Role of internalin proteins in the pathogenesis of Listeria monocytogenes

Abstract

Listeria monocytogenes is a food‐borne bacterium that causes gastroenteritis, meningitis, or abortion. L. monocytogenes induces its internalization (entry) into human cells and either spreads laterally in tissues or transcytoses to traverse anatomical barriers. In this review, we discuss mechanisms by which five structurally related proteins of the “internalin” family of L. monocytogenes (InlA, InlB, InlC, InlF, and InlP) interact with distinct host receptors to promote infection of human cells and/or crossing of the intestinal, blood–brain, or placental barriers. We focus on recent results demonstrating that the internalin proteins InlA, InlB, and InlC exploit exocytic pathways to stimulate transcytosis, entry, or cell‐to‐cell spread, respectively. We also discuss evidence that InlA‐mediated transcytosis contributes to traversal of the intestinal barrier, whereas InlF promotes entry into endothelial cells to breach the blood–brain barrier. InlB also facilitates the crossing of the blood–brain barrier, but does so by extending the longevity of infected monocytes that may subsequently act as a “Trojan horse” to transfer bacteria to the brain. InlA, InlB, and InlP each contribute to fetoplacental infection by targeting syncytiotrophoblast or cytotrophoblast layers of the placenta. This work highlights the diverse functions of internalins and the complex mechanisms by which these structurally related proteins contribute to disease.

Novel Internalin P homologs in Listeria

“…While it is possible that these species could encode inlP homologs elsewhere in their genomes, it seems unlikely considering their domain architectures and lower conservation in sequence compared to other homologs. It is more likely that the homologous proteins identified in Lc and Lin are independent of InlP, but in the same class of small, secreted internalins that encompasses InlP, InlC, and InlH, among others 11 . Notably, we found that L. ivanovii londoniensis encoded a homolog for inlP while L. ivanovii ivanovii did not.…”

“…Once in the digestive system, Lm uses several virulence factors, including the internalins, to colonize gut epithelial cells and spread throughout the host 5,6,11 . Internalins contribute to this spread by conferring tissue tropism; for example, InlA binds E-cadherin on gut epithelial cells while InlB binds C-Met expressed by hepatocytes 11 . These interactions are enabled by Leucine-Rich Repeat (LRR) domains found in all internalins 11,12 .…”

“…Internalins contribute to this spread by conferring tissue tropism; for example, InlA binds E-cadherin on gut epithelial cells while InlB binds C-Met expressed by hepatocytes 11 . These interactions are enabled by Leucine-Rich Repeat (LRR) domains found in all internalins 11,12 . LRR domains are found in an array of functionally diverse proteins across the domains of life, such as ribonuclease inhibitors in eukaryotes (humans, pigs) and virulence factors in prokaryotes (Yersinia pestis, L. monocytogenes) 12 .…”

“…Typically, listeriosis begins with the consumption of contaminated food items. Once in the digestive system, Lm uses several virulence factors, including the internalins, to colonize gut epithelial cells and spread throughout the host 5,6,11 . Internalins contribute to this spread by conferring tissue tropism; for example, InlA binds E-cadherin on gut epithelial cells while InlB binds C-Met expressed by hepatocytes 11 .…”

“…LRR domains are found in an array of functionally diverse proteins across the domains of life, such as ribonuclease inhibitors in eukaryotes (humans, pigs) and virulence factors in prokaryotes (Yersinia pestis, L. monocytogenes) 12 . Internalins may have as few as four (InlG) or as many as fourteen (InlA) LRR domains 5,11 are relatively well-conserved across the genus, including species that are considered non-pathogenic to humans, such as L. seeligeri and L. innocua 4,13,14 . While the details remain unclear, differences in pathogenicity have been attributed to minor genetic variations and differences in the expression of virulence factor genes 15 .…”