title: Interleukin-1 receptor but not Toll-like receptor 2 is essential for MyD88-dependent Th17 immunity to Coccidioides infection.
abstract: Interleukin-17A (IL-17A)-producing CD4(+) T helper (Th17) cells have been shown to be essential for defense against pulmonary infection with Coccidioides species. However, we have just begun to identify the required pattern recognition receptors and understand the signal pathways that lead to Th17 cell activation after fungal infection. We previously reported that Card9(-/-) mice vaccinated with formalin-killed spherules failed to acquire resistance to Coccidioides infection. Here, we report that both MyD88(-/-) and Card9(-/-) mice immunized with a live, attenuated vaccine also fail to acquire protective immunity to this respiratory disease. Like Card9(-/-) mice, vaccinated MyD88(-/-) mice revealed a significant reduction in numbers of both Th17 and Th1 cells in their lungs after Coccidioides infection. Both Toll-like receptor 2 (TLR2) and IL-1 receptor type 1 (IL-1r1) upstream of MyD88 have been implicated in Th17 cell differentiation. Surprisingly, vaccinated TLR2(-/-) and wild-type (WT) mice showed similar outcomes after pulmonary infection with Coccidioides, while vaccinated IL-1r1(-/-) mice revealed a significant reduction in the number of Th17 cells in their infected lungs compared to WT mice. Thus, activation of both IL-1r1/MyD88- and Card9-mediated Th17 immunity is essential for protection against Coccidioides infection. Our data also reveal that the numbers of Th17 cells were reduced in IL-1r1(-/-) mice to a lesser extent than in MyD88(-/-) mice, raising the possibility that other TLRs are involved in MyD88-dependent Th17 immunity to coccidioidomycosis. An antimicrobial action of Th17 cells is to promote early recruitment of neutrophils to infection sites. Our data revealed that neutrophils are required for vaccine immunity to this respiratory disease.
authors.affiliation: Department of Biology and South Texas Center for Emerging Infectious Diseases, University of Texas, San Antonio, Texas, USA.
authors.forename: Chiung-Yu
authors.initials: CY
authors.lastname: Hung
authors.forename: María del Pilar
authors.initials: Mdel P
authors.lastname: Jiménez-Alzate
authors.forename: Angel
authors.initials: A
authors.lastname: Gonzalez
authors.forename: Marcel
authors.initials: M
authors.lastname: Wüthrich
authors.forename: Bruce S
authors.initials: BS
authors.lastname: Klein
authors.forename: Garry T
authors.initials: GT
authors.lastname: Cole
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D053468:CARD Signaling Adaptor Proteins; D003045:Coccidioides; D003047:Coccidioidomycosis / Q000276:immunology*; D005657:Fungal Vaccines / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism*; D053573:Receptors, Interleukin-1 Type I / Q000235:genetics / Q000378:metabolism*; D058504:Th17 Cells; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D053468:CARD Signaling Adaptor Proteins; C513280:Card9 protein, mouse; D005657:Fungal Vaccines; C583355:IL1R1 protein, mouse; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D053573:Receptors, Interleukin-1 Type I; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2