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Campylobacter jejuni transcriptional and genetic adaptation during human infection

Nature Microbiology volume 3, pages 494–502 (2018)Cite this article

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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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References

  1. Lieberman, T. D. et al. Parallel bacterial evolution within multiple patients identifies candidate pathogenicity genes. Nat. Genet. 43, 1275–1280 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Yang, L. et al. Evolutionary dynamics of bacteria in a human host environment. Proc. Natl Acad. Sci. USA 108, 7481–7486 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Harris, S. R. et al. Evolution of MRSA during hospital transmission and intercontinental spread. Science 327, 469–474 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Kennemann, L. et al. Helicobacter pylori genome evolution during human infection. Proc. Natl Acad. Sci. USA 108, 5033–5038 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Zdziarski, J. et al. Host imprints on bacterial genomes—rapid, divergent evolution in individual patients. PLoS Pathog. 6, e1001078 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Copin, R. et al. Within host evolution selects for a dominant genotype of Mycobacterium tuberculosis while T cells increase pathogen genetic diversity. PLoS Pathog. 12, e1006111 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Bayliss, C. D. et al. Phase variable genes of Campylobacter jejuni exhibit high mutation rates and specific mutational patterns but mutability is not the major determinant of population structure during host colonization. Nucleic Acids Res. 40, 5876–5889 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Bergman, M., Del Prete, G., van Kooyk, Y. & Appelmelk, B. Helicobacter pylori phase variation, immune modulation and gastric autoimmunity. Nat. Rev. Microbiol. 4, 151–159 (2006).

    Article  CAS  PubMed  Google Scholar 

  9. Srikhanta, Y. N., Fox, K. L. & Jennings, M. P. The phasevarion: phase variation of type III DNA methyltransferases controls coordinated switching in multiple genes. Nat. Rev. Microbiol. 8, 196–206 (2010).

    Article  CAS  PubMed  Google Scholar 

  10. Kim, J. -S. et al. Passage of Campylobacter jejuni through the chicken reservoir or mice promotes phase variation in contingency genes Cj0045 and Cj0170 that strongly associates with colonization and disease in a mouse model. Microbiology 158, 1304–1316 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Jerome, J. P. et al. Standing genetic variation in contingency loci drives the rapid adaptation of Campylobacter jejuni to a novel host. PLoS ONE 6, e16399 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Mohawk, K. L., Poly, F., Sahl, J. W., Rasko, D. A. & Guerry, P. High frequency, spontaneous motA mutations in Campylobacter jejuni strain 81–176. PLoS ONE 9, e88043 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Amour, C. et al. Epidemiology and impact of Campylobacter infection in children in 8 low-resource settings: results from the MAL-ED study. Clin. Infect. Clin. Infect. Dis. 63, 1171–1179 (2016).

    PubMed  PubMed Central  Google Scholar 

  14. Cawthraw, S. A., Wassenaar, T. M., Ayling, R. & Newell, D. G. Increased colonization potential of Campylobacter jejuni strain 81116 after passage through chickens and its implication on the rate of transmission within flocks. Epidemiol. Infect. 117, 213–215 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Rimmer, J. E. et al. Rifaximin fails to prevent campylobacteriosis in the human challenge model: a randomized, double-blind, placebo-controlled trial. Clin. Infect. Dis. https://doi.org/10.1093/cid/cix1014 (2017).

  16. Baqar, S. et al. Recrudescent Campylobacter jejuni infection in an immunocompetent adult following experimental infection with a well-characterized organism. Clin. Vaccin. Immunol. CVI 17, 80–86 (2010).

    Article  CAS  Google Scholar 

  17. Palyada, K., Threadgill, D. & Stintzi, A. Iron acquisition and regulation in Campylobacter jejuni. J. Bacteriol. 186, 4714–4729 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Brás, A. M., Chatterjee, S., Wren, B. W., Newell, D. G. & Ketley, J. M. A novel Campylobacter jejuni two-component regulatory system important for temperature-dependent growth and colonization. J. Bacteriol. 181, 3298–3302 (1999).

