title: An Immature Myeloid/Myeloid-Suppressor Cell Response Associated with Necrotizing Inflammation Mediates Lethal Pulmonary Tularemia.
abstract: Inhalation of Francisella tularensis (Ft) causes acute and fatal pneumonia. The lung cytokine milieu favors exponential Ft replication, but the mechanisms underlying acute pathogenesis and death remain unknown. Evaluation of the sequential and systemic host immune response in pulmonary tularemia reveals that in contrast to overwhelming bacterial burden or cytokine production, an overt innate cellular response to Ft 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 and die, leading to subsequent necrotic lung damage, loss of pulmonary function, and host death that is partially dependent upon immature Ly6G+ cells. Acceleration of this process may account for the rapid lethality seen with 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 myeloid cell response may be the primary determinant of host mortality versus survival following Francisella infection.
authors.affiliation: Center for Immunology and Microbial Disease, Albany Medical College, Albany, New York, United States of America.
authors.forename: Sivakumar
authors.initials: S
authors.lastname: Periasamy
authors.affiliation: Center for Immunology and Microbial Disease, Albany Medical College, Albany, New York, United States of America.
authors.forename: Dorina
authors.initials: D
authors.lastname: Avram
authors.affiliation: Center for Immunology and Microbial Disease, Albany Medical College, Albany, New York, United States of America.
authors.forename: Amanda
authors.initials: A
authors.lastname: McCabe
authors.affiliation: Center for Immunology and Microbial Disease, Albany Medical College, Albany, New York, United States of America.
authors.forename: Katherine C
authors.initials: KC
authors.lastname: MacNamara
authors.affiliation: Center for Immunology and Microbial Disease, Albany Medical College, Albany, New York, United States of America.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Sellati
authors.affiliation: Center for Immunology and Microbial Disease, Albany Medical College, Albany, New York, United States of America.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Harton
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism; D005604:Francisella tularensis / Q000276:immunology*; D006801:Humans; D007249:Inflammation; D008168:Lung / Q000276:immunology; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000378:metabolism; D011014:Pneumonia / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D014406:Tularemia / Q000276:immunology*
chemical_list: D016207:Cytokines; D051195:Toll-Like Receptor 2