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Abstract Pandemic and endemic strains ofVibrio choleraearise from toxigenic conversion by the CTXφ bacteriophage, a process by which CTXφ infects nontoxigenic strains ofV. 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 inV. cholerae.Our results indicate that mucin‐associatedO‐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 structuresde 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 associatedO‐glycan structures affect CTXφ‐mediated evolution and pathogenicity ofV. cholerae, underscoring the potential regulatory power housed within mucus.
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This content will become publicly available on June 3, 2026
Allelic variations and gene cluster modularity act as nonlinear bottlenecks for cholera emergence
The underlying factors that lead to specific strains within a species to emerge as human pathogens remain mostly enigmatic. The diarrheal disease cholera is caused by strains from a phylogenetically confined group within theVibrio choleraespecies, the pandemic cholera group (PCG), making it an ideal model system to tackle this puzzling phenomenon. Comprehensive analyses of over 1,840V. choleraegenomes, including environmental isolates from this study, reveal that the species consists of eleven groups, with the PCG belonging to the largest and located within a lineage shared with environmental strains. This hierarchical classification provided us with a framework to unravel the ecoevolutionary dynamics of the genetic determinants associated with the emergence of toxigenicV. cholerae. Our analyses indicate that this phenomenon is largely dependent on the acquisition of unique modular gene clusters and allelic variations that confer a competitive advantage during intestinal colonization. We determined that certain PCG-associated alleles are essential for successful colonization whereas others provide a nonlinear competitive advantage, acting as a critical bottleneck that clarifies the isolated emergence of PCG. For instance, toxigenic strains encoding non-PCG alleles of a)tcpFor b) a sextuple allelic exchange mutant for genestcpA,toxT,VC0176,VC1791,rfbT,andompU, lose their ability to colonize the intestine. Interestingly, these alleles do not play a role in the colonization of newly established model environmental reservoirs. Our study uncovers the evolutionary roots of toxigenicV. choleraeoffering a tractable approach for investigating the emergence of pathogenic clones within an environmental population.
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- Award ID(s):
- 2533749
- PAR ID:
- 10627019
- Publisher / Repository:
- National Academy of Sciences
- Date Published:
- Journal Name:
- Proceedings of the National Academy of Sciences
- Volume:
- 122
- Issue:
- 22
- ISSN:
- 0027-8424
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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