Summary
Title: Role of the gut metabolite lactate on Campylobacter jejuni pathogenicity:
Campylobacter jejuni is a leading global source of human gastroenteritis caused by bacteria.
According to the most recent CDC FoodNet Surveillance System data, the incidence rate of
infection by Campylobacter was 17.8 cases per 100,000 population in United State. Due to
emergence of multidrug resistant strains, we need alternative therapeutic approaches to decrease
disease burden. This will require a better understanding of C. jejuni infection dynamics.
Progression of gastroenteritis mediated by microaerobic C. jejuni is poorly understood, especially
regarding its population expansion during the inflammatory stage of infection. Lack of a natural
disease model has limited our ability to study mechanisms of C. jejuni-mediated disease
progression in vivo. Our preliminary data demonstrate that young ferrets develop moderate to
acute gastroenteritis symptoms after infection with C. jejuni, which mimics human infection. We
also observed significant population expansion of colonic C. jejuni co-incident with an
inflammatory response in this tissue during the acute stage of infection. C. jejuni infection resulted
in colonic crypt hyperplasia, elevation of undifferentiated, proliferating Ki67+ cells in the lamina
propria, and alteration in gut metabolites compared to uninfected controls. Among elevated
metabolites was lactate, a growth substrate for C. jejuni. A strain of C. jejuni lacking the capacity
for lactate uptake was significantly less fit in this infection/inflammation model. We hypothesize
that infection by C. jejuni generates host derived lactate which contributes to pathogen expansion
in the gut lumen. Lactate also influences chemotaxis, flagellar dependent motility, and cell
adherence and invasion of C. jejuni, which are major pathogenicity traits. These findings will be
extended through the following specific aims:
Specific Aim 1: Determine the origin of elevated lactate level during C. jejuni infection.
Specific Aim 2: Define the effect of lactate on C. jejuni physiology.
By completing our two aims, we will uncover new knowledge of the molecular mechanisms of C.
jejuni infection, identifying host and bacterial factors that influence expansion of C. jejuni growth
during the inflammatory stage of infection. This work will contribute to developing therapeutic
approaches for reducing bacterial burden and disease symptoms.