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

The role of IL-1 beta 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 IFN gamma in BALF and serum compared to wild type C57BL/6J mice. Administration of IFN gamma rescued the survival of Il-18(-/-) mice, suggesting that their decreased resistance to tularemia is due to inability to produce IFN gamma. In contrast, mice lacking IL-1 receptor or IL-1 beta, but not IL-1 alpha, appeared to control the infection in its early stages, but eventually succumbed. IFN gamma 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 antiFt LPS IgM was generated in a IL-1 beta-, 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-1 beta and IL-18 activate non-redundant protective responses against tularemia and identify an essential role for IL-1 beta in the rapid generation of pathogen-specific IgM by B1a B cells.