Mucosal penetration primes Vibrio cholerae for host colonization by repressing quorum sensing

Departments of Microbiology, Physics, and Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 08/2008; 105(28):9769-74. DOI: 10.1073/pnas.0802241105
Source: PubMed


To successfully infect a host and cause the diarrheal disease cholera, Vibrio cholerae must penetrate the intestinal mucosal layer and express virulence genes. Previous studies have demonstrated that the transcriptional regulator HapR, which is part of the quorum sensing network in V. cholerae, represses the expression of virulence genes. Here, we show that hapR expression is also modulated by the regulatory network that governs flagellar assembly. Specifically, FliA, which is the alternative sigma-factor (sigma(28)) that activates late-class flagellin genes in V. cholerae, represses hapR expression. In addition, we show that mucin penetration by V. cholerae is sufficient to break flagella and so cause the secretion of FlgM, the anti-sigma factor that inhibits FliA activity. During initial colonization of host intestinal tissue, hapR expression is repressed because of low cell density. However, full repression of hapR expression does not occur in fliA mutants, which results in attenuated colonization. Our results suggest that V. cholerae uses flagellar machinery to sense particular intestinal signals before colonization and enhance the expression of virulence genes by modulating the output of quorum sensing signaling.

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Available from: Zhi Liu, Aug 25, 2014
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    • "Stators also appear to sense viscosity changes for the Vibrio parahaemolyticus motor and respond by altering flagellation patterns[57]. For Proteus mirabilis, viscosity-dependent sensing appears to use the FliL protein (found in the flagellar basal body) to activate swarmer-cell differentiation[58], while V. cholera can lose their flagella while passing through the mucus glycocalyx, leading to downstream virulence gene expression[59]. Finally, the flagellum is a known mechanosensor for biofilm differentiation at infection sites, with pathways in Pseudomonas aeruginosa, V. cholera, V. parahaemolyticus and P. mirabilis well investigated and reviewed[60]. Similar to sensing for swarmer-cell differentiation, sensing for biofilm formation involves the function of the flagellar motor stators. "
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    ABSTRACT: The bacterial flagellum is an amazingly complex molecular machine with a diversity of roles in pathogenesis including reaching the optimal host site, colonization or invasion, maintenance at the infection site, and post-infection dispersal. Multi-megadalton flagellar motors self-assemble across the cell wall to form a reversible rotary motor that spins a helical propeller - the flagellum itself - to drive the motility of diverse bacterial pathogens. The flagellar motor responds to the chemoreceptor system to redirect swimming toward beneficial environments, thus enabling flagellated pathogens to seek out their site of infection. At their target site, additional roles of surface swimming and mechanosensing are mediated by flagella to trigger pathogenesis. Yet while these motility-related functions have long been recognized as virulence factors in bacteria, many bacteria have capitalized upon flagellar structure and function by adapting it to roles in other stages of the infection process. Once at their target site, the flagellum can assist adherence to surfaces, differentiation into biofilms, secretion of effector molecules, further penetration through tissue structures, or in activating phagocytosis to gain entry into eukaryotic cells. Next, upon onset of infection, flagellar expression must be adapted to deal with the host's immune system defenses, either by reduced or altered expression or by flagellar structural modification. Finally, after a successful growth phase on or inside a host, dispersal to new infection sites is often flagellar motility-mediated. Examining examples of all these processes from different bacterial pathogens, it quickly becomes clear that the flagellum is involved in bacterial pathogenesis for motility and a whole lot more.
    Full-text · Article · Nov 2015 · Seminars in Cell and Developmental Biology
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    • "HapR is a transcriptional regulator involved in quorum sensing in V. cholerae which also regulates expression of virulence genes. HapR represses expression of several virulence genes [101] and hapR expression is regulated by an unknown mechanism involving FliA [102]. hapR expression is depressed in flgM and flgD mutants (both of these mutations alleviate FlgM repression on FliA activity), while deletion of fliA results in elevated hapR expression [102]. "
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    ABSTRACT: Flagellar biogenesis in bacteria is a complex process in which the transcription of dozens of structural and regulatory genes is coordinated with the assembly of the flagellum. Although the overall process of flagellar biogenesis is conserved among bacteria, the mechanisms used to regulate flagellar gene expression vary greatly among different bacterial species. Many bacteria use the alternative sigma factor σ 54 (also known as RpoN) to transcribe specific sets of flagellar genes. These bacteria include members of the Epsilonproteobacteria (e.g., Helicobacter pylori and Campylobacter jejuni), Gammaproteobacteria (e.g., Vibrio and Pseudomonas species), and Alphaproteobacteria (e.g., Caulobacter crescentus). This review characterizes the flagellar transcriptional hierarchies in these bacteria and examines what is known about how flagellar gene regulation is linked with other processes including growth phase, quorum sensing, and host colonization.
    Full-text · Article · Jan 2014
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    • "Flagellar motility is an environmentally regulated behavior by which a bacterium propels itself through its surroundings , directed by behavior-modifying machinery such as the chemotaxis system (Adler 1966; Henrichsen 1972; reviewed in Macnab 1996; and McCarter 2006). Within the unique environments present in different host– microbe associations, both flagellar motility and the flagellum itself can play important roles in bacterial transit , niche specificity, effector secretion, biofilm formation, host recognition, and gene regulation (Young et al. 1999; Hayashi et al. 2001; Butler and Camilli 2004; Lemon et al. 2007; Liu et al. 2008). While the process of flagellar motility is difficult to study in most host–microbe interactions, the symbiosis between the bioluminescent, gram-negative bacterium Vibrio fischeri and its host the Hawaiian bobtail squid, Euprymna scolopes, is an ideal model in which to study how this critical behavior mediates symbiotic initiation. "
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