Allelic variations and gene cluster modularity act as non-linear bottlenecks for cholera emergence

López‐Pérez, Mario; Grant, Trudy-Ann; Haro-Moreno, José M.; Zaragoza-Solas, Asier; Almagro‐Moreno, Salvador

doi:10.1101/2022.09.26.509565

Cited by 6 publications

(8 citation statements)

References 118 publications

(210 reference statements)

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“…cholerae genomes from public databases, including environmental strains of V . cholerae in our collection [ 27 , 29 , 34 ]. V .…”

Section: Resultsmentioning

confidence: 99%

“…To determine the diversity of OmpU and subsequently correlate it with AMR, we obtained all sequences of the ompU gene in V. cholerae genomes from public databases, including environmental strains of V. cholerae in our collection [27,29,34]. V. cholerae N16961 OmpU was used as a reference to search for all homologs obtaining a total of 1620 sequences.…”

Section: Ompu Forms Two Major Phylogenetic Clustersmentioning

confidence: 99%

“…Vibrio cholerae, a comma-shaped Gram-negative bacterium, is the etiological agent of the severe diarrheal disease cholera. Interestingly, the toxigenic strains that can cause the disease in humans belong to one phylogenetically confined group within the species, the pandemic cholera group (PCG) [27][28][29]. Recently, we determined that strains from PCG encode allelic variations in core genes that confer preadaptations for virulence [27].…”

Section: Introductionmentioning

confidence: 99%

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Allelic diversity uncovers protein domains contributing to the emergence of antimicrobial resistance

et al. 2023

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Antimicrobial resistance (AMR) remains a major threat to global health. To date, tractable approaches that decipher how AMR emerges within a bacterial population remain limited. Here, we developed a framework that exploits genetic diversity from environmental bacterial populations to decode emergent phenotypes such as AMR. OmpU is a porin that can make up to 60% of the outer membrane of Vibrio cholerae, the cholera pathogen. This porin is directly associated with the emergence of toxigenic clades and confers resistance to numerous host antimicrobials. In this study, we examined naturally occurring allelic variants of OmpU in environmental V. cholerae and established associations that connected genotypic variation with phenotypic outcome. We covered the landscape of gene variability and found that the porin forms two major phylogenetic clusters with striking genetic diversity. We generated 14 isogenic mutant strains, each encoding a unique ompU allele, and found that divergent genotypes lead to convergent antimicrobial resistance profiles. We identified and characterized functional domains in OmpU unique to variants conferring AMR-associated phenotypes. Specifically, we identified four conserved domains that are linked with resistance to bile and host-derived antimicrobial peptides. Mutant strains for these domains exhibit differential susceptibility patterns to these and other antimicrobials. Interestingly, a mutant strain in which we exchanged the four domains of the clinical allele for those of a sensitive strain exhibits a resistance profile closer to a porin deletion mutant. Finally, using phenotypic microarrays, we uncovered novel functions of OmpU and their connection with allelic variability. Our findings highlight the suitability of our approach towards dissecting the specific protein domains associated with the emergence of AMR and can be naturally extended to other bacterial pathogens and biological processes.

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“…cholerae genomes from public databases, including environmental strains of V . cholerae in our collection [ 27 , 29 , 34 ]. V .…”

Section: Resultsmentioning

confidence: 99%

Section: Ompu Forms Two Major Phylogenetic Clustersmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Allelic diversity uncovers protein domains contributing to the emergence of antimicrobial resistance

et al. 2023

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“…Despite the presence of over 200 serogroups, only V. cholerae strains from serogroups O1 and the now extinct O139 can cause cholera in humans [33][34][35] . Strains from these two serogroups are phylogenetically related and confined to a single clade containing all toxigenic V. cholerae called the pandemic cholera group 36 . We previously developed a comparative genomics framework to elucidate the evolutionary origins and emergence of toxigenic V. cholerae strains 37 .…”

