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Campylobacter jejuni transcriptional and genetic adaptation during human infection

Abstract

Campylobacter jejuni infections are a leading cause of bacterial food-borne diarrhoeal illness worldwide, and Campylobacter infections in children are associated with stunted growth and therefore long-term deficits into adulthood. Despite this global impact on health and human capital, how zoonotic C. jejuni responds to the human host remains unclear. Unlike other intestinal pathogens, C. jejuni does not harbour pathogen-defining toxins that explicitly contribute to disease in humans. This makes understanding Campylobacter pathogenesis challenging and supports a broad examination of bacterial factors that contribute to C. jejuni infection. Here, we use a controlled human infection model to characterize C. jejuni transcriptional and genetic adaptations in vivo, along with a non-human primate infection model to validate our approach. We found that variation in 11 genes is associated with either acute or persistent human infections and includes products involved in host cell invasion, bile sensing and flagella modification, plus additional potential therapeutic targets. In particular, a functional version of the cell invasion protein A (cipA) gene product is strongly associated with persistently infecting bacteria and we identified its biochemical role in flagella modification. These data characterize the adaptive C. jejuni response to primate infections and suggest therapy design should consider the intrinsic differences between acute and persistently infecting bacteria. In addition, RNA sequencing revealed conserved responses during natural host commensalism and human infections. Thirty-nine genes were differentially regulated in vivo across hosts, lifestyles and C. jejuni strains. This conserved in vivo response highlights important C. jejuni survival mechanisms such as iron acquisition and evasion of the host mucosal immune response. These advances highlight pathogen adaptability across host species and demonstrate the utility of multidisciplinary collaborations in future clinical trials to study pathogens in vivo.

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Fig. 1: The C. jejuni transcriptome in human infection and chick commensalism.
Fig. 2: C. jejuni genomic variants are consistently selected for during human infections.
Fig. 3: Particular genome variants are associated with C. jejuni recrudescent infection isolate populations.
Fig. 4: Validating C. jejuni genomic variant selection in non-human primates.

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Acknowledgements

We thank E.J. Rubin for support in developing nucleic acid extraction protocols; H. Ochman and M.A. Leibold for feedback on this project; S.M. Giovanetti for insightful discussion on figures. This work was supported by the National Institutes of Health (NIH) (AI064184 to M.S.T.), the Military Infectious Diseases Research Program (6000.RAD1.DA3.A0308), and the Navy Advanced Medical Development Program (NMRC enterprise Work Unit NumberA1406). This work was funded by the Military Infectious Diseases Research Program, Navy Work Unit 6000.RAD1.DA3.A0308 the Naval Medical Research Center’s Advanced Medical Development Program (NMRC enterprise Work Unit Number A1406). The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, nor the U.S. government. P.G., D.R.T., F.M.P., C.K.P., R.L.G., M.S.R. and A.J.M. are either employees of the U.S. government or military service members and this work was prepared as part of their official duties. Title 17 USC 105 provides that ‘Copyright protection under this title is not available for any work of the United States government.’ Title 17 USC 101 defines a U.S. government work as a work prepared by a military service member or employee of the U.S. government as part of that person’s official duties.

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A.A.C. conceived, designed, preformed and interpreted genetic and transcriptomic analyses and wrote the paper. P.G. and M.S.T. established this collaborative project and oversaw this study. B.W.D. and M.S.T. oversaw computational analyses. A.A.C., M.S.T. and P.G. provided critical biological interpretations of the data. J.E.R, C.H., D.S., K.R.T., C.K.P., R.L.G., B.D., J.B., R.M.L., A.C.M., K.J., A.A., D.R.T. and M.S.R. conducted the clinical trial. F.M.P. and J.M.K. collected specimens for transcriptomics. C.P.E. performed experiments relevant to biological interpretation of the data. A.R. and A.J.M. performed the non-human primate experiments. B.W.D., P.G. and M.S.T supervised this work and edited the manuscript.

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Correspondence to Patricia Guerry or M. Stephen Trent.

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Crofts, A.A., Poly, F.M., Ewing, C.P. et al. Campylobacter jejuni transcriptional and genetic adaptation during human infection. Nat Microbiol 3, 494–502 (2018). https://doi.org/10.1038/s41564-018-0133-7

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