Campylobacter jejuni transcriptional and genetic adaptation during human infection

• Published in: Nature microbiology Vol. 3; no. 4; pp. 494 - 502
• Main Authors: Crofts, Alexander A., Poly, Frédéric M., Ewing, Cheryl P., Kuroiwa, Janelle M., Rimmer, Joanna E., Harro, Clayton, Sack, David, Talaat, Kawsar R., Porter, Chad K., Gutierrez, Ramiro L., DeNearing, Barbara, Brubaker, Jessica, Laird, Renée M., Maue, Alexander C., Jaep, Kayla, Alcala, Ashley, Tribble, David R., Riddle, Mark. S., Ramakrishnan, Amritha, McCoy, Andrea J., Davies, Bryan W., Guerry, Patricia, Trent, M. Stephen
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-04-2018; Nature Publishing Group
• Subjects: 38/22; 38/23; 38/39; 38/43; 38/90; 38/91; 631/326/41/2530; 631/326/41/2531; 631/326/421; 692/308/2779/109; 692/699/1503/1581; 82/29; 82/83; Adaptability; Adaptations; Animals; Azithromycin - therapeutic use; Bacteria; Bacterial Proteins - genetics; Bile; Biomedical and Life Sciences; Campylobacter; Campylobacter Infections - drug therapy; Campylobacter Infections - microbiology; Campylobacter Infections - pathology; Campylobacter jejuni; Campylobacter jejuni - genetics; Campylobacter jejuni - pathogenicity; Chickens - microbiology; Children; Ciprofloxacin - therapeutic use; Clinical trials; Commensalism; Flagella; Flagella - genetics; Foodborne Diseases - drug therapy; Foodborne Diseases - microbiology; Foodborne Diseases - pathology; Gene Expression Regulation, Bacterial - genetics; Genetic Variation - genetics; Humans; Immune response; Infections; Infectious Diseases; Intestine; Intestines - microbiology; Intestines - pathology; Life Sciences; Medical Microbiology; Membrane Proteins - genetics; Microbiology; Mucosal immunity; Parasitology; Pathogens; Ribonucleic acid; Rifaximin - therapeutic use; RNA; Therapeutic applications; Transcription; Virology; Zoonoses
• ISSN: 2058-5276; 2058-5276
• DOI: 10.1038/s41564-018-0133-7

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.
A human challenge trial with
Campylobacter jejuni
uncovers transcriptional and genomic changes during infection, highlighting pathogen factors associated with acute and persistent infection.