Biology subjects

Mantri, C. K.

Publications and source records attributed to Mantri, C. K..

3 recordsLinked to original sources

bioRxiv2026

Reduced Complex III assembly dampens host inflammation as an adaptive response to viral infection

Mitochondrial electron transport and oxidative respiration are required for immunity and host tolerance. How the ETC contributes to viral infections - where a proinflammatory anti-viral response needs to be finely balanced with host-protective anti-inflammatory mechanisms - remains unclear. Here, we demonstrate that following infection by H1N1 influenza virus, murine macrophages reduce Complex III levels by downregulating the early CIII assembly factor called the COMB complex. To determine the effect of CIII suppression, we utilized Brawnin (Br or UQCC6) knockout mice, which lack COMB complexes and have reduced Complex III. Following H1N1 infection, Br KO bone marrow-derived macrophages (BMDMs) had reduced inflammation due to reduced CIII Qo site ROS. Br KO mice infected with a non-lethal dose of H1N1 had reduced lung immune pathology, viral burden and enhanced recovery following H1N1 infection. Single-cell RNAseq analysis revealed that H1N1-infected Br KO lungs had reduced abundance of hyper-inflammatory monocytes known to cause severe respiratory disease and reduced monocyte chemotaxis. Our study demonstrates that ETC Complex III suppression is part of an innate immune response to viral infection, and is a potential strategy to control host inflammation in acute respiratory viral infections.

immunology↗

bioRxiv2022

Mucosal vaccination for SARS-CoV-2 elicits superior systemic T central memory function and cross-neutralizing antibodies against variants of concern

COVID-19 vaccines used in humans are highly effective in limiting disease and death caused by the SARS-CoV-2 virus, yet improved vaccines that provide greater protection at mucosal surfaces, which could reduce break-through infections and subsequent transmission, are still needed. Here we show that intranasal (I.N.) vaccination with the receptor binding domain of Spike antigen of SARS-CoV-2 (S-RBD) in combination with the mucosal adjuvant mastoparan-7 improved systemic T cell responses compared to an equivalent dose of antigen delivered by the sub-cutaneous (S.C.) route, adjuvanted by either M7 or the gold-standard adjuvant, alum. T cell phenotypes induced by I.N. vaccine administration included enhanced polyfunctionality (combined IFN-{gamma} and TNF expression) and greater numbers of T central memory (TCM) cells. These phenotypes were T cell-intrinsic and could be recalled in the lungs and/or brachial LNs upon antigen challenge after adoptive T cell transfer to naive recipients. Furthermore, mucosal vaccination induced antibody responses that were similarly effective in neutralizing the binding of the parental strain of S-RBD to its ACE2 receptor, but showed greater cross-neutralizing capacity against multiple variants of concern (VOC), compared to S.C. vaccination. These results highlight the role of nasal vaccine administration in imprinting an immune profile associated with long-term T cell retention and diversified neutralizing antibody responses, which could be applied to improve vaccines for COVID-19 and other infectious diseases.

immunology↗

bioRxiv2019

Hyperinsulinemia promotes HMGB1 release leading to inflammation induced systemic insulin resistance: An interplay between pancreatic beta-cell and peripheral organs

Insulin resistance results from several pathophysiologic mechanisms, including chronic tissue inflammation and defective insulin signaling. Pancreatic {beta}-cells hypersecretion (hyperinsulinemia), is a central hallmark of peripheral insulin resistance. However, the underlying mechanism by which hyperinsulinemia perpetuates towards the development of insulin resistance remains unclear and is still a bigger therapeutic challenge. Here, we found hyperinsulinemia triggers inflammation and insulin resistance by stimulating TLR4-driven inflammatory cascades. We show that hyperinsulinemia activates the TLR4 signaling through HMGB1, an endogenous TLR4 ligand emanating from hyperinsulinemia exposed immune cells and peripheral organs like adipose tissue and liver. Further, our observation suggests hyperinsulinemia ensuring hyperacetylation, nuclear-to-cytoplasmic shuttling and release of HMGB1 into the extracellular space. HMGB1 was also found to be elevated in serum of T2DM patients. We found that extracellular HMGB1 plays a crucial role to promote proinflammatory responses and provokes systemic insulin resistance. Importantly, in-vitro and in-vivo treatment with naltrexone, a TLR4 antagonist led to an anti-inflammatory phenotype with protection from hyperinsulinemia mediated insulin resistance. In-vitro treatment with naltrexone directly enhanced SIRT1 activity, blocked the release of HMGB1 into extracellular milieu, suppressed release of proinflammatory cytokines and ultimately led to insulin-sensitizing effects. These observations elucidate a regulatory network between pancreatic {beta}-cells, macrophage and hepatocytes and assign an unexpected role of TLR4 - HMGB1 signaling axis in hyperinsulinemia mediated systemic insulin resistance.\n\nGraphical Abstract O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

physiology↗