Spleen Tyrosine Kinase Is a Critical Regulator of Neutrophil Responses to <italic toggle="yes">Candida</italic> Species

ABSTRACT Invasive fungal infections constitute a lethal threat, with patient mortality as high as 90%. The incidence of invasive fungal infections is increasing, especially in the setting of patients receiving immunomodulatory agents, chemotherapy, or immunosuppressive medications following solid-or...

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Autores principales:	Paige E. Negoro, Shuying Xu, Zeina Dagher, Alex Hopke, Jennifer L. Reedy, Michael B. Feldman, Nida S. Khan, Adam L. Viens, Natalie J. Alexander, Natalie J. Atallah, Allison K. Scherer, Richard A. Dutko, Jane Jeffery, John F. Kernien, J. Scott Fites, Jeniel E. Nett, Bruce S. Klein, Jatin M. Vyas, Daniel Irimia, David B. Sykes, Michael K. Mansour
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	neutrophils spleen tyrosine kinase Candida fungus Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/8ea9d37e9ee144ada176ccd4590e9d2d
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spelling	oai:doaj.org-article:8ea9d37e9ee144ada176ccd4590e9d2d2021-11-15T15:56:46ZSpleen Tyrosine Kinase Is a Critical Regulator of Neutrophil Responses to <italic toggle="yes">Candida</italic> Species10.1128/mBio.02043-192150-7511https://doaj.org/article/8ea9d37e9ee144ada176ccd4590e9d2d2020-06-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02043-19https://doaj.org/toc/2150-7511ABSTRACT Invasive fungal infections constitute a lethal threat, with patient mortality as high as 90%. The incidence of invasive fungal infections is increasing, especially in the setting of patients receiving immunomodulatory agents, chemotherapy, or immunosuppressive medications following solid-organ or bone marrow transplantation. In addition, inhibitors of spleen tyrosine kinase (Syk) have been recently developed for the treatment of patients with refractory autoimmune and hematologic indications. Neutrophils are the initial innate cellular responders to many types of pathogens, including invasive fungi. A central process governing neutrophil recognition of fungi is through lectin binding receptors, many of which rely on Syk for cellular activation. We previously demonstrated that Syk activation is essential for cellular activation, phagosomal maturation, and elimination of phagocytosed fungal pathogens in macrophages. Here, we used combined genetic and chemical inhibitor approaches to evaluate the importance of Syk in the response of neutrophils to Candida species. We took advantage of a Cas9-expressing neutrophil progenitor cell line to generate isogenic wild-type and Syk-deficient neutrophils. Syk-deficient neutrophils are unable to control the human pathogens Candida albicans, Candida glabrata, and Candida auris. Neutrophil responses to Candida species, including the production of reactive oxygen species and of cytokines such as tumor necrosis factor alpha (TNF-α), the formation of neutrophil extracellular traps (NETs), phagocytosis, and neutrophil swarming, appear to be critically dependent on Syk. These results demonstrate an essential role for Syk in neutrophil responses to Candida species and raise concern for increased fungal infections with the development of Syk-modulating therapeutics. IMPORTANCE Neutrophils are recognized to represent significant immune cell mediators for the clearance and elimination of the human-pathogenic fungal pathogen Candida. The sensing of fungi by innate cells is performed, in part, through lectin receptor recognition of cell wall components and downstream cellular activation by signaling components, including spleen tyrosine kinase (Syk). While the essential role of Syk in macrophages and dendritic cells is clear, there remains uncertainty with respect to its contribution in neutrophils. In this study, we demonstrated that Syk is critical for multiple cellular functions in neutrophils responding to major human-pathogenic Candida species. These data not only demonstrate the vital nature of Syk with respect to the control of fungi by neutrophils but also warn of the potential infectious complications arising from the recent clinical development of novel Syk inhibitors for hematologic and autoimmune disorders.Paige E. NegoroShuying XuZeina DagherAlex HopkeJennifer L. ReedyMichael B. FeldmanNida S. KhanAdam L. ViensNatalie J. AlexanderNatalie J. AtallahAllison K. SchererRichard A. DutkoJane JefferyJohn F. KernienJ. Scott FitesJeniel E. NettBruce S. KleinJatin M. VyasDaniel IrimiaDavid B. SykesMichael K. MansourAmerican Society for Microbiologyarticleneutrophilsspleen tyrosine kinaseCandidafungusMicrobiologyQR1-502ENmBio, Vol 11, Iss 3 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	neutrophils spleen tyrosine kinase Candida fungus Microbiology QR1-502
