India International Center for Excellence in Research

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications, trials & patents

Abstract

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.