Signaling through Syk or CARD9 Mediates Species-Specific Anti-<italic toggle="yes">Candida</italic> Protection in Bone Marrow Chimeric Mice

ABSTRACT The spleen tyrosine kinase (Syk) and the downstream adaptor protein CARD9 are crucial signaling molecules in antimicrobial immunity. Candida parapsilosis is an emerging fungal pathogen with a high incidence in neonates, while Candida albicans is the most common agent of candidiasis. While s...

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Autores principales:	Erik Zajta, Katalin Csonka, Adél Tóth, Laszló Tiszlavicz, Tamás Németh, Anita Orosz, Ádám Novák, Máté Csikós, Csaba Vágvölgyi, Attila Mócsai, Attila Gácser
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2021
Materias:	Candida parapsilosis Candida albicans Syk CARD9 antifungal immunity antifungal immune therapy Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/c011d03ff5bf4b71b4e56284953a58df
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spelling	oai:doaj.org-article:c011d03ff5bf4b71b4e56284953a58df2021-11-10T18:37:51ZSignaling through Syk or CARD9 Mediates Species-Specific Anti-<italic toggle="yes">Candida</italic> Protection in Bone Marrow Chimeric Mice10.1128/mBio.01608-212150-7511https://doaj.org/article/c011d03ff5bf4b71b4e56284953a58df2021-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01608-21https://doaj.org/toc/2150-7511ABSTRACT The spleen tyrosine kinase (Syk) and the downstream adaptor protein CARD9 are crucial signaling molecules in antimicrobial immunity. Candida parapsilosis is an emerging fungal pathogen with a high incidence in neonates, while Candida albicans is the most common agent of candidiasis. While signaling through Syk/CARD9 promotes protective host mechanisms in response to C. albicans, its function in immunity against C. parapsilosis remains unclear. Here, we generated Syk−/− and CARD9−/− bone marrow chimeric mice to study the role of Syk/CARD9 signaling in immune responses to C. parapsilosis compared to C. albicans. We demonstrate various functions of this pathway (e.g., phagocytosis, phagosome acidification, and killing) in Candida-challenged, bone marrow-derived macrophages with differential involvement of Syk and CARD9 along with species-specific differences in cytokine production. We report that Syk−/− or CARD9−/− chimeras rapidly display high susceptibility to C. albicans, while C. parapsilosis infection exacerbates over a prolonged period in these animals. Thus, our results establish that Syk and CARD9 contribute to systemic resistance to C. parapsilosis and C. albicans differently. Additionally, we confirm prior studies but also detail new insights into the fundamental roles of both proteins in immunity against C. albicans. Our data further suggest that Syk has a more prominent influence on anti-Candida immunity than CARD9. Therefore, this study reinforces the Syk/CARD9 pathway as a potential target for anti-Candida immune therapy. IMPORTANCE While C. albicans remains the most clinically significant Candida species, C. parapsilosis is an emerging pathogen with increased affinity to neonates. Syk/CARD9 signaling is crucial in immunity to C. albicans, but its role in in vivo responses to other pathogenic Candida species is largely unexplored. We used mice with hematopoietic systems deficient in Syk or CARD9 to comparatively study the function of these proteins in anti-Candida immunity. We demonstrate that Syk/CARD9 signaling has a protective role against C. parapsilosis differently than against C. albicans. Thus, this study is the first to reveal that Syk can exert immune responses during systemic Candida infections species specifically. Additionally, Syk-dependent immunity to a nonalbicans Candida species in an in vivo murine model has not been reported previously. We highlight that the contribution of Syk and CARD9 to fungal infections are not identical and underline this pathway as a promising immune-therapeutic target to fight Candida infections.Erik ZajtaKatalin CsonkaAdél TóthLaszló TiszlaviczTamás NémethAnita OroszÁdám NovákMáté CsikósCsaba VágvölgyiAttila MócsaiAttila GácserAmerican Society for MicrobiologyarticleCandida parapsilosisCandida albicansSykCARD9antifungal immunityantifungal immune therapyMicrobiologyQR1-502ENmBio, Vol 12, Iss 4 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Candida parapsilosis Candida albicans Syk CARD9 antifungal immunity antifungal immune therapy Microbiology QR1-502
