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

Abstract

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 infection.-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 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 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 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 infection.

Production of IFN-γ by splenic dendritic cells during innate immune responses against Francisella tularensis LVS depends on MyD88, but not TLR2, TLR4, or TLR9

“…None of these receptors appear to explain the susceptibility and poor IFN-γ production phenotype of MyD88 KO mice. IL-18 KO mice exhibit some defects in responses to Francisella [37,58], but overall the MyD88linked pattern recognition molecule critical to optimal responses to LVS by DC and other immune effector cells awaits future discovery. Rag1 KO mice were depleted in vivo of NK1.1 + cells and then infected with 10 5 LVS i.d, Splenocytes derived from these mice were enriched in vitro for CD11c + cells using magnetic beads, and the resulting cells were analyzed by flow cytometry.…”

Interleukin 1α (IL-1α) Promotes Pathogenic Immature Myeloid Cells and IL-1β Favors Protective Mature Myeloid Cells During Acute Lung Infection

“…Bacterial control is largely absent in Myd88 −/− mice, as liver and spleen bacterial burdens were similar to those in mice receiving 10 times the lethal dose of F. tularensis [7]. Although Myd88 −/− mice die from F. tularensis infection, they do not lose weight (data not shown) [45], and levels of the cytokines normally associated with septic shock are generally reduced. It is possible that burdens achieved in these mice are sufficient to interfere with normal organ function in the absence of other pathologic processes.…”

Innate Immune Recognition: An Issue More Complex Than Expected

“…Activation of myddosome formation initiates subsequently the NF-κB signaling pathway and pro-inflammatory cytokine production. But, in parallel, there is data indicating that the control of F. tularensis infection in tissues is dependent upon the activation of MyD88 signaling only in hematopoietic cells and not in myeloid and dendritic cells (Skyberg and Lacey, 2017). The TLRs-mediated signaling thus seems, under some circumstances, to be of secondary importance or, alternatively, is inhibited or modulated by signals originated from Francisella metabolic activities inside a cell.…”