Biology subjects

Samir, P.

Publications and source records attributed to Samir, P..

6 recordsLinked to original sources

bioRxiv2025

Stress granule component TIA-1 is a specific negative regulator of the non-canonical NLRP3 inflammasome.

Inflammasomes are cytosolic signaling hubs assembled upon pathogen- or damage associated molecular patterns (PAMP and DAMP) sensing by innate immune pattern recognition receptors (PRR). Lipopolysaccharide (LPS) present on the cell wall of gram-negative bacteria is a PAMP that activates caspase 11 (CASP11) dependent nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) inflammasome (known as non-canonical NLRP3 inflammasome) leading to pyroptosis. Several host factors are shown to promote non-canonical NLRP3 inflammasome activation by making LPS readily available for recognition by CASP11. Here, we report T-cell intracellular antigen-1 (TIA1), an RNA binding protein as a negative regulator of non-canonical NLRP3 inflammasome. Using bone marrow-derived macrophages (BMDMs), we demonstrated that the loss of TIA1 led to an increase in caspase-1 (CASP1) activity in response to cytosolic LPS. A previous study had demonstrated that mice lacking Tia1 are more susceptible to LPS mediated endotoxic shock. Our results provide a potential explanation for this observation by showing loss of TIA1 increases non-canonical NLRP3 inflammasome activation resulting in increased inflammation and pathogenesis during LPS mediated endotoxic shock. Further, TIA1 mediated inhibition of non-canonical NLRP3 inflammasome is independent of TIA1s regulatory role in gene transcription as well as its role in stress granule assembly. TIA1 is also dispensable for activation of the canonical NLRP3 inflammasome as well as AIM2 and NLRC4 inflammasomes. While, the exact mechanism by which TIA1 inhibits non-canonical inflammasome activation remains to be elucidated, our finding that TIA1 is a negative regulator indicates the presence of undiscovered regulatory mechanisms. Future studies will focus on unraveling these mechanisms for developing anti-inflammatory drugs that exploit non-canonical inflammasome activity modulation.

immunology↗

bioRxiv2025

Respiratory syncytial virus infection confers heterologous protection against SARS-CoV-2 via induction of γδ T cell-mediated trained immunity and SARS-CoV-2 reactive mucosal T cells

The respiratory viruses can concurrently or sequentially infect a host and influence the trajectory of each other. The underlying immune mechanisms are not well understood. Here, we investigated whether respiratory syncytial virus (RSV) infection affects host vulnerability to subsequent SARS-CoV-2 infection in two murine models of SARS-CoV-2 infection. We found that prior RSV infection-induced heterologous protection against subsequent SARS-CoV-2 infection was dose and time dependent. RNA-seq and immunological analyses revealed that RSV triggered the activation of lung antigen presenting cells (APC)s and SARS-CoV-2 reactive mucosal T cells at day 9, which declined at 1 month. RSV also induced the expansion of lung {gamma}{delta} T cells and the upregulation of their cellular metabolic pathways. Furthermore, RSV infection in TCR{delta}-/- mice, which are deficient of {gamma}{delta} T cells, resulted in a reduced SARS-CoV-2 reactive mucosal T cell response and subsequent increased viral loads and higher levels of virus-induced inflammatory responses in the lung upon SARS-CoV-2 challenge compared to the wild-type mice. In summary, our findings suggest that RSV infection provides heterologous protection against the subsequent SARS-CoV-2 infection via induction of {gamma}{delta} T cell-mediated trained immunity in the lung and SARS-CoV-2 reactive mucosal T cell responses.

microbiology↗

bioRxiv2025

Pharmacological interrogation of crosstalk between TLR signaling and stress granules reveals a compound with antiviral effect.

Stress granules (SG) are cytoplasmic membraneless compartments that regulate cellular stress responses and have been implicated in antiviral defense against Influenza A Virus (IAV). SG stabilization has been reported to be a viable strategy to develop antiviral drugs. To expand the repertoire of SG-modulating compounds, we performed a targeted pharmacological screen focusing on inhibitors of TLR signaling pathway, based on our previous work demonstrating an antagonistic relationship between SGs and TLR signaling. Using the synthetic dsRNA analog polyinosinic:polycytidylic acid (poly(I:C)) to induce SGs in A549 human lung cancer cell line, we screened a panel of TLR signaling pathway inhibitors for their effect on SG. We developed a robust image analysis pipeline utilizing ilastik for pixel classification and CellProfiler for object quantification, enabling high-throughput analysis of SG alterations. This screen identified multiple small molecules that destabilize SGs, including inhibitors of RIPK3, TBK1, PERK, IRAK1/4, and JNK1/2/3 and ERK1/2 kinases. Several inhibitors of NF-{kappa}B signaling also disrupted SG integrity. Most strikingly, PPM18, an NF-{kappa}B inhibitor, emerged as a dual-action compound, triggering spontaneous SG assembly via PERK-mediated eIF2 phosphorylation, while simultaneously suppressing poly(I:C)-induced SGs. Intriguingly, PPM18 exhibited potent IAV inhibition, but crucially, this antiviral activity was decoupled from SG formation as it robustly inhibited replication in G3BP1-/- cells which did not assemble SGs upon PPM18 treatment. Our work not only identifies PPM18 as a unique SG modulator and an antiviral agent but also challenges the prevailing belief linking SG assembly directly to antiviral activity as a general phenomenon. Our findings demonstrate that SG formation and antiviral activity can be functionally uncoupled, providing new insights into host-virus interactions. In summary, our results demonstrate feasibility of using SG screening for finding novel antiviral compounds while raising important questions about the role of SGs themselves in modulating host-virus interactions.

