Biology subjects

Bhimani, S.

Publications and source records attributed to Bhimani, S..

4 recordsLinked to original sources

bioRxiv2026

Vesicle architecture licenses antigen-specific memory T cell immunity after mucosal immunization with infection-derived vesicles

Small extracellular vesicles (sEVs) released by infected cells carry microbial antigens together with host immunomodulatory molecules, yet whether their structural integrity governs the durability of protective immunity is unknown. Using Salmonella infection as a model, we show that sEVs isolated from infected macrophages act as potent antigen carriers for intranasal immunization. In BALB/c mice, intact sEVs elicited antigen-specific serum IgG responses comparable in magnitude to those induced by live attenuated aroA Salmonella. Immunization further increased fecal IgA binding to Salmonella following lethal challenge and generated serum capable of enhancing macrophage-mediated bacterial uptake. Single-cell RNA sequencing of mesenteric lymph nodes revealed enrichment of mature B cells, effector CD8 T cells, and central memory-like CD4 T cells expressing CD69, CD44, CCR7, and Sell/CD62L, while defined recombinant sEV-associated antigens drove IFN-gamma and IL-2 production by memory T cells ex vivo. Disrupting vesicle architecture by sonication left total IgG and IgG1 induction intact but selectively impaired IgG2a responses and antigen-specific T-cell recall; intact sEVs, by contrast, drove greater dendritic-cell CD80 expression, IL-2 production by cocultured CD69+ CD4 T cells, and prolonged survival after lethal challenge. These findings establish that vesicle integrity is dispensable for the overall magnitude of antibody induction but is required to instruct dendritic-cell costimulation, Th1-associated IgG2a class switching, and durable memory T-cell recall after mucosal immunization, identifying infection-derived sEVs as structurally organized immunogens rather than passive antigen reservoirs.

immunology↗

bioRxiv2025

Cannabinoid receptor deficiencies drive immune response dynamics in Salmonella infection

This study investigated the roles of cannabinoid receptors 1 and 2 (CB1R and CB2R) in regulating host responses to Salmonella Typhimurium in C57BL/6 mice. The absence of both receptors significantly impaired host resilience, as evidenced by increased weight loss, deteriorated body condition, and reduced survival following infection. Notably, CB1R deficiency resulted in more pronounced weight loss and heightened susceptibility to bacterial proliferation, as demonstrated by increased Salmonella dissemination to organs. In addition, both CB1R and CB2R knockout mice exhibited alterations in immune cell recruitment and cytokine production. CB1R-KO mice displayed increased T cell and macrophage populations, whereas CB2R-KO mice showed a reduction in NK cells, indicating receptor-specific effects on immune cell mobilization. Cytokine profiling of macrophages post-infection revealed that CB1R-KO mice had reduced IL-10 levels, along with increased IL-6 and TGF-{beta}, suggesting a dysregulated polarization state that combines pro-inflammatory and regulatory elements. In contrast, CB2R-KO mice exhibited a profile consistent with a more straightforward pro-inflammatory shift. Furthermore, microbiota analysis demonstrated that CB2R-KO mice experienced significant gut dysbiosis, including reduced levels of beneficial Lactobacillus and Bifidobacterium species and an increase in pro-inflammatory Alistipes species post-infection. Functional microbiome analysis further indicated declines in key metabolic pathways, such as the Bifidobacterium shunt, L-glutamine biosynthesis, and L-lysine biosynthesis, suggesting microbiota-driven immune dysregulation. Together, these findings highlight the distinct, non-redundant roles of CB1R and CB2R in modulating innate immunity, host defense, and microbiota composition during bacterial infections. Significance StatementUnderstanding the role of cannabinoid receptors in immune regulation is important for identifying new therapeutic targets for bacterial infections. Our study demonstrates that CB1R and CB2R play distinct, non-redundant roles in host defense against Salmonella Typhimurium. The absence of these receptors impairs host resilience, increases bacterial dissemination, and alters immune cell recruitment and cytokine production. Notably, CB1R deficiency leads to enhanced weight loss, increased bacterial spread, and a dysregulated macrophage cytokine profile--characterized by reduced IL-10 and elevated IL-6 and TGF-{beta}--while CB2R deficiency is associated with reduced NK cell numbers and a more pronounced pro-inflammatory cytokine profile. These findings reveal a receptor-specific balance in immune responses, suggesting that cannabinoid signaling modulates infection outcomes. Targeting CB1R and CB2R pathways may offer novel strategies to enhance host immunity and improve treatments for bacterial infections in the future.

microbiology↗

bioRxiv2021

The immunomodulatory properties of the HDAC6 inhibitor ACY241 supports robust anti-tumor response in NSCLC when coupled with the chemotherapy drug Oxaliplatin

