Coxiella burnetii blocks intracellular interleukin-17 signaling in macrophages

Tatiana M. Clemente, Minal Mulye, Anna V. Justis, Srinivas Nallandhighal, Tuan M. Tran, Stacey D. Gilk

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

Coxiella burnetii is an obligate intracellular bacterium and the etiological agent of Q fever. Successful host cell infection requires the Coxiella type IVB secretion system (T4BSS), which translocates bacterial effector proteins across the vacuole membrane into the host cytoplasm, where they manipulate a variety of cell processes. To identify host cell targets of Coxiella T4BSS effector proteins, we determined the transcriptome of murine alveolar macrophages infected with a Coxiella T4BSS effector mutant. We identified a set of inflammatory genes that are significantly upregulated in T4BSS mutant-infected cells compared to mock-infected cells or cells infected with wild-type (WT) bacteria, suggesting that Coxiella T4BSS effector proteins downregulate the expression of these genes. In addition, the interleukin-17 (IL-17) signaling pathway was identified as one of the top pathways affected by the bacteria. While previous studies demonstrated that IL-17 plays a protective role against several pathogens, the role of IL-17 during Coxiella infection is unknown. We found that IL-17 kills intracellular Coxiella in a dose-dependent manner, with the T4BSS mutant exhibiting significantly more sensitivity to IL-17 than WT bacteria. In addition, quantitative PCR confirmed the increased expression of IL-17 downstream signaling genes in T4BSS mutant-infected cells compared to WT- or mock-infected cells, including the proinflammatory cytokine genes Il1a, Il1b, and Tnfa, the chemokine genes Cxcl2 and Ccl5, and the antimicrobial protein gene Lcn2. We further confirmed that the Coxiella T4BSS downregulates macrophage CXCL2/macrophage inflammatory protein 2 and CCL5/RANTES protein levels following IL-17 stimulation. Together, these data suggest that Coxiella downregulates IL-17 signaling in a T4BSSdependent manner in order to escape the macrophage immune response.

Original languageEnglish (US)
Article numbere00532-18
JournalInfection and immunity
Volume86
Issue number10
DOIs
StatePublished - Oct 1 2018

Keywords

  • Coxiella burnetii
  • IL-17
  • Innate immunity
  • Macrophage
  • Type 4 secretion

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Infectious Diseases

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  • Cite this

    Clemente, T. M., Mulye, M., Justis, A. V., Nallandhighal, S., Tran, T. M., & Gilk, S. D. (2018). Coxiella burnetii blocks intracellular interleukin-17 signaling in macrophages. Infection and immunity, 86(10), [e00532-18]. https://doi.org/10.1128/IAI.00532-18