The role of macrophages and neutrophils in pulmonary Francisella infection (55.24)

Abstract

Francisella tularensis is the causative agent of tularemia. Due to its ease of dissemination, high lethality, and low infectious dose required for respiratory infection, this bacterium poses a risk as an agent of bioterrorism. Though F. tularensis is believed to be an intracellular pathogen that requires replication within macrophages during respiratory infection, we have found that depletion of alveolar macrophages by intranasal treatment with liposomal Clodronate reduced mean time to death and total survival rates of infected mice. Furthermore, mice with a macrophage-specific insensitivity to interferon-γ (MIIG mice) similarly show heightened sensitivity to pulmonary Francisella infection. Such mice exhibited reduced expression of tumor necrosis factor-α, a potent neutrophil chemoattractant, in lung tissue, and systemic neutrophil depletion resulted in reduced mean time to death and total survival rates. Exogenous interleukin-12 promoted survival and bacterial clearance in mice, but this effect was lost upon neutrophil depletion and in IFN-γ-/- mice. The results suggest that rather than being a required reservoir for bacterial replication, alveolar macrophages are necessary for defense against F. tularensis infection by recruiting neutrophils to the lung, which are the primary cells responsible for clearing the bacterium.