BackgroundDurable treatments that benefit a wide pool of patients remain elusive for Non-small cell lung cancer (NSCLC). The success of immunotherapy in a subset of NSCLC patients highlights the potential contribution of immune response to anti-tumor immunity while underscoring a need for broadly applicable therapeutic strategies. HDAC inhibitors are a promising class of drugs whose immunomodulatory properties are now being appreciated. In the present study, we evaluated the effects of the HDAC6 inhibitor, ACY241 on lung tumor immune compartment with the goal of understanding the scope of its immunomodulatory properties and its therapeutic potential in combination with Oxaliplatin. MethodsLung adenocarcinoma-bearing mice were treated with ACY241 or vehicle after which the proportions and phenotype of tumor-associated T cells and macrophages were evaluated by comprehensive flow cytometric analysis. Bulk RNA-sequencing was also conducted on both cellular subsets to interrogate the transcriptomic changes associated with ACY241 treatment relative to vehicle controls. In vivo drug efficacy study was performed by administration of ACY241 and/or Oxaliplatin and assessing tumor growth and survival of tumor-bearing mice. Ex vivo functional studies was performed to assess tumor-associated T cell effector function as it correlates with measured outcomes. ResultsWe demonstrate that ACY241 promotes increased presence of T and NK cells in the lung tumors of treated mice. The tumor-associated T cells under ACY241 treatment displayed enhanced activation, proliferation, and effector profile. In addition, tumor-associated macrophages exhibited increased expression of MHC and co-stimulatory molecules while expression of inhibitory ligands were reduced. RNA-sequencing of both tumor-associated T cells and macrophages revealed significant genomic changes in both subsets that is consistent with ACY241-mediated enhancement of immune priming. These broad immunomodulatory properties of ACY241 were associated with significantly enhanced tumor-associated T cell effector functionality, robust anti-tumor response, and significantly prolonged survival of NSCLC-bearing mice when combined with the chemotherapy drug Oxaliplatin. ConclusionCollectively, our studies highlight the broad immunomodulatory effect of ACY241 as a promising HDAC6 inhibitor which coupled with Oxaliplatin promotes robust therapeutic outcomes in a pre-clinical model of NSCLC, providing compelling rationale for the clinical testing of this novel combinatorial regimen in NSCLC.

immunology↗

bioRxiv2019

Neuropilin 2 signaling mediates corticostriatal transmission, spine maintenance, and goal-directed learning in mice

The striatum represents the main input structure of the basal ganglia, receiving massive excitatory input from the cortex and the thalamus. The development and maintenance of cortical input to the striatum is crucial for all striatal function including many forms of sensorimotor integration, learning and action control. The molecular mechanisms regulating the development and maintenance of corticostriatal synaptic transmission are unclear. Here we show that the guidance cue, Semaphorin 3F and its receptor Neuropilin 2 (Nrp2), influence dendritic spine maintenance, corticostriatal short-term plasticity, and learning in adult male and female mice. We found that Nrp2 is enriched in adult layer V pyramidal neurons, corticostriatal terminals, and in developing and adult striatal spiny projection neurons (SPNs). Loss of Nrp2 increases SPN excitability and spine number, reduces short-term facilitation at corticostriatal synapses, and impairs goal-directed learning in an instrumental task. Acute deletion of Nrp2 selectively in adult layer V cortical neurons produces a similar increase in the number of dendritic spines and presynaptic modifications at the corticostriatal synapse in the Nrp2-/- mouse, but does not affect the intrinsic excitability of SPNs. Furthermore conditional loss of Nrp2 impairs sensorimotor learning on the accelerating rotarod without affecting goal-directed instrumental learning. Collectively, our results identify Nrp2 signaling as essential for the development and maintenance of the corticostriatal pathway and may shed novel insights on neurodevelopmental disorders linked to the corticostriatal pathway and semaphorin signaling.\n\nSignificance StatementThe corticostriatal pathway controls sensorimotor, learning and action control behaviors and its dysregulation is linked to neurodevelopmental disorders, such as autism spectrum disorder (ASD). Here we demonstrate that neuropilin 2 (Nrp2), a receptor for the axon-guidance cue semaphorin 3F, has important and previously unappreciated functions in the development and adult maintenance of dendritic spines on striatal spiny projection neurons (SPNs), corticostriatal short-term plasticity, intrinsic physiological properties of SPNs and learning in mice. Our findings, coupled with Nrp2s association with ASD in human populations, suggest that Nrp2 may play an important role in ASD pathophysiology. Overall, our work demonstrates Nrp2 as a key regulator of corticostriatal development, maintenance and function, and may lead to better understanding of neurodevelopmental disease mechanisms.

neuroscience↗