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Microevolution of Campylobacter jejuni during long-term infection in an immunocompromised host.

ABSTRACT: Campylobacteriosis typically manifests as a short-lived, self-limiting gastrointestinal infection in humans, however prolonged infection can be seen in cases with underlying immunodeficiency. Public Health England received 25 isolates of Campylobacter jejuni from an individual with combined variable immunodeficiency over a period of 15 years. All isolates were typed and archived at the time of receipt. Whole genome sequencing (WGS) and antimicrobial susceptibility testing were performed to examine the relatedness of the isolates and to investigate the changes in the genome that had taken place over the course of the infection. Genomic typing methods were compared to conventional phenotypic methods, and revealed that the infection was caused by a single, persistent strain of C. jejuni belonging to clonal complex ST-45, with evidence of adaptation and selection in the genome over the course of the infection. Genomic analysis of sequence variants associated with antimicrobial resistance identified the genetic background behind rRNA gene mutations causing variable levels of resistance to erythromycin. This application of WGS to examine a persistent case of campylobacteriosis provides insight into the mutations and selective pressures occurring over the course of an infection, some of which have important clinical relevance.

SUBMITTER: Barker CR

PROVIDER: S-EPMC7308304 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Microevolution of Campylobacter jejuni during long-term infection in an immunocompromised host.

Barker Clare R CR Painset Anaïs A Swift Craig C Jenkins Claire C Godbole Gauri G Maiden Martin C J MCJ Dallman Timothy J TJ

Scientific reports 20200622 1

Campylobacteriosis typically manifests as a short-lived, self-limiting gastrointestinal infection in humans, however prolonged infection can be seen in cases with underlying immunodeficiency. Public Health England received 25 isolates of Campylobacter jejuni from an individual with combined variable immunodeficiency over a period of 15 years. All isolates were typed and archived at the time of receipt. Whole genome sequencing (WGS) and antimicrobial susceptibility testing were performed to exami ...[more]

PMID: 32572150

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Project description: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.

Project description:BackgroundCampylobacter jejuni is considered as a chicken commensal. The gut microbiota and the immune status of the host may affect its colonization. Infectious bursal disease virus (IBDV) is an immunosuppressive virus of chickens, which allows secondary pathogens to invade or exacerbates their pathogenesis. To investigate the effect of IBDV-induced immunosuppression on the pathogenesis of C. jejuni, broiler chickens were inoculated with a very virulent (vv) strain of IBDV at 14 days post hatch followed by C. jejuni inoculation at 7 (Experiment A) or 9 (Experiment B) days post virus (IBDV) inoculation.ResultsvvIBDV-infection led to a depression in caecal lamina propria B lymphocytes and the anti-C. jejuni-antibody response starting at 14 days post C. jejuni inoculation (pbi). The C. jejuni-colonization pattern was comparable between mono-inoculated groups of both experiments, but it varied for vvIBDV + C. jejuni co-inoculated groups. In Experiment A significant higher numbers of colony forming units (CFU) of C. jejuni were detected in the caecum of co-inoculated birds compared to C. jejuni-mono-inoculated birds in the early phase after C. jejuni-inoculation. In Experiment B the clearance phase was affected in the co-inoculated group with significantly higher CFU at 21 days pbi compared to the mono-inoculated group (P < 0.05). No major differences were seen in numbers local lamina propria T lymphocyte populations between C. jejuni-inoculated groups with or without vvIBDV-infection. Interestingly, both pathogens affected the microbiota composition. The consequences of these microflora changes for the host have to be elucidated further.ConclusionOur data suggests that the timing between viral and bacterial infection might affect the outcome of C. jejuni colonization differently. Our results confirm previous studies that anti-Campylobacter-antibodies may specifically be important for the clearance phase of the bacteria. Therefore, as vvIBDV is widely distributed in the field, it may have a significant impact on the colonization and shedding rate of C. jejuni in commercial poultry flocks. Subsequently, successful IBDV-control strategies may indirectly also benefit the gut-health of chickens.

Dataset Information

Microevolution of Campylobacter jejuni during long-term infection in an immunocompromised host.

Publications

Microevolution of Campylobacter jejuni during long-term infection in an immunocompromised host.

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