, MMP-7, MMP-9 and MMP-13 and all four TIMPs TIMP-1, TIMP-2, TIMP-3 and TIMP-4 in the validation cohort were significantly higher in cases compared to controls. Plasma levels of MMPs and TIMPs were associated with increased risk of adverse outcomes in both univariate and multivariable analysis in the test cohort. Combined ROC analysis revealed significant AUC with high sensitivity and specificity in both cohorts. Baseline plasma MMP and TIMP levels are correlates of risk and prognostic biomarkers for treatment failure, relapse and death in PTB individuals, that merit further evaluation as predictive biomarkers for stratification to shortened or intensified treatment regimens.
B. Diminished circulating levels of angiogenic factors and RAGE ligands in helminth-diabetes comorbidity and reversal following anthelmintic treatment
Various epidemiological and experimental studies propose that helminths could play a preventive role against the progression of Type 2 diabetes mellitus (T2DM). T2DM induces microvascular and large vessel complications mediated by elevated levels of angiogenic factors and soluble RAGE ligands. However, the interactions between helminths and host angiogenic factors and RAGE ligands are unexplored. To assess the relationship between a soil-transmitted helminth, Strongyloides stercoralis (Ss) and T2DM, we measured plasma levels of VEGF-A, C, D, Angio-1 and Angio-2 and their receptors VEGF-R1, R2 and R3 as well as sRAGE and their ligands AGE, S100A12 and HMBG-1 in individuals with T2DM with Ss+ or without Ss infection (Ss-). In Ss+ individuals, we also measured the levels of aforementioned factors 6 months following anthelmintic therapy. Ss+ individuals exhibited significantly decreased levels of VEGF-A, C, D, Angio-1 and Angio-2 and their soluble receptors VEGF-R1, R2 and R3, that increased following anthelmintic therapy. Likewise, Ss+ individuals exhibited significantly decreased levels of AGE and their ligands sRAGE, S100A12 and HMBG-1 which reversed following anthelmintic therapy. Our data suggest that Ss infection could play a beneficial role by limiting or delaying the T2DM related vascular complications.
C. Plasma biomarker profiling of PIMS-TS, COVID-19 and SARS-CoV2 seropositive children a cross-sectional observational study from southern India
SARS-CoV-2 infection in children can present with varied clinical phenotypes and understanding the pathogenesis is essential, to inform about the clinical trajectory and management. We performed a multiplex immune assay analysis and compared the plasma biomarkers of Paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 infection (PIMS-TS), acute COVID-19 infection (COVID-19), SARS-CoV-2 seropositive and control children admitted to a tertiary care childrens hospital in Chennai, India. Pro-inflammatory cytokines, chemokines and growth factors were correlated with SARS-CoV-2 clinical phenotypes. PIMS-TS children had significantly elevated levels of cytokines, IFN, IL-2, TNF, IL-1, IFN, IFN, IL-6, IL-15, IL-17A, GM-CSF, IL-10, IL-33 and IL-Ra; elevated chemokines, CCL2, CCL19, CCL20 and CXCL10 and elevated VEGF, Granzyme B and PDL-1 in comparison to COVID-19, seropositive and controls. COVID-19 children had elevated levels of IFN, IL-2, TNF, IL-1, IFN, IFN, IL-6, IL-17A, IL-10, CCL2, CCL5, CCL11, CXCL10 and VEGF in comparison to seropositive and/or controls. Similarly, seropositive children had elevated levels of IFN, IL-2, IL-1, IFN, IL-17A, IL-10, CCL5 and CXCL10 in comparison to control children. Plasma biomarkers in PIMS-TS and COVID-19 children showed a positive correlation with CRP and a negative correlation with the lymphocyte count and sodium levels. We describe a comprehensive plasma biomarker profile of children with different clinical spectrum of SARS-CoV-2 infection from a low- and middle-income country (LMIC) and observed that PIMS-TS is a distinct and unique immunopathogenic paediatric illness related to SARS-CoV-2 presenting with cytokine storm different from acute COVID-19 infection and other hyperinflammatory conditions.
