Phagocytosis of Acanthamoeba by macrophages and neutrophils and “kiss and run” evasion by Entamoeba histolytica

Phagocytosis was discovered in the 19th century and is a cornerstone of innate immunity. Although amoebae species cause over 100 million cases of severe infections annually, one long-standing dogma remained unchallenged: that eukaryotic amoebae are too large to be phagocytosed. Here, we overturn this entrenched dogma and show that human macrophages and neutrophils efficiently phagocytose Acanthamoeba polyphaga and Vermamoeba vermiformis , in a phosphoinositide 3-kinase-dependent manner. In contrast, Entamoeba histolytica utilizes a “kiss and run” evasion strategy of phagocytosis. However, formalin-killed and UV-irradiated E. histolytica are efficiently phagocytosed. Macrophages respond to E. histolytica by formation of striking F-actin fibrillar projections, in contrast to the bona fide phagocytic cups that engulf killed E. histolytica , A. polyphaga , and V. vermiformis . Remarkably, neutrophils harboring phagocytosed amoebae are efferocytosed by macrophages. These findings redefine innate immunity to amoebae, the physical and biological limits of phagocytosis, and uncover divergent evolution among pathogenic amoebae to subvert phagocytosis. IMPORTANCE Eukaryotic amoebae have been presumed to be too large to be phagocytosed. We demonstrate that human macrophages and neutrophils can efficiently phagocytose diverse amoebae species, while Entamoeba histolytica evades phagocytosis, redefining innate immunity to amoebae and the physical limits of phagocytosis.