Gut metabolite L-lactate supportsCampylobacter jejunipopulation expansion during acute infection

Abstract

How the microaerobic pathogenCampylobacter jejuniestablishes its niche and expands in the gut lumen during infection is poorly understood. Using six-week-old ferrets as a natural disease model, we examined this aspect ofC. jejunipathogenicity. Unlike mice, which require significant genetic or physiological manipulation to become colonized withC. jejuni, ferrets are readily infected without the need to disarm the immune system or alter the gut microbiota. Disease afterC. jejuniinfection in ferrets reflects closely how humanC. jejuniinfection proceeds. Rapid growth ofC. jejuniand associated intestinal inflammation was observed within two-three days of infection. We observed pathophysiological changes that were noted by cryptic hyperplasia through the induction of tissue repair systems, accumulation of undifferentiated amplifying cells on the colon surface, and instability of HIF-1α in colonocytes, which indicated increased epithelial oxygenation. Metabolomic analysis demonstrated that lactate levels in colon content were elevated in infected animals. AC. jejunimutant lackinglctP, which encodes an L-lactate transporter, was significantly decreased for colonization during infection. Lactate also influences adhesion and invasion byC. jejunito a colon carcinoma cell line (HCT116). The oxygenation required for expression of lactate transporter (lctP) led to discovery of a putative thiol based redox switch regulator (LctR) that may represslctPtranscription under anaerobic conditions. Our work provides new insights into the pathogenicity ofC. jejuni.SignificanceThere is a gap in knowledge about the mechanisms by whichC. jejunipopulations expand during infection. Using an animal model which accurately reflects human infection without the need to alter the host microbiome or the immune system prior to infection, we explored pathophysiological alterations of the gut afterC. jejuniinfection. Our study identified the gut metabolite L-lactate as playing an important role as a growth substrate forC. jejuniduring acute infection. We identified a DNA binding protein, LctR, that binds to thelctPpromoter and may represslctPexpression, resulting in decreased lactate transport under low oxygen levels. This work provides new insights aboutC. jejunipathogenicity.

CemR atypical response regulator impacts energy conversion inCampylobacteria

“…We have shown that cysteine residues of HpCemR become oxidised under O 2 -triggered oxidative stress in vivo and in vitro, which changes the protein’s DNA-binding activity possibly by structural changes of DNA-protein complex rather than on-off mechanism 22,24 . Recent studies on CjCemR interactions with the promoter region of lctP suggested a similar mechanism of CjCemR activity control and lctP transcription regulation 26 . AbCemR protein also contains cysteine residues, one of which is conserved in all three species (C27 in HpCemR and CjCemR, C31 in AbCemR).…”

“…HP1021 interacts with the origin of chromosome replication region ( oriC ), probably participating in the control of the initiation of H. pylori chromosome replication 25 . As for Cj1608, in vitro, it interacts with the C. jejuni oriC region and the promoter of the lctP lactate transporter, probably participating in the control of the initiation of the C. jejuni chromosome replication and lactate metabolism 26,27 .…”