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Significance Clostridium difficile is a toxin-producing bacterium that is a frequent cause of hospital-acquired and antibiotic-associated diarrhea. The incidence, severity, and costs associated with C. difficile infection (CDI) are increasing, making C. difficile an important public health concern. As a toxin-mediated disease, there is significant interest in understanding the receptors that mediate the cellular entry and function of these toxins. The targeted disruption of toxin-receptor interactions could provide novel therapeutic strategies that can either augment or replace the need for antibiotic therapies in the treatment of CDI. Clostridium difficile is the leading cause of hospital-acquired diarrhea in the United States. The two main virulence factors of C. difficile are the large toxins, TcdA and TcdB, which enter colonic epithelial cells and cause fluid secretion, inflammation, and cell death. Using a gene-trap insertional mutagenesis screen, we identified poliovirus receptor-like 3 (PVRL3) as a cellular factor necessary for TcdB-mediated cytotoxicity. Disruption of PVRL3 expression by gene-trap mutagenesis, shRNA, or CRISPR/Cas9 mutagenesis resulted in resistance of cells to TcdB. Complementation of the gene-trap or CRISPR mutants with PVRL3 resulted in restoration of TcdB-mediated cell death. Purified PVRL3 ectodomain bound to TcdB by pull-down. Pretreatment of cells with a monoclonal antibody against PVRL3 or prebinding TcdB to PVRL3 ectodomain also inhibited cytotoxicity in cell culture. The receptor is highly expressed on the surface epithelium of the human colon and was observed to colocalize with TcdB in both an explant model and in tissue from a patient with pseudomembranous colitis. These data suggest PVRL3 is a physiologically relevant binding partner that can serve as a target for the prevention of TcdB-induced cytotoxicity in C. difficile infection.

Hidradenitis suppurativa (HS) is a chronic, heterogeneous inflammatory skin disorder with limited therapeutic options. The immune checkpoint receptor TIGIT is emerging as a regulator of chronic inflammation, yet its role in HS remains unknown. Here, we investigated TIGIT and its ligands in HS using tissue profiling, transcriptomics, and an ex vivo functional explant model. A tissue microarray containing 52 HS, 9 ruptured follicular cysts, and 4 normal skin samples demonstrated significantly increased TIGIT expression in HS lesions. In contrast, the TIGIT ligand PVRL3 was significantly decreased in HS, a finding also observed in a publicly available RNA-seq dataset. Because TIGIT suppresses inflammation only when adequately engaged by its ligands, reduced PVRL3 may impair inhibitory checkpoint signaling in HS. To test whether TIGIT engagement could suppress HS inflammation, we developed an ex vivo explant model using freshly obtained HS lesional tissue. The system was validated using triamcinolone, a corticosteroid, which consistently reduced IL-6 production. Treatment with a TIGIT agonist antibody significantly reduced IL-6 by 72 hours. These findings provide the first functional evidence that TIGIT activation attenuates inflammatory pathways in HS, supporting TIGIT agonism as a potential therapeutic strategy.

Triple-negative breast cancer (TNBC) represents an aggressive subtype of breast cancer, with a bad prognosis and lack of targeted therapeutic options. Characterized by the absence of estrogen receptors, progesterone receptors, and HER2 expression, TNBC is often associated with a significantly lower survival rate compared to other breast cancer subtypes. Our study aimed to explore the prognostic significance of 83 immune-related genes, by using transcriptomic data from the TCGA database. Our analysis identified the Poliovirus Receptor-Like 3 protein (PVRL3) as a critical negative prognostic marker in TNBC patients. Furthermore, we found that the Enhancer of Zeste Homolog 2 (EZH2), a well-known epigenetic regulator, plays a pivotal role in modulating PVRL3 levels in TNBC cancer cell lines expressing EZH2 along with high levels of PVRL3. The elucidation of the EZH2-PVRL3 regulatory axis provides valuable insights into the molecular mechanisms underlying TNBC aggressiveness and opens up potential pathways for personalized therapeutic intervention.