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Tor publishing discriminatory11/11/2022 ![]() ![]() However, compared to the Classical biotype, it is not clear how the additional expression of the accessory hlyA and MARTX toxins alters host innate immune responses to the V. cholerae O1 serogroup that caused all seven cholera pandemics thus far, the Classical and El Tor biotypes can be distinguished based on the absence or the presence, respectively, of both hlyA and MARTX ( 9– 14). While the molecular mechanisms by which they contribute to cholera pathology is less clear, the accessory toxins hemolysin (hlyA) and multifunctional auto-processing repeat-in-toxin (MARTX) are characterized by their pore-forming and cytoskeleton-disrupting cellular effects, respectively ( 7, 8). CT accomplishes this through its A subunit (CTA) that activates the adenylate cyclase in intestinal epithelial cells, which results in a net secretion of chloride ions and water into the intestinal lumen ( 6). Cholera toxin (CT) is the virulence factor responsible for triggering the diarrheal manifestations of cholera disease. cholerae carries an arsenal of toxins contributing to infection. cholerae pandemic for which the WHO registers 2–4 million cases and ~100.000 cholera-associated deaths annually worldwide, and has completely replaced the Classical biotype that caused former pandemics ( 4, 5). Indeed, the El Tor biotype is responsible for the ongoing seventh V. Similar El Tor driven epidemics have affected regions in Africa and Latin America in the past decades ( 3). cholerae strains collected in Yemen throughout 20 revealed that all of these strains belonged to the El Tor biotype ( 1, 2). ![]() Vibrio cholerae is a Gram-negative enteropathogen that caused numerous cholera outbreaks in the past and remains a public health threat also today, as illustrated by the current cholera epidemic in Yemen that is among the largest outbreaks in the last century ( 1). #Tor publishing discriminatory fullThese findings further unravel the complex inflammasome activating mechanisms that can be triggered when macrophages face the full arsenal of El Tor Vibrio cholerae toxins, and as such increase our understanding of host-pathogen interactions in the context of the Vibrio cholerae biotype associated with the ongoing cholera pandemic. cholerae El Tor biotype does not trigger caspase-11 activation, but instead triggers parallel Nlrp3- and Pyrin-dependent pathways toward canonical inflammasome activation to induce IL-1β-mediated inflammatory responses. We further reveal the capacity of this enteropathogen to engage the canonical Pyrin inflammasome as an accessory mechanism for IL-1β secretion in conditions when the pro-inflammatory hlyA-Nlrp3 axis is blocked. Instead, we show that El Tor Vibrio cholerae engages the canonical Nlrp3 inflammasome for IL-1β secretion through its accessory hlyA toxin. In contrast to the Classical biotype, we here show that El Tor Vibrio cholerae induces IL-1β maturation and secretion in a caspase-11- and CT-independent manner. Previous studies demonstrated that the Classical biotype of Vibrio cholerae triggers caspase-11-dependent non-canonical inflammasome activation in macrophages following CT-mediated cytosolic delivery of LPS. While both of these biotypes express the characteristic Cholera Toxin (CT), the El Tor biotype additionally expresses the accessory toxins hemolysin (hlyA) and multifunctional auto-processing repeat-in-toxin (MARTX). Genomic Vibrio cholerae research revealed that the strains causing this ongoing cholera pandemic are members of the El Tor biotype, which fully replaced the Classical biotype that caused former cholera pandemics. Vibrio cholerae is a Gram-negative enteropathogen causing potentially life-threatening cholera disease outbreaks, for which the World Health Organization currently registers 2–4 million cases and ~100.000 cholera-associated deaths annually worldwide. 5Janssen Immunosciences, World Without Disease Accelerator, Pharmaceutical Companies of Johnson & Johnson, Beerse, Belgium.4Ghent Gut Inflammation Group (GGIG), Ghent University, Ghent, Belgium.3Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.2VIB-UGent Center for Inflammation Research, VIB, Ghent, Belgium.1Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium.Frising 1,2, Tomoko Asaoka 1,2, Geert van Loo 2,3,4, Mohamed Lamkanfi 1,5 and Andy Wullaert 1,2,3,4 * ![]()
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