India International Center for Excellence in Research

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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.