Limits...
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.

Show MeSH

Related in: MedlinePlus

Histopathological images of lungs of wild-type, IL-1R knockout, IL-18R knockout, and MyD88 knockout mice 12 days following challenge with 2×104 C. neoformans organisms i.n.(A) Histological samples were prepared as described in Methods. Images of H & E stained slides were taken under the light microscope at 20X power objective. Moderate to severe BALT expansion is noted in the lung sections of wild-type (n = 10) and IL-1R knockout mice (n = 5) compared to MyD88 knockout (n = 6) or IL-18R knockout mice (n = 6). The arrows point to expanded BALT in the lung sections of wild-type and IL-1R knockout mice. (B) Histopathological assessment of lungs from wild-type and knockout mice after infection. Sections were scored blind by a pathologist for the indicated observations on a scale from zero (none seen) to three (severe or maximal). **, P<0.01 compared with wild-type infected mice.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3198470&req=5

pone-0026232-g003: Histopathological images of lungs of wild-type, IL-1R knockout, IL-18R knockout, and MyD88 knockout mice 12 days following challenge with 2×104 C. neoformans organisms i.n.(A) Histological samples were prepared as described in Methods. Images of H & E stained slides were taken under the light microscope at 20X power objective. Moderate to severe BALT expansion is noted in the lung sections of wild-type (n = 10) and IL-1R knockout mice (n = 5) compared to MyD88 knockout (n = 6) or IL-18R knockout mice (n = 6). The arrows point to expanded BALT in the lung sections of wild-type and IL-1R knockout mice. (B) Histopathological assessment of lungs from wild-type and knockout mice after infection. Sections were scored blind by a pathologist for the indicated observations on a scale from zero (none seen) to three (severe or maximal). **, P<0.01 compared with wild-type infected mice.

Mentions: Lung sections from WT and knockout mice 12 days post infection were evaluated for histopathological findings (Figure 3A). Individual and clusters of fungal microorganisms were seen in both conducting airways and alveolar spaces in addition to interstitium. However, fungal microorganisms were more abundant in the alveolar spaces in proximity to the conducting airways. Associated inflammatory cells were composed of both acute (neutrophils and lesser number of eosinophils) and chronic inflammatory cells (histiocytes, foamy macrophages, few multinucleated giant cells, and lymphocytes). A significant increase in the number and size of lymphoid aggregates in the interstitium around bronchiolovascular bundles was noted in lung sections (see arrows in Figure 3A). Scattered foci of dense neutrophilic infiltrates were noted in areas containing dense populations of fungal microorganisms in all groups. No goblet cell hyperplasia was seen in the conducting airways.


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)

Histopathological images of lungs of wild-type, IL-1R knockout, IL-18R knockout, and MyD88 knockout mice 12 days following challenge with 2×104 C. neoformans organisms i.n.(A) Histological samples were prepared as described in Methods. Images of H & E stained slides were taken under the light microscope at 20X power objective. Moderate to severe BALT expansion is noted in the lung sections of wild-type (n = 10) and IL-1R knockout mice (n = 5) compared to MyD88 knockout (n = 6) or IL-18R knockout mice (n = 6). The arrows point to expanded BALT in the lung sections of wild-type and IL-1R knockout mice. (B) Histopathological assessment of lungs from wild-type and knockout mice after infection. Sections were scored blind by a pathologist for the indicated observations on a scale from zero (none seen) to three (severe or maximal). **, P<0.01 compared with wild-type infected mice.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0026232-g003: Histopathological images of lungs of wild-type, IL-1R knockout, IL-18R knockout, and MyD88 knockout mice 12 days following challenge with 2×104 C. neoformans organisms i.n.(A) Histological samples were prepared as described in Methods. Images of H & E stained slides were taken under the light microscope at 20X power objective. Moderate to severe BALT expansion is noted in the lung sections of wild-type (n = 10) and IL-1R knockout mice (n = 5) compared to MyD88 knockout (n = 6) or IL-18R knockout mice (n = 6). The arrows point to expanded BALT in the lung sections of wild-type and IL-1R knockout mice. (B) Histopathological assessment of lungs from wild-type and knockout mice after infection. Sections were scored blind by a pathologist for the indicated observations on a scale from zero (none seen) to three (severe or maximal). **, P<0.01 compared with wild-type infected mice.
Mentions: Lung sections from WT and knockout mice 12 days post infection were evaluated for histopathological findings (Figure 3A). Individual and clusters of fungal microorganisms were seen in both conducting airways and alveolar spaces in addition to interstitium. However, fungal microorganisms were more abundant in the alveolar spaces in proximity to the conducting airways. Associated inflammatory cells were composed of both acute (neutrophils and lesser number of eosinophils) and chronic inflammatory cells (histiocytes, foamy macrophages, few multinucleated giant cells, and lymphocytes). A significant increase in the number and size of lymphoid aggregates in the interstitium around bronchiolovascular bundles was noted in lung sections (see arrows in Figure 3A). Scattered foci of dense neutrophilic infiltrates were noted in areas containing dense populations of fungal microorganisms in all groups. No goblet cell hyperplasia was seen in the conducting airways.

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