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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.

Production of Anti-LPS IgM by B1a B Cells Depends on IL-1β and Is Protective against Lung Infection with Francisella tularensis LVS