Campylobacter jejuni Type VI Secretion System: Roles in Adaptation to Deoxycholic Acid, Host Cell Adherence, Invasion, and In Vivo Colonization

Abstract

The recently identified type VI secretion system (T6SS) of proteobacteria has been shown to promote pathogenicity, competitive advantage over competing microorganisms, and adaptation to environmental perturbation. By detailed phenotypic characterization of loss-of-function mutants, in silico, in vitro and in vivo analyses, we provide evidence that the enteric pathogen, Campylobacter jejuni, possesses a functional T6SS and that the secretion system exerts pleiotropic effects on two crucial processes – survival in a bile salt, deoxycholic acid (DCA), and host cell adherence and invasion. The expression of T6SS during initial exposure to the upper range of physiological levels of DCA (0.075%–0.2%) was detrimental to C. jejuni proliferation, whereas down-regulation or inactivation of T6SS enabled C. jejuni to resist this effect. The C. jejuni multidrug efflux transporter gene, cmeA, was significantly up-regulated during the initial exposure to DCA in the wild type C. jejuni relative to the T6SS-deficient strains, suggesting that inhibition of proliferation is the consequence of T6SS-mediated DCA influx. A sequential modulation of the efflux transporter activity and the T6SS represents, in part, an adaptive mechanism for C. jejuni to overcome this inhibitory effect, thereby ensuring its survival. C. jejuni T6SS plays important roles in host cell adhesion and invasion as T6SS inactivation resulted in a reduction of adherence to and invasion of in vitro cell lines, while over-expression of a hemolysin co-regulated protein, which encodes a secreted T6SS component, greatly enhanced these processes. When inoculated into B6.129P2-IL-10tm1Cgn mice, the T6SS-deficient C. jejuni strains did not effectively establish persistent colonization, indicating that T6SS contributes to colonization in vivo. Taken together, our data demonstrate the importance of bacterial T6SS in host cell adhesion, invasion, colonization and, for the first time to our knowledge, adaptation to DCA, providing new insights into the role of T6SS in C. jejuni pathogenesis.

Salmonella Typhimurium utilizes a T6SS-mediated antibacterial weapon to establish in the host gut

“…Intriguingly, other gut pathogens such as Campylobacter jejuni, Helicobacter hepaticus, and V. cholerae also have a T6SS, and it would be interesting to determine whether gut colonization by these pathogens is mediated through a potential antibacterial activity (58)(59)(60). Altogether, this new colonization strategy could be a common theme among Gram-negative gut pathogens, and T6SS-mediated antibacterial interactions should be further studied to have a more comprehensive understanding of the interaction between the pathogen and the host in its entirety.…”

Targeting Bacillosamine Biosynthesis in Bacterial Pathogens: Development of Inhibitors to a Bacterial Amino-Sugar Acetyltransferase from Campylobacter jejuni

“…In this context, C. jejuni features both a formidable cell wall including inner and outer cell membranes flanking a peptidoglycan barrier together with a dense external glycocalyx, as well as an active CmeABC efflux pump system to guard against external chemical agents. 49 With respect to potency, the X-ray analysis of PglD with compound 17 provides an excellent foundation for further structure-guided optimization of the thienopyrimidine core. Concerning cellular uptake and efflux, which are common impediments to antibiotic activity in Gram-negative pathogens, the presented thienopyrimidine core also offers considerable opportunities.…”

The IbeA Invasin of Adherent-Invasive Escherichia coli Mediates Interaction with Intestinal Epithelia and Macrophages

“…As mentioned above, since intracellular levels of bacteria were still found upon disruption of ibeA, it is important to define other virulence determinants associated with AIEC invasion. Genes for a complete type VI secretion system (T6SS), which has been reported to contribute to invasion in other enteric pathogens (53), have been found in NRG857c (11), but it is unknown whether they play any functional role in this process.…”