The Stress-Induced Virulence Protein InlH Controls Interleukin-6 Production during Murine Listeriosis

Abstract

The genome of the pathogenic bacterium Listeria monocytogenes contains a family of genes encoding proteins with a leucine-rich repeat domain. One of these genes, inlH, is a B -dependent virulence gene of unknown function. Previously, inlH was proposed to be coexpressed with two adjacent internalin genes, inlG and inlE. Using tiling arrays, we showed that inlH expression is monocistronic and specifically induced in stationary phase as well as in the intestinal lumen of mice, independent of inlG and inlE expression. Consistent with inlH B -dependent regulation, surface expression of the InlH protein is induced when bacteria are subjected to thermal, acidic, osmotic, or oxidative stress. Disruption of inlH increases the amount of the invasion protein InlA without changing inlA transcript level, suggesting that there is a link between inlH expression and inlA posttranscriptional regulation. However, in contrast to InlA, InlH does not contribute to bacterial invasion of cultured cells in vitro or of intestinal cells in vivo. Strikingly, the reduced virulence of inlH-deficient L. monocytogenes strains is accompanied by enhanced production of interleukin-6 (IL-6) in infected tissues during the systemic phase of murine listeriosis but not by enhanced production of any other inflammatory cytokine tested. Since InlH does not modulate IL-6 secretion in macrophages at least in vitro, it may play a role in other immune cells or contribute to a pathway that modulates survival or activation of IL-6-secreting cells. These results strongly suggest that InlH is a stress-induced surface protein that facilitates pathogen survival in tissues by tempering the inflammatory response.

The arsenal of virulence factors deployed byListeria monocytogenesto promote its cell infection cycle

“…218 inlH is a virulence gene whose expression is dependent on σ B and is specifically induced during stationary phase and in the mouse intestinal lumen. 187,219 InlH is not involved in bacterial invasion of cultured cell lines or intestinal cells in vivo. However, the virulence decrease of L. monocytogenes strains lacking inlH is accompanied by an increase in IL-6 production in infected tissues, during the systemic phase of murine listeriosis.…”

“…This suggests that InlH improves bacterial survival in tissues by interfering with the inflammatory response. 219 Superoxide dismutases (SODs) are enzymes that protect organisms against superoxides and reactive oxygen species (ROS) produced during active metabolism. ROS are major mediators of phagocyte microbicidal activity.…”

Association of ActA to Peptidoglycan Revealed by Cell Wall Proteomics of Intracellular Listeria monocytogenes

“…With the exception of Lmo1666, which has recently been shown to be a new L. monocytogenes adhesion protein required for virulence (50), and Lmo0263 (InlH), which also contributes to virulence (51), the rest of these LPXTG proteins have orthologs in nonpathogenic Listeria species such as Listeria innocua (12). This fact suggests that the role of some abundant LPXTG proteins in Listeria could be related to the maintenance of cell wall integrity or other conserved physiological processes, such as nutrient transport.…”

Genome Sequence of the Nonpathogenic Listeria monocytogenes Serovar 4a Strain M7

“…Sixty-four genes that were conserved in pathogenic strains were absent in M7 (prophage genes excepted). At least three internalins (InlC, InlH, and InlJ) that contribute to Listeria pathogenicity were absent in M7 (13,14,15). On the other hand, 151 genes were identified as specific to M7 but absent in pathogenic strains (except the prophage genes).…”