Acanthamoeba and macrophages exhibit significant parallels in biochemical, physiological, cellular, and functional aspects. Given the ability of Acanthamoeba to contribute to the evolutionary gain of pathogenicity of a variety of microbial pathogens, here we propose the use of Acanthamoeba as a paradigm to study SARS-CoV-2 pathogenicity, infectivity, and evasion of cellular immune defenses.