D. Helminth coinfection associated with enhanced plasma levels of matrix metalloproteinases and tissue inhibitor of metalloproteinases in tuberculous lymphadenitis
Matrix metalloproteinases (MMPs) are crucial for tissue remodelling and repair and are expressed in diverse infections, whereas tissue-inhibitors of metalloproteinases (TIMPs) are endogenous inhibitors of MMPs. However, the interaction of MMPs and TIMPs in tuberculous lymphadenitis (TBL) an extra-pulmonary form of tuberculosis (EPTB) and helminth (Hel+) coinfection is not known. Therefore, this present study investigates the levels of circulating MMPs (1, 2, 3, 7, 8, 9, 12, 13) and TIMPs (1, 2, 3, 4) in TBL individuals with helminth (Strongyloides stercoralis Ss, hereafter Hel+) coinfection and without helminth coinfection (hereafter, Hel-). In addition, we have also carried out the regression analysis and calculated the MMP/TIMP ratios between the two study groups. We describe that the circulating levels of MMPs (except MMP-8 and MMP-12) were elevated in TBL-Hel+ coinfected individuals compared to TBL-Hel- individuals. Similarly, the systemic levels of TIMPs (1, 2, 3, 4) were increased in TBL-Hel+ compared to TBL-Hel- groups indicating that it is feature of helminth coinfection per se. Finally, our multivariate analysis data also revealed the changes in MMPs and TIMPs were independent of age, sex and culture status between TBL-Hel+ and TBL-Hel- individuals. We show MMP-2 ratio with all TIMPs were significantly associated with TBL-helminth coinfection. Thus, our results describe that helminth infection has a profound effect on the pathogenesis of TBL and both MMPs and TIMPs could dampen the immunity against the TBL-Hel+ coinfected individuals.
Terms: <(TNF)-α><0-11 years old><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><21+ years old><72-kDa Gelatinase><72-kDa Type IV Collagenase><72kD type IV Collagenase><92-kDa Gelatinase><92-kDa Type IV Collagenase><AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Active Follow-up><Acute><Address><Adult><Adult Human><Adult-Onset Diabetes Mellitus><Age><Angiogenesis Factor><Angiogenic Factor><Anthelmintics><Antihelminthic Agent><Antihelminthic Drugs><Antitubercular Agents><Area><B cell differentiation factor><B cell stimulating factor 2><B-Cell Differentiation Factor><B-Cell Differentiation Factor-2><B-Cell Stimulatory Factor-2><B7-H1><B7H1><BCDF><BMI><BMI percentile><BMI z-score><BSF-2><BSF2><Biological Markers><Blood Plasma><Blood Vessels><Body Tissues><Body mass index><CAAF1><CCL11><CCL11 gene><CCL19><CCL19 gene><CCL2><CCL2 gene><CCL20><CCL20 gene><CCL5><CD274><CKb11><COVID-19 infection><COVID-19 virus><COVID19 infection><COVID19 virus><CRG-2><CSIF><CSIF-10><CTLA-8><CTLA8><CXCL10><CXCL10 gene><Cachectin><Calcium-Binding Protein In Amniotic Fluid 1><Calcium-Binding Protein in Amniotic Fluid><Calgranulin C><Calgranulin-Related Protein><Cessation of life><Chemokine (C-C Motif) Ligand 5><Chemokine, CC Motif, Ligand 2><Chemokine, CC Motif, Ligand 20><Chemotactic Cytokines><Child><Child Youth><Childhood><Children (0-21)><Children's Hospital><Clinical><Co-Stimulator><CoV-2><CoV2><Communicable Diseases><Costimulator><Country><Cytokine Synthesis Inhibitory Factor><Cytotoxic T-Lymphocyte-Associated Antigen 8><Cytotoxic T-Lymphocyte-Associated Serine Esterase 8><D17S136E><Data><Data Analyses><Data Analysis><Death><Developing Countries><Developing Nations><Diabetes Mellitus><ENRAGE gene><ENRAGE protein><Emerging Communicable Diseases><Emerging Infectious Diseases><Endemic Diseases><Enrollment><Epidemiologic Research><Epidemiologic Studies><Epidemiological Studies><Epidemiology Research><Epidermal Thymocyte Activating Factor><Evaluation><Exhibits><Exodus 1><Extracellular Newly Identified RAGE-Binding Protein><FLK1><Female><Fostering><Future><GM-CSF><Gelatinase A><Gelatinase B><Gelatinase Neutrophil><Goals><Granulocyte-Macrophage