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

ABSTRACT: 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-? 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-?. Although IL-18 production was not significantly affected by MyD88 deficiency, IL-18 was essential for IFN-? production and restricted bacterial replication in an IFN-?-dependent manner. Caspase-1 was also found to be partially necessary for the production of IL-18 and IFN-? 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-?-dependent control of type A F. tularensis infection.

SUBMITTER: Skyberg JA

PROVIDER: S-EPMC5669634 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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

Skyberg Jerod A JA Lacey Carolyn A CA

Journal of leukocyte biology 20170926 6

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, ...[more]

PMID: 28951422

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Project description:Francisella tularensis is a Gram-negative, facultative intracellular pathogen that replicates in the cytosol of macrophages and is the causative agent of the potentially fatal disease tularemia. A characteristic feature of F. tularensis is its limited proinflammatory capacity, but the mechanisms that underlie the diminished host response to this organism are only partially defined. Recently, microRNAs have emerged as important regulators of immunity and inflammation. In the present study we investigated the microRNA response of primary human monocyte-derived macrophages (MDMs) to F. tularensis and identified 10 microRNAs that were significantly differentially expressed after infection with the live vaccine strain (LVS), as judged by Taqman Low Density Array profiling. Among the microRNAs identified, miR-155 is of particular interest as its established direct targets include components of the Toll-like receptor (TLR) pathway, which is essential for innate defense and proinflammatory cytokine production. Additional studies demonstrated that miR-155 acted by translational repression to downregulate the TLR adapter protein MyD88 and the inositol 5'-phosphatase SHIP-1 in MDMs infected with F. tularensis LVS or the fully virulent strain Schu S4. Kinetic analyses indicated that miR-155 increased progressively 3-18 hours after infection with LVS or Schu S4, and target proteins disappeared after 12-18 hours. Dynamic modulation of MyD88 and SHIP-1 was confirmed using specific pre-miRs and anti-miRs to increase and decrease miR-155 levels, respectively. Of note, miR-155 did not contribute to the attenuated cytokine response triggered by F. tularensis phagocytosis. Instead, this microRNA was required for the ability of LVS-infected cells to inhibit endotoxin-stimulated TNF? secretion 18-24 hours after infection. Thus, our data are consistent with the ability of miR-155 to act as a global negative regulator of the inflammatory response in F. tularensis-infected human macrophages.

Dataset Information

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

Publications

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

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