Biology subjects

Pahwa, F.

Publications and source records attributed to Pahwa, F..

5 recordsLinked to original sources

bioRxiv2024

Diabetes-Tuberculosis Comorbidity Characterized by Reduced Type-II Interferon and Elevated Th17 Responses.

Understanding the perturbed lung immune cells distribution and its functionality in tuberculosis (TB) is well documented; however, limited reports have covered their disruption, if any, in diabetes-tuberculosis (DM-TB) comorbid conditions. Here, we employed single-cell RNA-seq to investigate the molecular mechanisms that govern the heterogeneity in host immune response in DM-TB comorbid conditions. Diabetes is associated with chronic hyperinflammation and reduced lung-infiltrating immune cells, which delays the immune response to Mycobacterial infection. scRNA-seq of lung CD3 and CD11c cells revealed compromised adaptive and innate immunity, with decreased Th1 and M1 macrophage populations in DM-TB mice. A dampened immune response, marked by increased IL-16 signaling and reduced TNF and IFN-II responses, was observed in DM-TB. This study highlights chronic inflammation, hyperglycemia, and dyslipidemia associated with diabetes impairing anti-TB immunity. Selective inhibition of aberrant IL-16 secretion and Th17 cell activation might provide strategies for better managing DM-TB comorbidity.

immunology↗

bioRxiv2024

Lung Mycobacterium tuberculosis infection perturbs metabolic pathways in non-pulmonary tissues

Mycobacterium tuberculosis (Mtb), through aerosol, reaches the lungs to cause pulmonary tuberculosis (TB); however, it may also affect the metabolism of other tissues in age-specific ways. In this study, female C57BL/6 mice (2 and 5 months old; M) were infected with a low aerosol dose (100-200 cfu) of Mtb H37Rv to monitor tissue mycobacterial load and multi-tissue metabolite profiling using gas chromatography and mass spectrometry (GC-MS). 5M C57BL/6 mice showed separate tissue metabolic phenotype with significantly higher lung aspartic acid, fecal oxalic acid and tryptophan levels with lower liver lysine and aspartic acid and fecal phenylalanine levels (log2FC: 5M/2M> {+/-}1.0, p<0.1) compared to 2M young controls. Upon Mtb infection, the lung mycobacterial load of 2M and 5M mice were similar till 6 weeks post-infection. However, significantly higher lung phosphoric acid, malonic acid and lower mannose levels (log2FC: Mtb infected/healthy> {+/-}1.0, p<0.1) were observed in Mtb-infected 5M C57BL/6 mice. Meanwhile, Mtb-infected 2M mice showed higher liver xylose and lower lysine levels. The thigh muscles of Mtb-infected 2M and 5M mice showed increased malic acid and oxalic acid and decreased glycine, serine, and glycerol levels. Fecal aspartic acid level was higher in Mtb-infected 5M mice, while a decreased abundance of fecal lysine was observed in Mtb-infected 2M mice. Overall, this study demonstrates a deregulated tissue-specific amino acid metabolism in Mtb-infected mice groups of different age groups, which might be targeted for managing TB infection-related adverse effects.

biochemistry↗

bioRxiv2023

Splenic T follicular helper cells compromise Mycobacterium tuberculosis clearance in aged C57BL/6 mice

Immunosenescence increases susceptibility to infectious diseases like tuberculosis (TB) in older subjects ([≥]60 years) and may impact containment of Mycobacterium tuberculosis (Mtb) during therapeutic intervention. A deeper understanding of cellular and molecular changes with age could inform new strategies to improve therapeutic outcomes. Here, we monitored the immunopathology, frequency and functionality of immune cells across extreme age groups of C57BL/6 mice following low aerosol dose infection (100-120 cfu) with Mtb H37Rv and treatment with rifampicin and isoniazid (RIF-INH). Up to 6 weeks of infection, tissue (lung, spleen and liver) mycobacterial load in old (17-19 months; M) and aged (31M) C57BL/6 mice was similar compared to young (2-4M) mice. However, at two weeks post-treatment, older mice showed a slower rate of Mtb clearance in the lungs. Old Mtb-infected mice had higher splenic T-follicular cytotoxic (TFC)-like cells and proteomic analysis of flow-sorted CD4+CD44+ T cells revealed deregulated mitochondrial proteins (4-hydroxy-2-oxoglutarate aldolase, aspartate aminotransferase and prostaglandin E synthase), pointing to impaired mitochondrial function. Collectively, these findings suggest that age-associated immune alterations may impair immunometabolic processes contributing to delayed Mtb clearance. These results highlight the potential importance of targeting immunometabolic dysfunction to improve TB treatment outcomes in older populations and reduce morbidity. SummaryThe elderly population is particularly susceptible to tuberculosis (TB), making it crucial to understand the cellular and molecular mechanisms contributing to the decline in immune responses with age. Evaluating the immunopathology, frequency and functionality of immune cells and Mtb-specific antibody responses across different age groups is essential for developing adjunct therapies for geriatric TB patients.