Colony-Stimulating Factor><Granzyme><Growth Agents><Growth Factor><Growth Substances><HIV><HPGF><Helminths><Hepatocyte-Stimulating Factor><Histamine-Producing Cell-Stimulating Factor><Homologous Chemotactic Cytokines><Human Immunodeficiency Viruses><Hybridoma Growth Factor><IFI10><IFN><IFN-beta 2><IFNB2><IL-1><IL-10><IL-15><IL-17><IL-17A><IL-2><IL-6><IL1><IL10><IL10A><IL15><IL15 Protein><IL17 Protein><IL17A><IL2 Protein><IL6 Protein><INP10><IP-10><Immunity><Immunology procedure><India><Individual><Infection><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Inflammatory><Institution><Intercrines><Interferons><Interleukin 10 Precursor><Interleukin 17 (Cytotoxic T-Lymphocyte-Associated Serine Esterase 8)><Interleukin 17 Precursor><Interleukin 2><Interleukin 2 Precursor><Interleukin I><Interleukin II><Interleukin-1><Interleukin-10><Interleukin-15><Interleukin-15 Precursor><Interleukin-17><Interleukin-2><Interleukin-6><Interleukine 2><Interleukine 2 Precursor><Interleukine II><Interstitial Collagenase><KDR gene><Ketosis-Resistant Diabetes Mellitus><LARC><LAV-HTLV-III><LMIC><Less-Developed Countries><Less-Developed Nations><Ligands><Lung><Lung Respiratory System><Lung TB><Lung Tuberculosis><Lymph Node Tuberculosis><Lymphadenopathy-Associated Virus><Lymphocyte Count><Lymphocyte Mitogenic Factor><Lymphocyte Number><Lymphocyte-Stimulating Hormone><M tuberculosis infection><M. tb infection><M. tuberculosis infection><M.tb infection><M.tuberculosis infection><MCAF><MCP-1><MCP1><MGC17164><MGC22554><MGC34433><MGC9721><MGI-2><MIP-3b><MIP3A><MIP3B><MIS-C><MME gene><MMP Inhibitor><MMP-1><MMP-13><MMP-13 gene product><MMP-1Fibroblast Collagenase><MMP-2><MMP-3><MMP-7><MMP-8><MMP-9><MMP-9 Protein><MMP1><MMP12><MMP13 gene product><MMPs><MOB-1><MTB infection><Macrophage Cell Factor><Macrophage Gelatinase><Macrophage Inflammatory Protein 3-Alpha><Macrophage-Derived TNF><Malaria><Mali><Matrilysin><Matrin><Matrix Metalloproteinase 3><Matrix Metalloproteinase Inhibitor><Matrix Metalloproteinase-1><Matrix Metalloproteinase-2><Matrix Metalloproteinase-7><Matrix Metalloproteinase-8><Matrix Metalloproteinase-9><Matrix Metalloproteinases><Maturity-Onset Diabetes Mellitus><Measures><Mediating><Medical Research><Mitogenic Factor><Molecular Marker of Prognosis><Molgramostin><Monocyte Chemoattractant Protein-1><Monocyte Chemotactic Protein-1><Monocyte Chemotactic and Activating Factor><Monocyte Chemotactic and Activating Protein><Monocyte Chemotactive and Activating Factor><Monocyte Secretory Protein JE><Monocyte-Derived TNF><Multiorgan Inflammatory Syndrome in Children><Multisystem Inflammatory Syndrome in Children><Multivariate Analyses><Multivariate Analysis><Mycobacterium tuberculosis (MTB) infection><Mycobacterium tuberculosis infection><Myeloid Differentiation-Inducing Protein><NIDDM><Na element><Nested Case-Control Study><Neutrophil Collagenase><Newly Diagnosed><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Observation research><Observation study><Observational Study><Observational research><Outcome><PD-L1><PDL-1><PDL1><PMNL Collagenase><PUMP-1><Paludism><Parasitic Worms><Participant><Pathogenesis><Patient Recruitments><Patients><Pediatric Hospitals><Physicians><Plasma><Plasma Enhancement><Plasma Serum><Plasmacytoma Growth Factor><Plasmodium Infections><Play><Preventive><Primary Care><Primary Health Care><Primary Healthcare><Prognosis Marker><Prognostic Marker><Programmed Cell Death 1 Ligand 1><Programmed Death Ligand 1><Proteins Growth Factors><Pulmonary TB><Pulmonary Tuberculosis><Quetelet index><RANTES><ROC Analyses><ROC Curve><Recurrence><Recurrent><Regression Analyses><Regression Analysis><Regression Diagnostics><Relapse><Research><Research Institute><Reticuloendothelial System, Serum, Plasma><Risk><Role><S100 Calcium Binding Protein A12><S100A12><S100A12 gene><SARS corona virus 2><SARS-CoV-2><SARS-CoV-2 