Journal Article

Vibrio cholerae cytolysin induces pro-inflammatory and death signals through novel TLR assembly

Chattopadhyay, Kausik, Gandhi, Shraddha, Mondal, Anish Kumar, Mukhopadhaya, Arunika, Yadav, Shashi Prakash, Puravankara, Sindhoora, Chauhan, Aakanksha

2025

Overview

Vibrio cholerae cytolysin (VCC) is a potent exotoxin secreted by Vibrio cholerae , the etiological agent of the severe diarrheal disease cholera. VCC is a membrane-damaging pore-forming toxin by nature, and is well known for its ability to cause host cell death. Using wild type V. cholerae and VCC-deleted mutant variant of the bacteria, we show that VCC plays an important role in the inflammatory responses during infection in mice. This observation supports that VCC can function as a pathogen-associated molecular pattern (PAMP). Toll-like receptors (TLRs) are the key initiators of inflammation. Upon ligand recognition, TLR1 and TLR6 generally form heterodimers with TLR2 for triggering pro-inflammatory signals. In the present study, we show that VCC engages novel TLR1/4 heterodimer assembly, and elicits pro-inflammatory responses in both dendritic cells (DCs) and macrophages. Along with TLR1/4, VCC-induced pro-inflammatory response in macrophages also involves TLR2. It has been shown earlier that VCC is implicated in the V. cholerae -mediated killing of the immune cells following biofilm formation. Here we show that TLRs play an important role in VCC-mediated killing of DCs and macrophages following V. cholerae infection. Interestingly, we find that TLR1/4 signalling is specifically crucial for the VCC-induced inflammatory and death responses in DCs, as well as in mice. Additionally, we observe that similar to DCs and macrophages, TLR1/4-MyD88 play an important role in VCC-mediated inflammatory responses in another crucial immune cell type, neutrophils. Taken together, our study shows novel TLR heterodimer formation, differential recognition of the same ligand by different TLR combination in cell type-dependent manner, and their implications in the context of V. cholerae and VCC-induced immune cell death and mortality.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Animals / Antigens / Bacteria / Bacterial toxins / Biofilms / Biology and Life Sciences / Cell death / Cholera / Cholera - immunology / Cholera - metabolism / Cholera toxin / Cytokines / Cytotoxins - immunology / Cytotoxins - metabolism / Dendritic cells / Dendritic Cells - immunology / Dendritic Cells - metabolism / Dendritic Cells - microbiology / Development and progression / Diarrhea / Engineering and Technology / Exotoxins / Funding / Health aspects / Immune response / Immune system / Inflammation / Inflammation - immunology / Inflammation - metabolism / Inflammatory response / Leukocytes (neutrophilic) / Ligands / Lipids / Macrophages / Macrophages - immunology / Macrophages - metabolism / Macrophages - microbiology / Medicine and Health Sciences / Membranes / Mice / Mice, Inbred C57BL / Mortality / MyD88 protein / Myeloid Differentiation Factor 88 - metabolism / Neutrophils / Pathogens / Perforin - immunology / Perforin - metabolism / Physical Sciences / Physiological aspects / Pore formation / Proteins / Receptor mechanisms / Recognition / Research and Analysis Methods / Signal Transduction - immunology / Streptococcus infections / TLR1 protein / TLR2 protein / Toll-Like Receptor 1 - genetics / Toll-Like Receptor 1 - immunology / Toll-Like Receptor 1 - metabolism / Toll-Like Receptor 2 - immunology / Toll-Like Receptor 2 - metabolism / Toll-Like Receptor 4 - genetics / Toll-Like Receptor 4 - immunology / Toll-Like Receptor 4 - metabolism / Toll-like receptors / Toll-Like Receptors - immunology / Toll-Like Receptors - metabolism / Toxins / Tumor necrosis factor-TNF / Vibrio cholerae / Vibrio cholerae - immunology / Vibrio cholerae - metabolism / Vibrio cholerae - pathogenicity / Vibrio infections / Waterborne diseases