Ameobal Pathogen Mimivirus Infects Macrophages through Phagocytosis

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Abstract
Mimivirus, or Acanthamoeba polyphaga mimivirus (APMV), a giant double-stranded DNA virus that grows in amoeba, was identified for the first time in 2003. Entry by phagocytosis within amoeba has been suggested but not demonstrated. We demonstrate here that APMV was internalized by macrophages but not by non-phagocytic cells, leading to productive APMV replication. Clathrin- and caveolin-mediated endocytosis pathways, as well as degradative endosome-mediated endocytosis, were not used by APMV to invade macrophages. Ultrastructural analysis showed that protrusions were formed around the entering virus, suggesting that macropinocytosis or phagocytosis was involved in APMV entry. Reorganization of the actin cytoskeleton and activation of phosphatidylinositol 3-kinases were required for APMV entry. Blocking macropinocytosis and the lack of APMV colocalization with rabankyrin-5 showed that macropinocytosis was not involved in viral entry. Overexpression of a dominant-negative form of dynamin-II, a regulator of phagocytosis, inhibited APMV entry. Altogether, our data demonstrated that APMV enters macrophages through phagocytosis, a new pathway for virus entry in cells. This reinforces the paradigm that intra-amoebal pathogens have the potential to infect macrophages. The giant (750 nm) double-stranded DNA virus Acanthamoeba polyphaga mimivirus (APMV) is likely responsible for pneumonia. We demonstrate here that APMV was internalized by macrophages but not by non-phagocytic cells, leading to productive replication. We also show that APMV invaded macrophages through phagocytosis. This is the first evidence that a virus is internalized by macrophages via a mechanism normally used by bacteria and parasites. This finding adds a supplementary pathway to already known strategies used by viruses to enter cells. This underlines that intra-amoebal pathogens also infect macrophages. Finally, we can hypothesize that APMV replicates within alveolar macrophages, leading to human and murine pneumonia.