infection><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><SCYA11><SCYA19><SCYA2><SCYA20><SCYA5><SCYB10><SIS cytokines><SIS delta><SIS-delta><SISd><Scientist><Sensitivity and Specificity><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 corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome related corona virus 2><Site><Slow-Onset Diabetes Mellitus><Small Inducible Cytokine A2><Small Inducible Cytokine A5><Small Inducible Cytokine Subfamily A, Member 20><Sodium><Soil><Sputum><Stable Diabetes Mellitus><Statistical Regression><Stratification><Stromelysin><Stromelysin 1><Strongyloides stercoralis><T Helper Factor><T cell growth factor><T-Cell Growth Factor><T-Cell RANTES Protein><T-Cell Specific Protein p288><T-Cell Stimulating Factor><T2 DM><T2D><T2DM><TB infection><TC-GM-CSF><TCP228><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><Testing><Third-World Countries><Third-World Nations><Thymocyte Stimulating Factor><Tissue Inhibitor of Metalloproteinases><Tissues><Total Lymphocyte Count><Training><Transin-1><Treatment Failure><Treatment Protocols><Treatment Regimen><Treatment Schedule><Treatment outcome><Tuberculosis><Tuberculostatic Agents><Tuberculous Lymphadenitis><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Tumor-Cell Human GM Colony-Stimulating Factor><Type 2 Diabetes Mellitus><Type 2 diabetes><Type II Diabetes Mellitus><Type II diabetes><Type V Collagenase><Uganda><Under-Developed Countries><Under-Developed Nations><VEGF><VEGF Receptors><VEGFR><VEGFR-2><VEGFR2><VEGFs><VPF Receptor><Validation><Vascular Endothelial Cell Growth Factor Receptor><Vascular Endothelial Growth Factor Receptor 2><Vascular Endothelial Growth Factors><Vascular Permeability Factor Receptor><Vermifuges><Virus-HIV><Wuhan coronavirus><active followup><adult onset diabetes><adulthood><adverse consequence><adverse outcome><ages><anti-tuberculosis><antihelminthic><antituberculosis><bio-markers><biologic marker><biomarker><burden of disease><burden of illness><chemoattractant cytokine><chemokine><clinical phenotype><co-infection><co-morbid><co-morbidity><cohort><coinfection><collagenase 3><collagenase activating protein><comorbidity><coronavirus disease 2019 infection><coronavirus disease 2019 virus><cytokine><cytokine release syndrome><cytokine storm><data interpretation><developing country><developing nation><diabetes><diagnostic biomarker><diagnostic marker><disease burden><disseminated TB><disseminated tuberculosis><drug-sensitive><enroll><epidemiologic investigation><epidemiology study><experiment><experimental research><experimental study><follow up><follow-up><followed up><followup><gIP-10><granulocyte macrophage colony stimulating factor><hCoV19><helminth infection><helminthic infection><immunologic assay><immunologic assay/test><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><ketosis resistant diabetes><low and middle-income countries><lymphocyte activating factor><macrophage metalloelastase><macrophage-specific metalloelastase><male><matrix metalloproteinase 12><matrix metalloproteinase-13><maturity onset diabetes><mortality><nCoV2><participant recruitment><pediatric><pediatric inflammatory multisystem syndrome><potential biological marker><potential biomarker><predictive biomarkers><predictive marker><predictive molecular biomarker><procollagenase activator><prognostic biomarker><prognostic indicator><programmed cell death ligand 1><programmed cell death protein ligand 1><programs><proteoglycanase><pulmonary><receiver operating characteristic analyses><receiver operating characteristic curve><repair><repaired><response to treatment><sRAGE><seropositive><sex><social role><soluble RAGE><tertiary care><therapeutic response><therapy failure><treatment response><tuberculosis chemotherapy><tuberculosis infection><tuberculous spondyloarthropathy><type 2 DM><type II DM><type two diabetes><vascular><years of life lost to disability><years of life lost to disease><youngster>