Entamoeba histolytica evades innate immunity by triggering the degradation of macrophage cytoskeletal‐associated proteins (152.4)

Entamoeba histolytica (Eh) is the causative agent of amebiasis, a disease responsible for ~100 000 deaths/year. In most cases, Eh colonizes the mucus layer of the colon without causing symptoms, however in some individuals Eh invades the colonic mucosa causing amebic colitis. The first response of the host at sites of Eh invasion is a robust acute inflammatory response mediated by macrophages. Eh‐macrophage interaction is thus a critical first step in determining how the innate immune response will be shaped, yet the mechanisms that regulate this interaction remain largely unknown. In this study, we investigated the early cellular events triggered in macrophages in response to Eh and the putative virulent factors involved. Through biochemical and microscopy techniques, we have unravelled that only live Eh in direct contact with human naïve macrophages triggered an instantaneous degradation of the cytoskeletal‐associated proteins Pyk2 and paxillin. This event was critically dependent on the major surface virulent factor, cysteine proteinase 5 (EhCP5) as revealed using EhCP5‐deficient Eh and protease inhibitors. As macrophage cytosketal proteins are critically involved in cell adhesion, migration and inflammation, we surmise that Eh has evolved mechanisms to “stun” macrophages during infection to dampen the innate immune response. Taken together, our findings advance a unique mechanism by which Eh modulates immune cells by interfering with the cell cytoskeleton, which may favour parasite colonization and/or altering pro‐inflammatory responses in Eh pathogenesis. Grant Funding Source : Supported by the Natural Sciences and Engineering Research Council of Canada (NSERC)