Natural Isoforms of Listeria monocytogenes Virulence Factor Inlb Differ in c-Met Binding Efficiency and Differently Affect Uptake and Survival Listeria in Macrophage

Abstract

Listeria monocytogenes virulence factor InlB specifically interacts with the receptors c-Met and gC1q-R. Both receptors are present in non-professional and professional phagocytes, including macrophages. Phylogenetically defined InlB isoforms differently support invasion into non-professional phagocytes. This work deals with the effects of InlB isoforms on L. monocytogenes uptake and intracellular proliferation in human macrophages. Three isoforms of the receptor binding domain (idInlB) were derived from phylogenetically distinct L. monocytogenes strains belonging to the highly virulent CC1 (idInlB_CC1), medium-virulence CC7 (idInlB_CC7), and low-virulence CC9 (idInlB_CC9) clonal complexes. The constant dissociation increased in the order idInlB_CC1 << idInlB_CC7 < idInlB_CC9 for interactions with c-Met, and idInlB_CC1 ≈ idInlB_CC7 < idInlB_CC9 for interactions with gC1q-R. The comparison of uptake and intracellular proliferation of isogenic recombinant strains which expressed full-length InlBs revealed that the strain expressing idInlB_CC1 proliferated in macrophages twice as efficiently as other strains. Macrophage pretreatment with idInlB_CC1 followed by recombinant L. monocytogenes infection disturbed macrophage functions decreasing pathogen uptake and improving its intracellular multiplication. Similar pretreatment with idInlB_CC7 decreased bacterial uptake but also impaired intracellular multiplication. The obtained results demonstrated that InlB impaired macrophage functions in an idInlB isoform-dependent manner. These data suggest a novel InlB function in L. monocytogenes virulence.

Keywords: InlB; Listeria monocytogenes; M1 macrophages; c-Met; gC1qR; listeriosis.