Abstract
The role of IL-1β and IL-18 during lung infection with the gram-negative bacterium Francisella tularensis LVS has not been characterized in detail. Here, using a mouse model of pneumonic tularemia, we show that both cytokines are protective, but through different mechanisms. Il-18-/- mice quickly succumb to the infection and showed higher bacterial burden in organs and lower level of IFNγ in BALF and serum compared to wild type C57BL/6J mice. Administration of IFNγ rescued the survival of Il-18-/- mice, suggesting that their decreased resistance to tularemia is due to inability to produce IFNγ. In contrast, mice lacking IL-1 receptor or IL-1β, but not IL-1α, appeared to control the infection in its early stages, but eventually succumbed. IFNγ administration had no effect on Il-1r1-/- mice survival. Rather, Il-1r1-/- mice were found to have significantly reduced titer of Ft LPS-specific IgM. The anti-Ft LPS IgM was generated in a IL-1β-, TLR2-, and ASC-dependent fashion, promoted bacteria agglutination and phagocytosis, and was protective in passive immunization experiments. B1a B cells produced the anti-Ft LPS IgM and these cells were significantly decreased in the spleen and peritoneal cavity of infected Il-1b-/- mice, compared to C57BL/6J mice. Collectively, our results show that IL-1β and IL-18 activate non-redundant protective responses against tularemia and identify an essential role for IL-1β in the rapid generation of pathogen-specific IgM by B1a B cells.
Highlights
Francisella tularensis (Ft) is a Gram-negative bacterium that infects macrophages and other cell types causing tularemia [1]
Our results show that IL-1β and IL-18 activate non-redundant protective responses against tularemia and identify an essential role for IL-1β in the rapid generation of pathogen-specific IgM by B1a B cells
F. tularensis is considered a potential bioterrorism agent and is a prime model intracellular bacterium to study the interaction of pathogens with the host immune system
Summary
Francisella tularensis (Ft) is a Gram-negative bacterium that infects macrophages and other cell types causing tularemia [1]. The other innate immune pathway preferentially stimulated by Ft in mice is the inflammasome composed of AIM2-ASC-caspase-1 [14]. It is believed that genomic DNA released by lysing bacteria localized in the cytosol activates this inflammasome, leading to secretion of IL-1β and IL-18 and death of the infected cells by pyroptosis. This form of caspase-1-dependent cell death has been shown to effectively restrict intracellular replication of several bacteria, including Ft, by exposing them to extracellular microbicidal mechanisms [15]. Activation of the NLRP3 inflammasome in human macrophages has been reported [16].
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