title: Contributions of the MyD88-dependent receptors IL-18R, IL-1R, and TLR9 to host defenses following pulmonary challenge with Cryptococcus neoformans.
abstract: Signaling via the adapter protein, MyD88, is important in the host defense against Cryptococcus neoformans infection. While certain Toll-like receptors (TLRs) can enhance the clearance of Cryptococcus, the contributions of MyD88-dependent, TLR-independent pathways have not been fully investigated. We examined the roles of IL-1R and IL-18R in vivo by challenging C57BL/6 mice with a lethal strain of Cryptococcus. We found that the absence of IL-18R, but not IL-1R, causes a shift in the survival curve following pulmonary delivery of a virulent strain of C. neoformans (H99). Specifically, IL-18R-deficient mice have significantly shorter median survival times compared to wild-type mice following infection. Cytokine analysis of lung homogenates revealed that deficiency of IL-IR, IL-18R, or MyD88 is associated with diminished lung levels of IL-1β. In order to compare these findings with those related to TLR-deficiency, we studied the effects of TLR9-deficiency and found that deficiency of TLR9 also affects the survival curve of mice following challenge with C. neoformans. Yet the lungs from infected TLR9-deficient mice have robust levels of IL-1β. In summary, we found that multiple signaling components can contribute the MyD88-dependent host responses to cryptococcal infection in vivo and each drives distinct pulmonary responses.
authors: Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America. Jennifer.wang@umassmed.edu
authors: Jennifer P
authors: JP
authors: Wang
authors: Chrono K
authors: CK
authors: Lee
authors: Ali
authors: A
authors: Akalin
authors: Robert W
authors: RW
authors: Finberg
authors: Stuart M
authors: SM
authors: Levitz
mesh_terms: D000818:Animals; D003455:Cryptococcus neoformans / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000502:physiology*; D017472:Receptors, Interleukin-1 / Q000502:physiology*; D053724:Receptors, Interleukin-18 / Q000502:physiology*; D051217:Toll-Like Receptor 9 / Q000502:physiology*
chemical_list: D053594:Myeloid Differentiation Factor 88; D017472:Receptors, Interleukin-1; D053724:Receptors, Interleukin-18; D051217:Toll-Like Receptor 9