Distinct modes of cell division drive <i>Anaplasma phagocytophilum</i> morphotype development and the infection cycle

Pleomorphism is an evolutionary adaptation by which diverse microorganisms maximize their fitness by transitioning between morphologically distinct forms that perform disparate functions in response to the local microenvironment. Cell division is critical for morphotype transition in many pleomorphic bacterial systems. <i>Anaplasma phagocytophilum</i>, which causes the emerging disease granulocytic anaplasmosis, is a pleomorphic obligate intracellular bacterium that lives in a pathogen-modified vacuole except for when it is exocytically released for dissemination to naïve cells. This bacterium cycles between non-infectious, replicative reticulate cell (RC) and infectious, non-replicative dense-cored (DC) forms. Here, we establish that differential modes of <i>A. phagocytophilum</i> cell division drive morphotype development where RC bacteria divide symmetrically to expand the intravacuolar population after which they switch to sacrificial asymmetric division to produce DCs. <i>A. phagocytophilum</i> MreB is crucial for cell division, specifically septation, and thereby formation of both morphotypes. Inhibition of cell division prevents not only DC formation but also <i>A. phagocytophilum</i> vacuole maturation and infectious progeny release, which suggests that these pathogenic processes are coordinated. This study advances understanding of <i>A. phagocytophilum</i> growth and morphotype development and, thus, pathobiology. It also provides the first evidence linking cell division to morphotype development in the <i>Anaplasmataceae</i>.IMPORTANCE<i>Anaplasma phagocytophilum</i>, an obligate intracellular bacterial pathogen that lives in a host cell-derived vacuole, causes human and veterinary diseases of global importance. In the pathogen-occupied vacuole, <i>A. phagocytophilum</i> transitions from a replicative, non-infectious morphotype to a non-replicative, infectious morphotype that is released to spread infection. We established that distinct modes of bacterial cell division drive not only <i>A. phagocytophilum</i> replication but also its differentiation to the infectious form and dissemination to naïve cells. How pleomorphism is regulated in most vacuole-adapted bacterial pathogens is poorly understood. Therefore, this study advances fundamental knowledge of vacuole-adapted pleomorphic bacteria pathobiology and could ultimately identify common novel antibiotic targets for treating the diseases they cause.