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Myeloid Differentiation Factor 88 and Interleukin-1R1 Signaling Contribute to Resistance to Coccidioides immitis

Suganya Viriyakosol1,2, Lorraine Walls2, Sharon Okamoto1

  • 1Department of Medicine, UC San Diego School of Medicine, San Diego, California, USA.

Infection and Immunity
|April 4, 2018
PubMed

Insights

Interleukin-1 receptor 1 (IL-1R1) signaling is crucial for fighting Coccidioides immitis fungal infections in mice. Myeloid differentiation factor 88 (MyD88) pathway is less critical than IL-1R1 for host defense.

Area of Science:

  • Immunology
  • Mycology
  • Infectious Diseases

Background:

  • Rodents serve as natural reservoirs for Coccidioides fungi, making mice valuable models for studying human coccidioidomycosis.
  • Dectin-1 and Toll-like receptor 2 (TLR2) on myeloid cells are known to enhance immune responses to Coccidioides fungal forms.
  • While Dectin-1 is essential for resistance, the in vivo role of TLR2 in coccidioidomycosis remains unclear.

Purpose of the Study:

  • To investigate the roles of specific immune receptors and adapter proteins in host defense against Coccidioides immitis pulmonary infection.
  • To elucidate the contribution of Myeloid differentiation factor 88 (MyD88) and Interleukin-1 receptor 1 (IL-1R1) in Coccidioides immitis pathogenesis.

Main Methods:

  • Utilized Myeloid differentiation factor 88 (MyD88)/TRIF knockout and MyD88 knockout mouse models to assess susceptibility to Coccidioides immitis.
  • Evaluated the necessity of specific surface receptors, including IL-1R1, for resistance against Coccidioides immitis infection.
  • Assessed cytokine production, specifically IL-1 receptor antagonist (IL-1Ra), from bone marrow-derived dendritic cells (BMDCs) stimulated with formalin-killed spherules (FKS).

Main Results:

  • MyD88 knockout mice exhibited equal susceptibility to Coccidioides immitis infection as MyD88/TRIF knockout mice, indicating a significant role for MyD88.
  • Interleukin-1 receptor 1 (IL-1R1) was identified as the sole receptor among those studied that is required for resistance to Coccidioides immitis.
  • Formalin-killed spherules (FKS) induced IL-1Ra production in a MyD88 and Dectin-1 independent manner, and high IL-1Ra levels were found in infected mouse lungs.

Conclusions:

  • Interleukin-1 receptor 1 (IL-1R1) signaling plays a critical role in the host immune defense against Coccidioides immitis infection.
  • The findings partially explain the susceptibility observed in MyD88-deficient mice, highlighting the importance of IL-1R1 signaling.
  • The study suggests that IL-1Ra may contribute to the host's immune response, potentially influencing the outcome of coccidioidomycosis.
Keywords:
CoccidioidesIL-18IL-1R1IL-1RaMyD88TLR2TLR4innate immunityβ-glucan

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