immunology↗

bioRxiv2022

Dysregulated cysteine metabolism leads to worsened liver pathology in diabetes-tuberculosis comorbid mice.

Diabetes mellitus (DM) is a well-known risk factor for tuberculosis (TB). Interestingly, DM is growing to pandemic proportions in TB endemic South-East Asian countries. DM-TB comorbidity induced pathophysiological changes warrants a better understanding to develop effective therapeutics. Tissue metabolomic profiling of streptozotocin (STZ) induced diabetic animals, infected with Mycobacterium tuberculosis H37Rv, showed metabolic dysregulation in the lungs, liver, brain, kidney and thigh muscle. At 3 w.p.i., the tissue (lungs, spleen, liver) bacterial loads were similar between DM-TB and TB with worsened lung pathology. Enrichment analysis of the deregulated liver metabolites (n=20; log2DM-TB/TB>{+/-}1.0) showed major perturbation in the cysteine-methionine, glycine-serine, branched chain amino acid (BCAA) and fatty acid metabolism. Parallel relative quantification of liver proteome of DM-TB and control mice groups (TB, DM and healthy) identified 1833 proteins which showed group specific variations. Enrichment analysis of significantly altered proteins (n=60; log2DM-TB/TB>{+/-}1.0) showed major perturbations in cysteine-methionine metabolism corroborating the metabolomics data. In addition, amino acid biosynthesis, retinol metabolism and polyol biosynthetic process were also differentially enriched in DM-TB groups compared to controls. Furthermore, a global correlation analysis of liver metabolome and proteome data showed strong association between aspartic acid, pyruvic acid, leucine and isoleucine with Cyp450 enzymes (Cyp2a5, Cyp3a11, Cyp4a10, Cyp4a14) involved in retinol metabolism. Whereas iminodiacetic acid, isoleucine and {gamma}-aminobutyric acid strongly correlated to enzymes (Cth, Ahcy, Kyat3, Mat1a) involved in the cysteine metabolism. So, targeting the perturbed liver cysteine and retinol metabolism in DM-TB comorbid condition might improve therapeutic outcomes and prevent organ damage.

biochemistry↗

bioRxiv2020

RRBP1 rewires cisplatin resistance in Oral Squamous Cell Carcinoma by regulating YAP-1

Cisplatin-based chemotherapy still remains as one of the primary treatment modalities for OSCC. Several OSCC patients experience relapse owing to development of chemoresistance. To identify key resistance triggering molecules, we performed global proteomic profiling of human OSCC lines presenting with sensitive, early and late cisplatin resistance patterns. From the proteomic profiling study, human RRBP1 was identified to be upregulated in both early and late cisplatin-resistant cells with respect to the sensitive counterpart. Analysis of OSCC patient sample indicates that RRBP1 expression is elevated in chemotherapy-non-responder tumors as compared to chemotherapy-naive tumors. Knocking out RRBP1 resulted in restoring cisplatin mediated cell death in chemoresistant lines and patient derived cells (PDC). Mechanistically, RRBP1 regulates YAP-1 to induce chemoresistance in OSCC. The chemoresistant PDC xenograft data suggests that knock out of RRBP1 induces cisplatin mediated cell death and facilitates a significant reduction of tumor burden. We also found Radezolid, a novel oxazolidinone antibiotic represses the expression of RRBP1 and restores cisplatin-induced cell death in chemoresistant OSCC. This unique combinatorial approach needs further clinical investigation to target advanced OSCC. Here with for the first time, we uncover the novel role of RRBP1 as potential modulator of cisplatin resistance in advanced OSCC.

cancer biology↗