spellingShingle	Candida parapsilosis Candida albicans Syk CARD9 antifungal immunity antifungal immune therapy Microbiology QR1-502 Erik Zajta Katalin Csonka Adél Tóth Laszló Tiszlavicz Tamás Németh Anita Orosz Ádám Novák Máté Csikós Csaba Vágvölgyi Attila Mócsai Attila Gácser Signaling through Syk or CARD9 Mediates Species-Specific Anti-<italic toggle="yes">Candida</italic> Protection in Bone Marrow Chimeric Mice
description	ABSTRACT The spleen tyrosine kinase (Syk) and the downstream adaptor protein CARD9 are crucial signaling molecules in antimicrobial immunity. Candida parapsilosis is an emerging fungal pathogen with a high incidence in neonates, while Candida albicans is the most common agent of candidiasis. While signaling through Syk/CARD9 promotes protective host mechanisms in response to C. albicans, its function in immunity against C. parapsilosis remains unclear. Here, we generated Syk−/− and CARD9−/− bone marrow chimeric mice to study the role of Syk/CARD9 signaling in immune responses to C. parapsilosis compared to C. albicans. We demonstrate various functions of this pathway (e.g., phagocytosis, phagosome acidification, and killing) in Candida-challenged, bone marrow-derived macrophages with differential involvement of Syk and CARD9 along with species-specific differences in cytokine production. We report that Syk−/− or CARD9−/− chimeras rapidly display high susceptibility to C. albicans, while C. parapsilosis infection exacerbates over a prolonged period in these animals. Thus, our results establish that Syk and CARD9 contribute to systemic resistance to C. parapsilosis and C. albicans differently. Additionally, we confirm prior studies but also detail new insights into the fundamental roles of both proteins in immunity against C. albicans. Our data further suggest that Syk has a more prominent influence on anti-Candida immunity than CARD9. Therefore, this study reinforces the Syk/CARD9 pathway as a potential target for anti-Candida immune therapy. IMPORTANCE While C. albicans remains the most clinically significant Candida species, C. parapsilosis is an emerging pathogen with increased affinity to neonates. Syk/CARD9 signaling is crucial in immunity to C. albicans, but its role in in vivo responses to other pathogenic Candida species is largely unexplored. We used mice with hematopoietic systems deficient in Syk or CARD9 to comparatively study the function of these proteins in anti-Candida immunity. We demonstrate that Syk/CARD9 signaling has a protective role against C. parapsilosis differently than against C. albicans. Thus, this study is the first to reveal that Syk can exert immune responses during systemic Candida infections species specifically. Additionally, Syk-dependent immunity to a nonalbicans Candida species in an in vivo murine model has not been reported previously. We highlight that the contribution of Syk and CARD9 to fungal infections are not identical and underline this pathway as a promising immune-therapeutic target to fight Candida infections.
format	article
author	Erik Zajta Katalin Csonka Adél Tóth Laszló Tiszlavicz Tamás Németh Anita Orosz Ádám Novák Máté Csikós Csaba Vágvölgyi Attila Mócsai Attila Gácser
author_facet	Erik Zajta Katalin Csonka Adél Tóth Laszló Tiszlavicz Tamás Németh Anita Orosz Ádám Novák Máté Csikós Csaba Vágvölgyi Attila Mócsai Attila Gácser
author_sort	Erik Zajta
title	Signaling through Syk or CARD9 Mediates Species-Specific Anti-<italic toggle="yes">Candida</italic> Protection in Bone Marrow Chimeric Mice
title_short	Signaling through Syk or CARD9 Mediates Species-Specific Anti-<italic toggle="yes">Candida</italic> Protection in Bone Marrow Chimeric Mice
title_full	Signaling through Syk or CARD9 Mediates Species-Specific Anti-<italic toggle="yes">Candida</italic> Protection in Bone Marrow Chimeric Mice
title_fullStr	Signaling through Syk or CARD9 Mediates Species-Specific Anti-<italic toggle="yes">Candida</italic> Protection in Bone Marrow Chimeric Mice
title_full_unstemmed	Signaling through Syk or CARD9 Mediates Species-Specific Anti-<italic toggle="yes">Candida</italic> Protection in Bone Marrow Chimeric Mice
title_sort	signaling through syk or card9 mediates species-specific anti-<italic toggle="yes">candida</italic> protection in bone marrow chimeric mice
publisher	American Society for Microbiology
publishDate	2021
url	https://doaj.org/article/c011d03ff5bf4b71b4e56284953a58df
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Signaling through Syk or CARD9 Mediates Species-Specific Anti-<italic toggle="yes">Candida</italic> Protection in Bone Marrow Chimeric Mice

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