A Critical Role for CARD9 in Pneumocystis Pneumonia Host Defense
| Autor: | Deanne Hebrink, Vijayalakshmi Nandakumar, Eva M. Carmona, Andrew H. Limper, Theodore J. Kottom |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Immunology
Colony Count Microbial Inflammation Lung injury Biology Pneumocystis pneumonia Pneumocystis carinii Microbiology Article Proinflammatory cytokine 03 medical and health sciences Immunocompromised Host Mice Virology Macrophages Alveolar medicine Macrophage Animals Lectins C-Type Lung 030304 developmental biology Peroxidase 0303 health sciences Innate immune system 030306 microbiology Pneumocystis Tumor Necrosis Factor-alpha Pneumonia Pneumocystis Adaptor Signaling Protein Membrane Proteins Cell Differentiation T-Lymphocytes Helper-Inducer medicine.disease Rats CARD Signaling Adaptor Proteins Mice Inbred C57BL Cytokines medicine.symptom Signal transduction Mitogen-Activated Protein Kinases |
| Zdroj: | Cell Microbiol |
| Popis: | Caspase recruitment domain-containing protein 9 (CARD9) is an adaptor molecule critical for key signaling pathways initiated through C-type lectin receptors (CLRs). Previous studies demonstrated that Pneumocystis organisms are recognized through a variety of CLRs. However, the role of the downstream CARD9 adaptor signaling protein in host defense against Pneumocystis infection remains to be elucidated. Herein, we analyzed the role of CARD9 in host defense against Pneumocystis both in CD4-depleted CARD9-/- and immunocompetent hosts. Card9 gene-disrupted (CARD9-/- ) mice were more susceptible to Pneumocystis, as evidenced by reduced fungal clearance in infected lungs compared to wild-type infected mice. Our data suggests that this defect was due to impaired proinflammatory responses. Furthermore, CARD9-/- macrophages were severely compromised in their ability to differentiate and express M1 and M2 macrophage polarization markers, to enhanced mRNA expression for Dectin-1 and Mincle, and most importantly, to kill Pneumocystis in vitro. Remarkably, compared to wild-type mice, and despite markedly increased organism burdens, CARD9-/- animals did not exhibit worsened survival during PCP, perhaps related to decreased lung injury due to altered influx of inflammatory cells and decreased levels of proinflammatory cytokines in response to the organism. Lastly, although innate phase cytokines were impaired in the CARD9-/- animals during PCP, T-helper cell cytokines were normal in immunocompetent CARD9-/- animals infected with Pneumocystis. Taken together, our data demonstrate that CARD9 has a critical function in innate immune responses against Pneumocystis. This article is protected by copyright. All rights reserved. |
| Databáze: | OpenAIRE |
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