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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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Mice were infected i.n. with 2×104 C. neoformans organisms and euthanized 12 days post-infection.(A) Fungal burden of C57BL/6 wild-type (n = 10), IL-1R knockout (n = 5), IL-18R knockout (n = 6), and MyD88 knockout (n = 6) mice after infection with C. neoformans. Numbers of CFU in the lungs, brain, and spleen were determined, with results expressed as log10 CFU per gram of tissue and as individual data points for each animal. Bars represent the mean values and the dotted line indicates the lower limit of detection. *, P<0.05 and **, P<0.01 compared with wild-type mice. (B) Cytokine levels in the lungs of wild-type and knockout mice after infection with C. neoformans. Cytokines were measured by Bio-Plex assay. Lung cytokine levels were also determined in uninfected mice to establish baseline levels. Data are expressed as picograms of cytokine per gram of lung. Results are means ± SEM. *, P<0.05, **, P<0.01, and ***, P<0.001 compared with wild-type infected mice.
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pone-0026232-g002: Mice were infected i.n. with 2×104 C. neoformans organisms and euthanized 12 days post-infection.(A) Fungal burden of C57BL/6 wild-type (n = 10), IL-1R knockout (n = 5), IL-18R knockout (n = 6), and MyD88 knockout (n = 6) mice after infection with C. neoformans. Numbers of CFU in the lungs, brain, and spleen were determined, with results expressed as log10 CFU per gram of tissue and as individual data points for each animal. Bars represent the mean values and the dotted line indicates the lower limit of detection. *, P<0.05 and **, P<0.01 compared with wild-type mice. (B) Cytokine levels in the lungs of wild-type and knockout mice after infection with C. neoformans. Cytokines were measured by Bio-Plex assay. Lung cytokine levels were also determined in uninfected mice to establish baseline levels. Data are expressed as picograms of cytokine per gram of lung. Results are means ± SEM. *, P<0.05, **, P<0.01, and ***, P<0.001 compared with wild-type infected mice.

Mentions: At day 12 post-infection, the CFU burden was minimally elevated in the lung homogenates from IL-1R knockout mice compared to WT mice (Figure 2A). This was observed despite the fact that the absence of IL-1R neither enhanced nor impaired survival following challenge with H99 at this dose. Cryptococcal levels were significantly elevated in the brains and spleens of IL-18R knockout mice compared to WT mice (Figure 2A). Otherwise, no differences were significant for WT versus knockout mouse CFU burdens.


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)

Mice were infected i.n. with 2×104 C. neoformans organisms and euthanized 12 days post-infection.(A) Fungal burden of C57BL/6 wild-type (n = 10), IL-1R knockout (n = 5), IL-18R knockout (n = 6), and MyD88 knockout (n = 6) mice after infection with C. neoformans. Numbers of CFU in the lungs, brain, and spleen were determined, with results expressed as log10 CFU per gram of tissue and as individual data points for each animal. Bars represent the mean values and the dotted line indicates the lower limit of detection. *, P<0.05 and **, P<0.01 compared with wild-type mice. (B) Cytokine levels in the lungs of wild-type and knockout mice after infection with C. neoformans. Cytokines were measured by Bio-Plex assay. Lung cytokine levels were also determined in uninfected mice to establish baseline levels. Data are expressed as picograms of cytokine per gram of lung. Results are means ± SEM. *, P<0.05, **, P<0.01, and ***, P<0.001 compared with wild-type infected mice.
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Related In: Results  -  Collection

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pone-0026232-g002: Mice were infected i.n. with 2×104 C. neoformans organisms and euthanized 12 days post-infection.(A) Fungal burden of C57BL/6 wild-type (n = 10), IL-1R knockout (n = 5), IL-18R knockout (n = 6), and MyD88 knockout (n = 6) mice after infection with C. neoformans. Numbers of CFU in the lungs, brain, and spleen were determined, with results expressed as log10 CFU per gram of tissue and as individual data points for each animal. Bars represent the mean values and the dotted line indicates the lower limit of detection. *, P<0.05 and **, P<0.01 compared with wild-type mice. (B) Cytokine levels in the lungs of wild-type and knockout mice after infection with C. neoformans. Cytokines were measured by Bio-Plex assay. Lung cytokine levels were also determined in uninfected mice to establish baseline levels. Data are expressed as picograms of cytokine per gram of lung. Results are means ± SEM. *, P<0.05, **, P<0.01, and ***, P<0.001 compared with wild-type infected mice.
Mentions: At day 12 post-infection, the CFU burden was minimally elevated in the lung homogenates from IL-1R knockout mice compared to WT mice (Figure 2A). This was observed despite the fact that the absence of IL-1R neither enhanced nor impaired survival following challenge with H99 at this dose. Cryptococcal levels were significantly elevated in the brains and spleens of IL-18R knockout mice compared to WT mice (Figure 2A). Otherwise, no differences were significant for WT versus knockout mouse CFU burdens.

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