    PubMed  PubMed Central  Google Scholar 

  19. Del Rocio Leon-Kempis, M., Guccione, E., Mulholland, F., Williamson, M. P. & Kelly, D. J. The Campylobacter jejuni PEB1a adhesin is an aspartate/glutamate-binding protein of an ABC transporter essential for microaerobic growth on dicarboxylic amino acids. Mol. Microbiol. 60, 1262–1275 (2006).

    Article  Google Scholar 

  20. Ziprin, R. L. et al. Role of Campylobacter jejuni potential virulence genes in cecal colonization. Avian. Dis. 45, 549–557 (2001).

    Article  CAS  PubMed  Google Scholar 

  21. Jones, M. A. et al. Adaptation of Campylobacter jejuni NCTC11168 to high-level colonization of the avian gastrointestinal tract. Infect. Immun. 72, 3769–3776 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Fields, J. A. & Thompson, S. A. Campylobacter jejuni CsrA mediates oxidative stress responses, biofilm formation, and host cell invasion. J. Bacteriol. 190, 3411–3416 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Taveirne, M. E., Theriot, C. M., Livny, J. & DiRita, V. J. The complete Campylobacter jejuni transcriptome during colonization of a natural host determined by RNAseq. PLoS ONE 8, e73586 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Corcionivoschi, N. et al. Mucosal reactive oxygen species decrease virulence by disrupting Campylobacter jejuni phosphotyrosine signaling. Cell Host Microbe 12, 47–59 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Pryjma, M., Apel, D., Huynh, S., Parker, C. T. & Gaynor, E. C. FdhTU-modulated formate dehydrogenase expression and electron donor availability enhance recovery of Campylobacter jejuni following host cell infection. J. Bacteriol. 194, 3803–3813 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Johnson, J. G., Gaddy, J. A. & DiRita, V. J. The PAS domain-containing protein HeuR regulates heme uptake in Campylobacter jejuni. mBio 7, e01691–16 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Naikare, H. et al. Campylobacter jejuni ferric-enterobactin receptor CfrA is TonB3 dependent and mediates iron acquisition from structurally different catechol siderophores. Met. Integr. Biometal Sci. 5, 988–996 (2013).

    Article  CAS  Google Scholar 

  28. Hoang, K. V., Wang, Y. & Lin, J. Identification of genetic loci that contribute to Campylobacter resistance to fowlicidin-1, a chicken host defense peptide. Front. Cell. Infect. Microbiol. 2, 32 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Cameron, A. et al. High-frequency variation of purine biosynthesis genes is a mechanism of success in Campylobacter jejuni. mBio 6, e00612–15 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Barrero-Tobon, A. M. & Hendrixson, D. R. Identification and analysis of flagellar coexpressed determinants (Feds) of Campylobacter jejuni involved in colonization. Mol. Microbiol. 84, 352–369 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Luethy, P. M., Huynh, S., Parker, C. T. & Hendrixson, D. R. Analysis of the activity and regulon of the two-component regulatory system composed by Cjj81176_1484 and Cjj81176_1483 of Campylobacter jejuni. J. Bacteriol. 197, 1592–1605 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Javed, M. A. et al. Transposon mutagenesis in a hyper-invasive clinical isolate of Campylobacter jejuni reveals a number of genes with potential roles in invasion. Microbiology 156, 1134–1143 (2010).

    Article  CAS  PubMed  Google Scholar 

  33. Poli, V. F. S., Thorsen, L., Olesen, I., Wik, M. T. & Jespersen, L. Differentiation of the virulence potential of Campylobacter jejuni strains by use of gene transcription analysis and a Caco-2 assay. Int. J. Food Microbiol. 155, 60–68 (2012).

    Article  CAS  PubMed  Google Scholar 

  34. Guo, B. et al. CmeR functions as a pleiotropic regulator and is required for optimal colonization of Campylobacter jejuni in vivo. J. Bacteriol. 190, 1879–1890 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Lei, H. -T. et al. Crystal structures of CmeR-bile acid complexes from Campylobacter jejuni. Protein Sci. Publ. Protein Soc. 20, 712–723 (2011).

