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.
Highlights
Francisella tularensis (Ft) is a highly pathogenic gram-negative bacterium classified as a category ‘A’ biothreat agent by the CDC [1]
Work to date suggests that a failure to control bacteria, delayed cytokines, endotoxic shock, suppression of immunity, or a combination of these is responsible for fatal disease
We have evaluated the sequence of systemic host immune responses and found that an inappropriate response of mostly immature, ineffective, and dying phagocytic cells likely explains the tissue damage and death accompanying Ft pneumonia
Summary
Francisella tularensis (Ft) is a highly pathogenic gram-negative bacterium classified as a category ‘A’ biothreat agent by the CDC [1]. A virulent strain (SchuS4) of Ft subsp. Tularensis (Type A) is highly pathogenic to humans and animals, while the less virulent live vaccine strain (LVS) of Ft subsp. Unlike non-fatal skin infection, inhalation of as few as 10 cfu of SchuS4 results in acute pulmonary tularemia with high mortality in mice, while lethal LVS infection requires higher bacterial numbers. Ft initially replicates in host cells without eliciting inflammatory cytokines such as TNFα, IL-1β and IL-6 [3,4,5,6]. Unfettered exponential Ft replication results in overwhelming bacterial burden that account for acute death in SchuS4 infection [7]. Inflammatory cytokines manifest in lungs later (>3 dpi), but are too late to prevent death [8]. Multiple cytokines and HMGB-1 elaborated in later days, suggest bacterial sepsis-associated death [4, 5]
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