immunology↗

bioRxiv2024

A Murine Model of Post-acute Neurological Sequelae Following SARS-CoV-2 Variant Infection

Viral variant is one known risk factor associated with post-acute sequelae of COVID-19 (PASC), yet the pathogenesis is largely unknown. Here, we studied SARS-CoV-2 Delta variant-induced PASC in K18-hACE2 mice. The virus replicated productively, induced robust inflammatory responses in lung and brain tissues, and caused weight loss and mortality during the acute infection. Longitudinal behavior studies in surviving mice up to 4 months post-acute infection revealed persistent abnormalities in neuropsychiatric state and motor behaviors, while reflex and sensory functions recovered over time. Surviving mice showed no detectable viral RNA in the brain and minimal neuroinflammation post-acute infection. Transcriptome analysis revealed persistent activation of immune pathways, including humoral responses, complement, and phagocytosis, and reduced levels of genes associated with ataxia telangiectasia, impaired cognitive function and memory recall, and neuronal dysfunction and degeneration. Furthermore, surviving mice maintained potent T helper 1 prone cellular immune responses and high neutralizing antibodies against Delta and Omicron variants in the periphery for months post-acute infection. Overall, infection in K18-hACE2 mice recapitulates the persistent clinical symptoms reported in long COVID patients and may be useful for future assessment of the efficacy of vaccines and therapeutics against SARS-CoV-2 variants.

microbiology↗

bioRxiv2022

Snip1-PRC2 governs the intrinsic apoptosis program in the developing brain

Brain development requires the intricate balance between division, death, and differentiation of neural progenitor cells (NPCs). Here, we report the discovery of Snip1 as a key regulator of these NPC phases. The conditional deletion of Snip1 in the mouse embryonic brain causes dysplasia with robust induction of caspase 9-dependent apoptosis. In NPCs, Snip1 suppresses the genetic programs of apoptosis and developmental signaling pathways and promotes the genetic programs of cell cycle, neurogenesis, and cortical development. Mechanistically, Snip1 binds to the Polycomb complex PRC2, co-occupies gene targets with PRC2, and regulates H3K27 marks. Deletion of PRC2 is sufficient to reduce apoptosis and brain dysplasia and partially restore genetic programs and tissue development in the Snip1-depleted brain. Our findings suggest that Snip1 exerts loci-dependent regulation of PRC2 and H3K27me3 to toggle between cell fates in the developing brain.

developmental biology↗

bioRxiv2020

COVID-19 cytokines and the hyperactive immune response: Synergism of TNF-α and IFN-γ in triggering inflammation, tissue damage, and death

The COVID-19 pandemic has caused significant morbidity and mortality. Currently, there is a critical shortage of proven treatment options and an urgent need to understand the pathogenesis of multi-organ failure and lung damage. Cytokine storm is associated with severe inflammation and organ damage during COVID-19. However, a detailed molecular pathway defining this cytokine storm is lacking, and gaining mechanistic understanding of how SARS-CoV-2 elicits a hyperactive inflammatory response is critical to develop effective therapeutics. Of the multiple inflammatory cytokines produced by innate immune cells during SARS-CoV-2 infection, we found that the combined production of TNF- and IFN-{gamma} specifically induced inflammatory cell death, PANoptosis, characterized by gasdermin-mediated pyroptosis, caspase-8-mediated apoptosis, and MLKL-mediated necroptosis. Deletion of pyroptosis, apoptosis, or necroptosis mediators individually was not sufficient to protect against cell death. However, cells deficient in both RIPK3 and caspase-8 or RIPK3 and FADD were resistant to this cell death. Mechanistically, the JAK/STAT1/IRF1 axis activated by TNF- and IFN-{gamma} co-treatment induced iNOS for the production of nitric oxide. Pharmacological and genetic deletion of this pathway inhibited pyroptosis, apoptosis, and necroptosis in macrophages. Moreover, inhibition of PANoptosis protected mice from TNF- and IFN-{gamma}-induced lethal cytokine shock that mirrors the pathological symptoms of COVID-19. In vivo neutralization of both TNF- and IFN-{gamma} in multiple disease models associated with cytokine storm showed that this treatment provided substantial protection against not only SARS-CoV-2 infection, but also sepsis, hemophagocytic lymphohistiocytosis, and cytokine shock models, demonstrating the broad physiological relevance of this mechanism. Collectively, our findings suggest that blocking the cytokine-mediated inflammatory cell death signaling pathway identified here may benefit patients with COVID-19 or other cytokine storm-driven syndromes by limiting inflammation and tissue damage. The findings also provide a molecular and mechanistic description for the term cytokine storm. Additionally, these results open new avenues for the treatment of other infectious and autoinflammatory diseases and cancers where TNF- and IFN-{gamma} synergism play key pathological roles.

immunology↗