Compartment-Specific and Sequential Role of MyD88 and CARD9 in Chemokine Induction and Innate Defense during Respiratory Fungal Infection

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Our understanding of how epithelial and hematopoietic cells in the lung coordinate immunity against inhaled fungal conidia (spores) remains limited. The mold Aspergillus fumigatus is a major cause of infectious mortality in immune compromised patients. Host defense against A. fumigatus involves the activation of two host signal transducers, MyD88 and CARD9, leading to neutrophil recruitment to the infection site. In this study, we define how MyD88- and CARD9-coupled signals operate in epithelial and hematopoietic compartments to regulate neutrophil-mediated defense against A. fumigatus. Our studies support a two-stage model in which MyD88 activation in epithelial cells, via the interleukin-1 receptor, supports the rapid induction of neutrophil-recruiting chemokines. This process is essential for the first phase of neutrophil recruitment. Mortality observed in MyD88-deficient mice can be significantly reversed by administration of a chemokine termed CXCL1 to infected airways. The second phase of neutrophil recruitment is initiated by CARD9 signaling in hematopoietic cells. Loss of both phases of chemokine induction and neutrophil recruitment dramatically increases murine susceptibility to tissue-invasive disease. In sum, our study defines a temporal sequence of events, initiated by interleukin-1 receptor/MyD88 signaling in the pulmonary epithelium and propagated by CARD9 signaling in hematopoietic cells, that induces protective immunity against inhaled fungal conidia.

Vyšlo v časopise: Compartment-Specific and Sequential Role of MyD88 and CARD9 in Chemokine Induction and Innate Defense during Respiratory Fungal Infection. PLoS Pathog 11(1): e32767. doi:10.1371/journal.ppat.1004589
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004589

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