Abstract
Campylobacter jejuni outer membrane vesicles (OMVs) contain numerous virulence-associated proteins including the cytolethal distending toxin and three serine proteases. As C. jejuni lacks the classical virulence-associated secretion systems of other enteric pathogens that deliver effectors directly into target cells, OMVs may have a particularly important role in virulence. C. jejuni OMV production is stimulated by the presence of physiological concentrations of the bile salt sodium taurocholate (ST) through an unknown mechanism. The maintenance of lipid asymmetry (MLA) pathway has been implicated in a novel mechanism for OMV biogenesis, open to regulation by host signals. In this study we investigated the role of the MLA pathway in C. jejuni OMV biogenesis with ST as a potential regulator. OMV production was quantified by analyzing protein and lipid concentrations of OMV preparations and OMV particle counts produced by nanoparticle tracking analysis. Mutation of mlaA which encodes the outer membrane component of the MLA pathway significantly increased OMV production compared to the wild-type strain. Detergent sensitivity and membrane permeability assays confirmed the increased OMV production was not due to changes in membrane stability. The presence of 0.2% (w/v) ST increased wild-type OMV production and reduced OMV size, but did not further stimulate mlaA mutant OMV production or significantly alter mlaA mutant OMV size. qRT-PCR analysis demonstrated that the presence of ST decreased expression of both mlaA and mlaC in C. jejuni wild-type strains 11168 and 488. Collectively the data in this study suggests C. jejuni can regulate OMV production in response to host gut signals through changes in expression of the MLA pathway. As the gut bile composition is dependent on both diet and the microbiota, this study highlights the potential importance of diet and lifestyle factors on the varying disease presentations associated with gut pathogen infection.
Highlights
Campylobacter jejuni is a microaerophilic Gramnegative bacterium that is the leading cause of foodborne bacterial gastroenteritis worldwide (Silva et al, 2011; Kaakoush et al, 2015)
Cj1371 and Cj1372 in C. jejuni 11168 are within the same gene cluster and are homologous to MlaA and MlaC in E. coli and VacJ and YrbC in H. influenzae
Cj1646, Cj1647, and Cj1648 in C. jejuni 11168 are encoded by the same gene cluster and are homologous to MlaEFD in E. coli, and YrbEFD in H. influenzae
Summary
Campylobacter jejuni is a microaerophilic Gramnegative bacterium that is the leading cause of foodborne bacterial gastroenteritis worldwide (Silva et al, 2011; Kaakoush et al, 2015). An alternative machinery to deliver potential virulence determinants are outer membrane vesicles (OMVs), which can act as a general secretion pathway among Gram-negative bacteria and maybe are of particular importance for C. jejuni virulence and survival. OMV production has been observed under a range of conditions in both pathogenic and nonpathogenic Gram-negative bacteria (Mashburn-Warren et al, 2008; Elmi et al, 2012; Altindis et al, 2014; Zakharzhevskaya et al, 2017); both on solid and in liquid media (Schooling and Beveridge, 2006; Schwechheimer and Kuehn, 2015), and in the presence or absence of stress (Schwechheimer and Kuehn, 2015). OMVs have been suggested to have a variety of functions important in survival and virulence via processes such as competition for growth (Manning and Kuehn, 2011; Kulkarni et al, 2015), immunomodulation (Koeppen et al, 2016; Tsatsaronis et al, 2018), biofilm formation (Schooling and Beveridge, 2006), bacterial communication (Mashburn and Whiteley, 2005; Mashburn-Warren et al, 2008), and the delivery of biomolecules such as toxins (Bielaszewska et al, 2017; Elmi et al, 2018)
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