Section: Introductionmentioning

confidence: 99%

Modular small RNA drives pathogen emergence

Balasubramanian

Almagro‐Moreno

2023

Preprint

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Pathogen emergence is a poorly understood complex phenomenon. To date, the molecular mechanisms that allow strains within a bacterial population to emerge as human pathogens remain mostly enigmatic. We recently uncovered that toxigenic Vibrio cholerae encode preadaptations to host colonization, what we term virulence adaptive polymorphisms (VAPs), however, the molecular mechanisms driving them are not known. ompU is a VAP-encoding gene that is associated with the production of the major outer membrane porin OmpU. Here, we show that the ompU ORF also encodes a modular small RNA overlapping its 3 terminus that plays a major role in V. cholerae physiology. We determined that the OmpU-encoded sRNA (OueS) strongly suppresses biofilm formation, a phenotype that is essential for host intestinal colonization, via repression of iron uptake. OueS controls over 84% of the genes regulated by ToxR, a major virulence regulator, and plays an integral role during the infection process. We demonstrate that OueS is critical for intestinal colonization and its bimodular nature dictates the virulence potential of V. cholerae. Overall, our study reveals specific molecular mechanisms leading to the emergence of pathogenic traits in bacteria unveiling the hidden genetics associated with this process. We propose a scenario where a limited number of modular genes could explain the emergence of novel phenotypic traits in biological systems.

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“…Vibrio cholerae, a comma-shaped Gram-negative bacterium, is the etiological agent of the severe diarrheal disease cholera. Interestingly, only a phylogenetically confined group within the species, the pandemic cholera group (PCG), can cause the disease in humans [27][28][29]. Recently, we determined that strains from PCG encode allelic variations in core genes that confer preadaptations for virulence [27].…”

Section: Introductionmentioning

confidence: 99%

Allelic diversity uncovers protein domains contributing to the emergence of antimicrobial resistance

Grant

López‐Pérez

Almagro‐Moreno

2022

Preprint

Self Cite

View full text Add to dashboard Cite

Antimicrobial resistance (AMR) remains a major threat to global health. To date, tractable approaches that decipher how AMR emerges within a bacterial population remain limited. Here, we developed a framework that exploits genetic diversity from environmental bacterial populations to decode emergent phenotypes such as AMR. OmpU, is a porin that makes up to 60% of the outer membrane of Vibrio cholerae, the cholera pathogen. This porin is directly associated with the emergence of the bacterium and confers resistance to numerous host antimicrobials. In this study, we examined naturally occurring allelic variants of OmpU in environmental V. cholerae and established associations that connected genotypic variation with phenotypic outcome. We covered the landscape of gene variability and found that the porin forms two major phylogenetic clusters with striking genetic diversity. We generated 14 isogenic mutant strains, each encoding a unique ompU allele, and found that divergent genotypes lead to convergent antimicrobial resistance profiles. We identified and characterized functional domains in OmpU unique to variants conferring AMR-associated phenotypes. Specifically, we identified four conserved domains that are linked with resistance to bile and host-derived antimicrobial peptides. Mutant strains for these domains exhibit differential susceptibility patterns to these and other antimicrobials. Interestingly, a mutant strain in which we exchanged the four domains of the clinical allele for those of a sensitive strain exhibits a resistance profile closer to a porin deletion mutant. Finally, using phenotypic microarrays, we uncovered novel functions of OmpU and their connection with allelic variability. Our findings highlight the suitability of our approach towards dissecting the specific protein domains associated with the emergence of AMR and can be naturally extended to other bacterial pathogens and biological processes.

show abstract

Allelic variations and gene cluster modularity act as non-linear bottlenecks for cholera emergence

Cited by 6 publications

References 118 publications

Allelic diversity uncovers protein domains contributing to the emergence of antimicrobial resistance

Allelic diversity uncovers protein domains contributing to the emergence of antimicrobial resistance

Modular small RNA drives pathogen emergence

Allelic diversity uncovers protein domains contributing to the emergence of antimicrobial resistance

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