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

ABSTRACT Caspase 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 protectiv...

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Autores principales:	Althea Campuzano, Natalia Castro-Lopez, Amanda J. Martinez, Michal A. Olszewski, Anutosh Ganguly, Chrissy Leopold Wager, Chiung-Yu Hung, Floyd L. Wormley
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	CARD9 Cryptococcus neoformans cryptococcosis fungal immunology fungal pathogenesis host-pathogen interactions Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/6c21d53c72894c5282dc76e76f285e1a
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spelling	oai:doaj.org-article:6c21d53c72894c5282dc76e76f285e1a2021-11-15T15:56:57ZCARD9 Is Required for Classical Macrophage Activation and the Induction of Protective Immunity against Pulmonary Cryptococcosis10.1128/mBio.03005-192150-7511https://doaj.org/article/6c21d53c72894c5282dc76e76f285e1a2020-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.03005-19https://doaj.org/toc/2150-7511ABSTRACT Caspase 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.Althea CampuzanoNatalia Castro-LopezAmanda J. MartinezMichal A. OlszewskiAnutosh GangulyChrissy Leopold WagerChiung-Yu HungFloyd L. WormleyAmerican Society for MicrobiologyarticleCARD9Cryptococcus neoformanscryptococcosisfungal immunologyfungal pathogenesishost-pathogen interactionsMicrobiologyQR1-502ENmBio, Vol 11, Iss 1 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	CARD9 Cryptococcus neoformans cryptococcosis fungal immunology fungal pathogenesis host-pathogen interactions Microbiology QR1-502
spellingShingle	CARD9 Cryptococcus neoformans cryptococcosis fungal immunology fungal pathogenesis host-pathogen interactions Microbiology QR1-502 Althea Campuzano Natalia Castro-Lopez Amanda J. Martinez Michal A. Olszewski Anutosh Ganguly Chrissy Leopold Wager Chiung-Yu Hung Floyd L. Wormley CARD9 Is Required for Classical Macrophage Activation and the Induction of Protective Immunity against Pulmonary Cryptococcosis
description	ABSTRACT Caspase 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.
format	article
author	Althea Campuzano Natalia Castro-Lopez Amanda J. Martinez Michal A. Olszewski Anutosh Ganguly Chrissy Leopold Wager Chiung-Yu Hung Floyd L. Wormley
author_facet	Althea Campuzano Natalia Castro-Lopez Amanda J. Martinez Michal A. Olszewski Anutosh Ganguly Chrissy Leopold Wager Chiung-Yu Hung Floyd L. Wormley
author_sort	Althea Campuzano
title	CARD9 Is Required for Classical Macrophage Activation and the Induction of Protective Immunity against Pulmonary Cryptococcosis
title_short	CARD9 Is Required for Classical Macrophage Activation and the Induction of Protective Immunity against Pulmonary Cryptococcosis
title_full	CARD9 Is Required for Classical Macrophage Activation and the Induction of Protective Immunity against Pulmonary Cryptococcosis
title_fullStr	CARD9 Is Required for Classical Macrophage Activation and the Induction of Protective Immunity against Pulmonary Cryptococcosis
title_full_unstemmed	CARD9 Is Required for Classical Macrophage Activation and the Induction of Protective Immunity against Pulmonary Cryptococcosis
title_sort	card9 is required for classical macrophage activation and the induction of protective immunity against pulmonary cryptococcosis
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/6c21d53c72894c5282dc76e76f285e1a
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CARD9 Is Required for Classical Macrophage Activation and the Induction of Protective Immunity against Pulmonary Cryptococcosis

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