CARD9 Is Required for Classical Macrophage Activation and the Induction of Protective Immunity against Pulmonary Cryptococcosis

dc.contributor.authorCampuzano, Althea
dc.contributor.authorCastro-Lopez, Natalia
dc.contributor.authorMartinez, Amanda J.
dc.contributor.authorOlszewski, Michal A.
dc.contributor.authorGanguly, Anutosh
dc.contributor.authorLeopold Wager, Chrissy
dc.contributor.authorHung, Chiung-Yu
dc.contributor.authorWormley, Floyd L. Jr.
dc.creator.orcidhttps://orcid.org/0000-0003-1091-3420en_US
dc.date.accessioned2023-06-28T17:41:25Z
dc.date.available2023-06-28T17:41:25Z
dc.date.issued2020-01-07
dc.description.abstractCaspase recruitment domain-containing protein 9 (CARD9) is a critical adaptor molecule triggered by the interaction of C-type lectin receptors (CLRs) with carbohydrate motifs found in fungi. Consequently, clinical and animal studies indicate that CARD9 is an important regulator of protective immunity against fungal pathogens. Previous studies suggest that CARD9 is important for the induction of protection against Cryptococcus neoformans, an opportunistic fungal pathogen that causes life-threatening infections of the central nervous system in immunocompromised patients. However, the effect of CARD9 deficiency on the induction of protective immune responses against C. neoformans is unknown. Immunization with a C. neoformans mutant that overexpresses the transcription factor zinc finger 2, denoted LW10, results in protection against an otherwise lethal challenge with wild-type (WT) C. neoformans. Our results showed that CARD9 is essential for the induction of vaccine-mediated immunity against C. neoformans infection. We observed significant decreases in interleukin-17 (IL-17) production and significant increases in Th2-type cytokine (IL-4, IL-5, and IL-13) production in CARD9-deficient mice after inoculation with strain LW10. While leukocyte infiltration to the lungs of CARD9-deficient mice was similar in LW10 and WT C. neoformans-infected mice, macrophages derived from CARD9-deficient mice inherently skewed toward an M2 activation phenotype, were unable to contain the growth of LW10, and failed to produce nitric oxide in response to infection with LW10 or stimulation with lipopolysaccharide. These results suggest that CARD9-mediated signaling is required for M1 macrophage activation and fungicidal activity necessary for the induction of vaccine-mediated immunity against C. neoformans. IMPORTANCE: Cryptococcus neoformans is a fungal pathogen that is found throughout the environment and can cause life-threatening infections of the lung and central nervous system in severely immunocompromised individuals. Caspase recruitment domain-containing protein 9 (CARD9) is a critical molecule that is activated after interactions of C-type lectin receptors (CLRs) found on the surfaces of specific immune cells, with carbohydrate structures associated with fungi. Patients with defects in CARD9 are significantly more susceptible to a multitude of fungal infections. C. neoformans contains several carbohydrate structures that interact with CLRs on immune cells and activate CARD9. Consequently, these studies evaluated the necessity of CARD9 for the induction of protective immunity against C. neoformans infection. These results are important, as they advance our understanding of cryptococcal pathogenesis and host factors necessary for the induction of protective immunity against C. neoformans.en_US
dc.description.departmentMolecular Microbiology and Immunologyen_US
dc.description.sponsorshipNational Institute on Minority Health and Health Disparities; National Institute of Allergy and Infectious Diseases; U.S. Department of Veterans Affairs; Alberta Lung Association; Canadian Institute for Health Researchen_US
dc.identifier.citationCampuzano, A., Castro-Lopez, N., Martinez, A. J., Olszewski, M. A., Ganguly, A., Wager, C. L., . . . Wormley, F. L. (2020). CARD9 Is Required for Classical Macrophage Activation and the Induction of Protective Immunity against Pulmonary Cryptococcosis. mBio, 11(1), 10.1128/mbio.03005-03019. doi:10.1128/mbio.03005-19en_US
dc.identifier.issn2150-7511
dc.identifier.otherhttps://doi.org/10.1128/mbio.03005-19
dc.identifier.urihttps://hdl.handle.net/20.500.12588/1961
dc.language.isoen_USen_US
dc.publisherAmerican Society for Microbiologyen_US
dc.relation.ispartofseriesmBio;Vol. 11, No. 1
dc.rightsAttribution 3.0 United States*
dc.rights.urihttp://creativecommons.org/licenses/by/3.0/us/*
dc.subjectCryptococcus neoformansen_US
dc.subjectCARD9en_US
dc.subjectcryptococcosisen_US
dc.subjectfungal immunologyen_US
dc.subjectfungal pathogenesisen_US
dc.subjecthost-pathogen interactionsen_US
dc.subjectinnate immunityen_US
dc.subjectmacrophagesen_US
dc.subjectmedical mycologyen_US
dc.subjectpattern recognition receptorsen_US
dc.titleCARD9 Is Required for Classical Macrophage Activation and the Induction of Protective Immunity against Pulmonary Cryptococcosisen_US
dc.typeArticleen_US

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