Biology subjects

Aditi, A.

Publications and source records attributed to Aditi, A..

3 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

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↗