Immature myeloid/myeloid-suppressor cells and myeloid cell necroptosis mediate lethal pulmonary tularemia

Abstract Inhalation of Francisella tularensis (Ft) causes acute and fatal pneumonia. The lung cytokine milieu favors exponential Ft replication, but mechanisms underlying acute pathogenesis and death remain unknown. Evaluation of the sequential and systemic host immune response in pulmonary tularemia reveals that an overt innate cellular response to Ft, not bacterial burden per se, drives tissue pathology and host mortality. Lethal infection with Ft elicits medullary and extra-medullary myelopoiesis supporting recruitment of large numbers of immature myeloid cells and MDSC to the lungs. These cells fail to mature, but subsequently die leading to necrotic lung damage, loss of pulmonary function, and host death. Ensuing tissue damage and host mortality is Necrostatin sensitive and depletion of dying immature Ly6G+ cells is beneficial, implicating a contribution of necroptotic cell death in tularemia pathogenesis. Accelerated recruitment of immature myeloid cells and/or myeloid cell death may account for the rapid mortality seen with a virulent strain of Ft SchuS4. In contrast, during sub-lethal infection with Ft LVS the pulmonary cellular response is characterized by a predominance of mature neutrophils and monocytes required for protection, suggesting a required threshold for lethal bacterial infection. Further, eliciting a mature phagocyte response provides transient, but dramatic, innate protection against Ft SchuS4. This study reveals that the nature of the innate myeloid cell response may be the primary determinant of host mortality versus survival following Francisella infection