    Article  CAS  Google Scholar 

  36. Lin, J., Overbye Michel, L. & Zhang, Q. CmeABC functions as a multidrug efflux system in Campylobacter jejuni. Antimicrob. Agents Chemother. 46, 2124–2131 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Grinnage-Pulley, T. & Zhang, Q. Genetic basis and functional consequences of differential expression of the CmeABC efflux pump in Campylobacter jejuni isolates. PLoS ONE 10, e0131534 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Lin, J., Sahin, O., Michel, L. O. & Zhang, Q. Critical role of multidrug efflux pump CmeABC in bile resistance and in vivo colonization of Campylobacter jejuni. Infect. Immun. 71, 4250–4259 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Guerry, P. et al. Changes in flagellin glycosylation affect Campylobacter autoagglutination and virulence. Mol. Microbiol. 60, 299–311 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Howard, S. L. et al. Campylobacter jejuni glycosylation island important in cell charge, legionaminic acid biosynthesis, and colonization of chickens. Infect. Immun. 77, 2544–2556 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Murray, J. L., Kwon, T., Marcotte, E. M. & Whiteley, M. Intrinsic antimicrobial resistance determinants in the super bug Pseudomonas aeruginosa. mBio 6, e01603–15 2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Turner, K. H., Wessel, A. K., Palmer, G. C., Murray, J. L. & Whiteley, M. Essential genome of Pseudomonas aeruginosa in cystic fibrosis sputum. Proc. Natl Acad. Sci. USA 112, 4110–4115 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Kaas, R. S., Leekitcharoenphon, P., Aarestrup, F. M. & Lund, O. Solving the problem of comparing whole bacterial genomes across different sequencing platforms. PLoS ONE 9, e104984 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Monteiro, M. A. et al. Capsule polysaccharide conjugate vaccine against diarrheal disease caused by Campylobacter jejuni. Infect. Immun. 77, 1128–1136 (2009).

    Article  CAS  PubMed  Google Scholar 

  45. Jones, F. R. et al. New World monkey Aotus nancymae as a model for Campylobacter jejuni infection and immunity. Infect. Immun. 74, 790–793 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Pequegnat, B. et al. Phase variable changes in the position of O-methyl phosphoramidate modifications on the polysaccharide capsule of Campylobacter jejuni modulate serum resistance. J. Bacteriol. 199, e00027–17 (2017).

  47. Thibault, P. et al. Identification of the carbohydrate moieties and glycosylation motifs in Campylobacter jejuni flagellin. J. Biol. Chem. 276, 34862–34870 (2001).

    Article  CAS  PubMed  Google Scholar 

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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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Authors and Affiliations

  1. Department of Molecular Biosciences, University of Texas at Austin, Austin, TX, USA

    Alexander A. Crofts & Bryan W. Davies

  2. Enteric Diseases Department, Naval Medical Research Center, Silver Spring, MD, USA

    Frédéric M. Poly, Cheryl P. Ewing, Janelle M. Kuroiwa, Joanna E. Rimmer, Chad K. Porter, Ramiro L. Gutierrez, Renée M. Laird, Alexander C. Maue, Kayla Jaep, Ashley Alcala, Mark. S. Riddle & Patricia Guerry

  3. School of Immunity and Infection, University of Birmingham, Birmingham, UK

    Joanna E. Rimmer

  4. Academic Department of Military Medicine, Royal Centre for Defense Medicine, Medical Directorate, Joint Medical Command, Birmingham Research Park, Birmingham, UK

    Joanna E. Rimmer

  5. Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

    Clayton Harro, David Sack, Kawsar R. Talaat, Barbara DeNearing & Jessica Brubaker

  6. Infectious Disease Clinical Research Program, Uniformed Services University of the Health Sciences, Bethesda, MD, USA

    David R. Tribble

  7. Naval Medical Research Unit-6, Lima, Peru

    Amritha Ramakrishnan & Andrea J. McCoy

  8. Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, TX, USA

    Bryan W. Davies

  9. Department of Infectious Diseases, University of Georgia at Athens, College of Veterinary Medicine, Athens, GA, USA

    M. Stephen Trent

  10. Center for Vaccines and Immunology, University of Georgia at Athens, College of Veterinary Medicine, Athens, GA, USA

    M. Stephen Trent

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  1. Alexander A. Crofts
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Contributions

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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