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.
Highlights
Cryptococcus neoformans is a fungal pathogen that causes lifethreatening disease preferentially in individuals with impaired T cell function, persons with AIDS [1]
The median survival time was days for WT mice and days for IL-1R deficient mice. At this same dose, IL-18 receptor (IL-18R) knockout mice had a significant decrease in median survival time compared to WT mice following infection with C. neoformans strain H99 (Figure 1B)
Previous studies have shown that MyD88 and certain Toll-like receptors (TLRs) contribute to host protective responses in cryptococcal infection
Summary
Cryptococcus neoformans is a fungal pathogen that causes lifethreatening disease preferentially in individuals with impaired T cell function, persons with AIDS [1]. Investigations of the host responses to C. neoformans using murine models of infection have broadened our understanding of the signaling pathways involved in defense. Toll-like receptors (TLRs) are innate immune receptors that are critical in the host defense against many types of invading pathogens. Following activation via TLRs and MyD88, innate immune cells produce cytokines and effector molecules essential for the adaptive immune response. The importance of MyD88 in host defense in cryptococcal infection was demonstrated when MyD88-deficient mice exhibited decreased survival and increased fungal burden in the lungs following fungal challenge [3,4]. Recent investigations have focused on the role of TLR9 in cryptococcal infection. Namakura et al found that TLR9-deficient mice had an increased cryptococcal burden in lungs than wildtype (WT) mice and established that following stimulation with
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