Hematopoietic MyD88 and IL-18 are essential for IFN-γ-dependent restriction of type A Francisella tularensis infection.

Francisella tularensis is a highly infectious intracellular bacterium that causes the potentially fatal disease tularemia. We used mice with conditional MyD88 deficiencies to investigate cellular and molecular mechanisms by which MyD88 restricts type A F. tularensis infection. F. tularensis -induced weight loss was predominately dependent on MyD88 signaling in nonhematopoietic cells. In contrast, MyD88 signaling in hematopoietic cells, but not in myeloid and dendritic cells, was essential for control of F. tularensis infection in tissue. Myeloid and dendritic cell MyD88 deficiency also did not markedly impair cytokine production during infection. Although the production of IL-12 or -18 was not significantly reduced in hematopoietic MyD88-deficient mice, IFN-γ production was abolished in these animals. In addition, neutralization studies revealed that control of F. tularensis infection mediated by hematopoietic MyD88 was entirely dependent on IFN-γ. Although IL-18 production was not significantly affected by MyD88 deficiency, IL-18 was essential for IFN-γ production and restricted bacterial replication in an IFN-γ-dependent manner. Caspase-1 was also found to be partially necessary for the production of IL-18 and IFN-γ and for control of F. tularensis replication. Our collective data show that the response of leukocytes to caspase-1-dependent IL-18 via MyD88 is critical, whereas MyD88 signaling in myeloid and dendritic cells is dispensable for IFN-γ-dependent control of type A F. tularensis infection.