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Contributions of the MyD88-dependent receptors IL-18R, IL-1R, and TLR9 to host defenses following pulmonary challenge with Cryptococcus neoformans.

Wang JP, Lee CK, Akalin A, Finberg RW, Levitz SM - PLoS ONE (2011)

Bottom Line: Signaling via the adapter protein, MyD88, is important in the host defense against Cryptococcus neoformans 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 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America. Jennifer.wang@umassmed.edu

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.

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Survival of C57BL/6 wild-type, IL-18R knockout, IL-1R knockout, and MyD88 knockout mice following infection with C. neoformans.Mice were infected i.n. with 2×104 C. neoformans organisms and were monitored for signs of disease and euthanized when the signs of disease were severe. (A) No difference in survival was observed following infection of wild-type (n = 24) and IL-1R knockout (n = 21) mice with C. neoformans. Data are combined from two independent experiments, each with similar results. (B) The survival curves were significantly different between IL-18R knockout mice (n = 17) and wild-type mice (n = 32), P<0.0001. The data are combined from three independent experiments, each of which had similar results. (C) MyD88 knockout mice (n = 7) had a trend towards diminished survival compared to wild-type (n = 12), P = 0.058.
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pone-0026232-g001: Survival of C57BL/6 wild-type, IL-18R knockout, IL-1R knockout, and MyD88 knockout mice following infection with C. neoformans.Mice were infected i.n. with 2×104 C. neoformans organisms and were monitored for signs of disease and euthanized when the signs of disease were severe. (A) No difference in survival was observed following infection of wild-type (n = 24) and IL-1R knockout (n = 21) mice with C. neoformans. Data are combined from two independent experiments, each with similar results. (B) The survival curves were significantly different between IL-18R knockout mice (n = 17) and wild-type mice (n = 32), P<0.0001. The data are combined from three independent experiments, each of which had similar results. (C) MyD88 knockout mice (n = 7) had a trend towards diminished survival compared to wild-type (n = 12), P = 0.058.

Mentions: IL-1R knockout mice did not exhibit any significant survival differences compared to WT mice (Figure 1A). The median survival time was 24 days for WT mice and 25 days for IL-1R deficient mice. In contrast, at this same dose, 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). The median survival time for IL-18R knockout mice was 22 days compared to 25 days for WT mice (P<0.0001). MyD88-deficient mice had a decrease in median survival time compared to WT mice following challenge with a lethal dose of Cryptococcus, which was consistent with previously reported findings [3], [4] (Figure 1C). Median survival for MyD88 knockout mice was 21 days compared to 26 days for WT mice.


Contributions of the MyD88-dependent receptors IL-18R, IL-1R, and TLR9 to host defenses following pulmonary challenge with Cryptococcus neoformans.

Wang JP, Lee CK, Akalin A, Finberg RW, Levitz SM - PLoS ONE (2011)

Survival of C57BL/6 wild-type, IL-18R knockout, IL-1R knockout, and MyD88 knockout mice following infection with C. neoformans.Mice were infected i.n. with 2×104 C. neoformans organisms and were monitored for signs of disease and euthanized when the signs of disease were severe. (A) No difference in survival was observed following infection of wild-type (n = 24) and IL-1R knockout (n = 21) mice with C. neoformans. Data are combined from two independent experiments, each with similar results. (B) The survival curves were significantly different between IL-18R knockout mice (n = 17) and wild-type mice (n = 32), P<0.0001. The data are combined from three independent experiments, each of which had similar results. (C) MyD88 knockout mice (n = 7) had a trend towards diminished survival compared to wild-type (n = 12), P = 0.058.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3198470&req=5

pone-0026232-g001: Survival of C57BL/6 wild-type, IL-18R knockout, IL-1R knockout, and MyD88 knockout mice following infection with C. neoformans.Mice were infected i.n. with 2×104 C. neoformans organisms and were monitored for signs of disease and euthanized when the signs of disease were severe. (A) No difference in survival was observed following infection of wild-type (n = 24) and IL-1R knockout (n = 21) mice with C. neoformans. Data are combined from two independent experiments, each with similar results. (B) The survival curves were significantly different between IL-18R knockout mice (n = 17) and wild-type mice (n = 32), P<0.0001. The data are combined from three independent experiments, each of which had similar results. (C) MyD88 knockout mice (n = 7) had a trend towards diminished survival compared to wild-type (n = 12), P = 0.058.
Mentions: IL-1R knockout mice did not exhibit any significant survival differences compared to WT mice (Figure 1A). The median survival time was 24 days for WT mice and 25 days for IL-1R deficient mice. In contrast, at this same dose, 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). The median survival time for IL-18R knockout mice was 22 days compared to 25 days for WT mice (P<0.0001). MyD88-deficient mice had a decrease in median survival time compared to WT mice following challenge with a lethal dose of Cryptococcus, which was consistent with previously reported findings [3], [4] (Figure 1C). Median survival for MyD88 knockout mice was 21 days compared to 26 days for WT mice.

Bottom Line: Signaling via the adapter protein, MyD88, is important in the host defense against Cryptococcus neoformans 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 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America. Jennifer.wang@umassmed.edu

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.

Show MeSH
Related in: MedlinePlus