Campylobacter jejuni BumSR directs a response to butyrate via sensor phosphatase activity to impact transcription and colonization

Abstract

<jats:p><jats:italic>Campylobacter jejuni</jats:italic>monitors intestinal metabolites produced by the host and microbiota to initiate intestinal colonization of avian and animal hosts for commensalism and infection of humans for diarrheal disease. We previously discovered that<jats:italic>C. jejuni</jats:italic>has the capacity to spatially discern different intestinal regions by sensing lactate and the short-chain fatty acids acetate and butyrate and then alter transcription of colonization factors appropriately for in vivo growth. In this study, we identified the<jats:italic>C. jejuni</jats:italic>butyrate-modulated regulon and discovered that the BumSR two-component signal transduction system (TCS) directs a response to butyrate by identifying mutants in a genetic screen defective for butyrate-modulated transcription. The BumSR TCS, which is important for infection of humans and optimal colonization of avian hosts, senses butyrate likely by indirect means to alter transcription of genes encoding important colonization determinants. Unlike many canonical TCSs, the predicted cytoplasmic sensor kinase BumS lacked in vitro autokinase activity, which would normally lead to phosphorylation of the cognate BumR response regulator. Instead, BumS has likely evolved mutations to naturally function as a phosphatase whose activity is influenced by exogenous butyrate to control the level of endogenous phosphorylation of BumR and its ability to alter transcription of target genes. To our knowledge, the BumSR TCS is the only bacterial signal transduction system identified so far that mediates responses to the microbiota-generated intestinal metabolite butyrate, an important factor for host intestinal health and homeostasis. Our findings suggest that butyrate sensing by this system is vital for<jats:italic>C. jejuni</jats:italic>colonization of multiple hosts.</jats:p>

Caecal microbiota compositions from 7-day-old chicks reared in high-performance and low-performance industrial farms and systematic culturomics to select strains with anti-Campylobacter activity

“…Conversely, it has also been reported that Short Chain Fatty Acids (SCFAs), and especially butyrate can trigger the expression of C . jejuni genes that are important for host colonization, whereas lactate which is present in higher concentrations in the upper part of the digestive tract has an inhibitory effect on this expression [ 22 , 23 ]. In our study, F .…”

“…Specific butyrate-sensing mechanisms have been recently described, altering transcription of target genes and being therefore proposed as a vital mechanism allowing C . jejuni to recognize and colonize specific intestinal niches [ 22 , 23 ].…”

Revisiting Campylobacter jejuni Virulence and Fitness Factors: Role in Sensing, Adapting, and Competing

“…However, in the context of C. jejuni avian and human colonization, the abundance of butyrate and acetate in the lower GI tract provides the bacterium with a competitive advantage to thrive in this niche ( Burnham and Hendrixson, 2018 ). A prevailing belief is that C. jejuni has the ability to spatially differentiate between sections of the GI tract by sensing the presence of acetate and butyrate, and thereby modifying the transcription of its colonization factors ( Goodman et al., 2020 ). This enables C. jejuni to obtain sufficient nutrients and resources to allow for optimal survival and persistence in both avian and human intestinal tracts.…”

“…This enables C. jejuni to obtain sufficient nutrients and resources to allow for optimal survival and persistence in both avian and human intestinal tracts. C. jejuni specifically senses butyrate via a noncanonical TCS termed BumSR ( Goodman et al., 2020 ). BumS functions as a phosphatase, via a noncanonical mechanism for signal transduction in place of a sensor kinase, to control the activity of the cognate BumR response regulator.…”

From Welfare to Warfare: The Arbitration of Host-Microbiota Interplay by the Type VI Secretion System

“…These compounds commonly promote IL-10 production and suppress inflammation; however, they may also contribute toward effector T cell differentiation, depending on the overall local immunological context (Zhang et al, 2019). On the other hand, microbial metabolites in the intestine may stimulate virulence programs of invading bacteria, with several two-component signal transduction systems in T6SS-positive pathogens having been shown to respond to SCFAs and other metabolites produced by the microbiome (Lawhon et al, 2002;Gonzalez-Chavez et al, 2010;Kohli et al, 2018;Goodman et al, 2020). It is likely that T6SS-mediated turbulent population dynamics occurring during the microbiome development results in variation in the levels of these metabolites.…”