RESUMO
Pandemic and endemic strains of Vibrio cholerae arise from toxigenic conversion by the CTXφ bacteriophage, a process by which CTXφ infects nontoxigenic strains of V. cholerae. CTXφ encodes the cholera toxin, an enterotoxin responsible for the watery diarrhea associated with cholera infections. Despite the critical role of CTXφ during infections, signals that affect CTXφ-driven toxigenic conversion or expression of the CTXφ-encoded cholera toxin remain poorly characterized, particularly in the context of the gut mucosa. Here, we identify mucin polymers as potent regulators of CTXφ-driven pathogenicity in V. cholerae. Our results indicate that mucin-associated O-glycans block toxigenic conversion by CTXφ and suppress the expression of CTXφ-related virulence factors, including the toxin co-regulated pilus and cholera toxin, by interfering with the TcpP/ToxR/ToxT virulence pathway. By synthesizing individual mucin glycan structures de novo, we identify the Core 2 motif as the critical structure governing this virulence attenuation. Overall, our results highlight a novel mechanism by which mucins and their associated O-glycan structures affect CTXφ-mediated evolution and pathogenicity of V. cholerae, underscoring the potential regulatory power housed within mucus.
Assuntos
Bacteriófagos , Toxina da Cólera , Mucinas , Vibrio cholerae , Virulência , Bacteriófagos/genética , Bacteriófagos/patogenicidade , Toxina da Cólera/genética , Toxina da Cólera/metabolismo , Mucinas/genética , Mucinas/metabolismo , Vibrio cholerae/genética , Vibrio cholerae/metabolismo , Virulência/genética , Virulência/fisiologia , Polissacarídeos/genética , Polissacarídeos/metabolismoRESUMO
With the concerning rise in antibiotic-resistant infections, novel treatment options against pathogens are urgently sought. Several recent studies have identified mucin O-glycan mixtures as potent down-regulators of virulence-related gene expression in diverse pathogens. As individual mucin glycans cannot be isolated in sufficient purity and quantity for biological evaluation of discrete structures, we have developed an optimized synthetic approach to generate a small library of mucin glycans which were identified as most likely to display activity. The glycans have been prepared in sufficient quantity to assess biological function, studies of which are currently ongoing.