Biology subjects

Thirugnanam, S.

Publications and source records attributed to Thirugnanam, S..

3 recordsLinked to original sources

bioRxiv2025

Dietary Indoles Modulate Gut Barrier Integrity via the AhR-IL-22 Axis in ART-Treated SIV Infection

HIV infection rapidly impairs the gastrointestinal (GI) barrier, contributing to persistent mucosal immune dysfunction, microbial translocation, and systemic inflammation despite antiretroviral therapy (ART). Using SIV-infected rhesus macaques on long-term ART, we investigated mechanisms underlying impairment in gut barrier-protective IL-17/IL-22 responses and the potential modulation of this pathway by dietary indoles. Longitudinal profiling of colonic epithelial and lamina propria cells revealed a selective loss of IL-17/IL-22-producing {gamma}{delta} T cells and type 3 innate lymphoid cells (ILC3s). This loss correlated with reduced expression of the transcription factors AhR and ROR{gamma}t and was associated with elevated plasma markers of intestinal epithelial barrier disruption (IEBD), including intestinal fatty acid-binding protein (iFABP), zonulin, and LPS-binding protein (LBP). Targeting this transcriptional deficiency, dietary indole supplementation for one month restored colonic AhR IL-22-producing {gamma}{delta} T cells and ROR{gamma}t ILC3s and V{delta}1 T cells, and was associated with reduced iFABP and zonulin levels. Our findings indicate that disruption of the AhR-ROR{gamma}t-IL-17/IL-22 axis is a key pathogenic mechanism underlying persistent IEBD in chronic SIV/HIV infection. Modulation of gut AhR signaling may represent a potential approach to reinforce mucosal barrier function and reduce chronic inflammation that persists in people living with HIV.

immunology↗

bioRxiv2025

Persistent Activation of Monocytes/Macrophages and Cell Senescence in SIV-Infected Macaques on ART

Despite effective viral suppression with antiretroviral therapy (ART), people living with HIV (PLWH) experience persistent inflammation, immune dysfunction, and premature onset of cardiovascular and aging-related comorbidities. To define the underlying mechanisms, we performed longitudinal transcriptomic profiling in peripheral blood mononuclear cells (PBMCs) from a cohort of simian immunodeficiency virus (SIV)-infected rhesus macaques spanning four key stages: pre-infection, acute infection, short-term ART, and long-term ART. Bulk RNA sequencing revealed dynamic immune remodeling across infection and treatment. Acute SIV infection induced robust antiviral and inflammatory programs, with upregulation of interferon-stimulated genes (ISGs), IL-27, JAK/STAT, and NF-{kappa}B signaling, coupled with suppression of T- and B-cell activation pathways. Short-term ART effectively reversed these transcriptional perturbations, restoring adaptive immune gene expression and reducing innate antiviral responses to near-baseline levels. In contrast, chronic SIV infection on long-term ART maintained viral suppression but was characterized by reactivation of innate immune pathways, including TLR2/TLR4/MYD88, NF-{kappa}B, and inflammasome (NLRP3/or NLRP12, caspase-1) signaling, along with sustained macrophage activation, platelet/coagulation signaling, and senescence-associated secretory phenotype. Protein analyses confirmed persistent CASPASE-1 and NF-{kappa}B activation in spleen tissue. Pathologic evaluation of a carotid artery from an SIV-infected, long-term ART- treated macaque revealed macrophage-rich plaques with p21 senescent cells with intraluminal thrombus formation, recapitulating key features of HIV-associated atherogenesis. Together, these findings demonstrate that while ART normalizes acute infection-induced immune dysregulation, chronic SIV infection sustains a chronic, macrophage- and TLR-driven inflammatory state linked to vascular injury and aging process regardless of long-term suppression of viremia. Targeting inflammasome, NF-{kappa}B, and senescence pathways may mitigate non-AIDS comorbidities in PLWH.

immunology↗

bioRxiv2024

High IL-1β and IL-18 Levels Associate with Gut Barrier Disruption and Monocyte Activation During Chronic SIV Infection with Long-Term Suppressive Antiretroviral Therapy

HIV-induced persistent immune activation is a key mediator of inflammatory comorbidities such as cardiovascular disease (CVD) and neurocognitive disorders. While a preponderance of data indicate that gut barrier disruption and microbial translocation are drivers of chronic immune activation, the molecular mechanisms of this persistent inflammatory state remain poorly understood. Here, utilizing the nonhuman primate model of HIV infection with suppressive antiretroviral therapy (ART), we investigated activation of inflammasome pathways and their association with intestinal epithelial barrier disruption and CVD pathogenesis. Longitudinal blood samples obtained from rhesus macaques with chronic SIV infection and long-term suppressive ART were evaluated for biomarkers of intestinal epithelial barrier disruption (IEBD), inflammasome activation (IL-1{beta} and IL-18), inflammatory cytokines, and triglyceride (TG) levels. Activated monocyte subpopulations and glycolytic potential were investigated in peripheral blood mononuclear cells (PBMCs). Higher plasma levels of IL-1{beta} and IL-18 were observed following the hallmark increase in IEBD biomarkers, intestinal fatty acid-binding protein (IFABP) and LPS-binding protein (LBP), during the chronic phase of treated SIV infection. Further, significant correlations of plasma IFABP levels with IL-1{beta} and IL-18 were observed between 10-12 months of ART. Higher levels of sCD14, IL-6, and GM-CSF, among other inflammatory mediators, were also observed only during the long-term SIV+ART phase along with a trend of increase in frequencies of activated CD14+CD16+ intermediate monocyte subpopulations. Lastly, we found elevated levels of blood TG and higher glycolytic capacity in PBMCs of chronic SIV-infected macaques with long-term ART. The increase in circulating IL-18 and IL-1{beta} following IEBD and their significant positive correlation with IFABP suggest a connection between gut barrier disruption and inflammasome activation during chronic SIV infection, despite viral suppression with ART. Additionally, the increase in markers of monocyte activation, along with elevated TG and enhanced glycolytic pathway activity, indicates metabolic remodeling that could accelerate CVD pathogenesis. Further research is needed to understand mechanisms by which gut dysfunction and inflammasome activation contribute to HIV-associated CVD and metabolic complications, enabling targeted interventions in people with HIV.

immunology↗