spellingShingle	neutrophils spleen tyrosine kinase Candida fungus Microbiology QR1-502 Paige E. Negoro Shuying Xu Zeina Dagher Alex Hopke Jennifer L. Reedy Michael B. Feldman Nida S. Khan Adam L. Viens Natalie J. Alexander Natalie J. Atallah Allison K. Scherer Richard A. Dutko Jane Jeffery John F. Kernien J. Scott Fites Jeniel E. Nett Bruce S. Klein Jatin M. Vyas Daniel Irimia David B. Sykes Michael K. Mansour Spleen Tyrosine Kinase Is a Critical Regulator of Neutrophil Responses to <italic toggle="yes">Candida</italic> Species
description	ABSTRACT Invasive fungal infections constitute a lethal threat, with patient mortality as high as 90%. The incidence of invasive fungal infections is increasing, especially in the setting of patients receiving immunomodulatory agents, chemotherapy, or immunosuppressive medications following solid-organ or bone marrow transplantation. In addition, inhibitors of spleen tyrosine kinase (Syk) have been recently developed for the treatment of patients with refractory autoimmune and hematologic indications. Neutrophils are the initial innate cellular responders to many types of pathogens, including invasive fungi. A central process governing neutrophil recognition of fungi is through lectin binding receptors, many of which rely on Syk for cellular activation. We previously demonstrated that Syk activation is essential for cellular activation, phagosomal maturation, and elimination of phagocytosed fungal pathogens in macrophages. Here, we used combined genetic and chemical inhibitor approaches to evaluate the importance of Syk in the response of neutrophils to Candida species. We took advantage of a Cas9-expressing neutrophil progenitor cell line to generate isogenic wild-type and Syk-deficient neutrophils. Syk-deficient neutrophils are unable to control the human pathogens Candida albicans, Candida glabrata, and Candida auris. Neutrophil responses to Candida species, including the production of reactive oxygen species and of cytokines such as tumor necrosis factor alpha (TNF-α), the formation of neutrophil extracellular traps (NETs), phagocytosis, and neutrophil swarming, appear to be critically dependent on Syk. These results demonstrate an essential role for Syk in neutrophil responses to Candida species and raise concern for increased fungal infections with the development of Syk-modulating therapeutics. IMPORTANCE Neutrophils are recognized to represent significant immune cell mediators for the clearance and elimination of the human-pathogenic fungal pathogen Candida. The sensing of fungi by innate cells is performed, in part, through lectin receptor recognition of cell wall components and downstream cellular activation by signaling components, including spleen tyrosine kinase (Syk). While the essential role of Syk in macrophages and dendritic cells is clear, there remains uncertainty with respect to its contribution in neutrophils. In this study, we demonstrated that Syk is critical for multiple cellular functions in neutrophils responding to major human-pathogenic Candida species. These data not only demonstrate the vital nature of Syk with respect to the control of fungi by neutrophils but also warn of the potential infectious complications arising from the recent clinical development of novel Syk inhibitors for hematologic and autoimmune disorders.
format	article
author	Paige E. Negoro Shuying Xu Zeina Dagher Alex Hopke Jennifer L. Reedy Michael B. Feldman Nida S. Khan Adam L. Viens Natalie J. Alexander Natalie J. Atallah Allison K. Scherer Richard A. Dutko Jane Jeffery John F. Kernien J. Scott Fites Jeniel E. Nett Bruce S. Klein Jatin M. Vyas Daniel Irimia David B. Sykes Michael K. Mansour
author_facet	Paige E. Negoro Shuying Xu Zeina Dagher Alex Hopke Jennifer L. Reedy Michael B. Feldman Nida S. Khan Adam L. Viens Natalie J. Alexander Natalie J. Atallah Allison K. Scherer Richard A. Dutko Jane Jeffery John F. Kernien J. Scott Fites Jeniel E. Nett Bruce S. Klein Jatin M. Vyas Daniel Irimia David B. Sykes Michael K. Mansour
author_sort	Paige E. Negoro
title	Spleen Tyrosine Kinase Is a Critical Regulator of Neutrophil Responses to <italic toggle="yes">Candida</italic> Species
title_short	Spleen Tyrosine Kinase Is a Critical Regulator of Neutrophil Responses to <italic toggle="yes">Candida</italic> Species
title_full	Spleen Tyrosine Kinase Is a Critical Regulator of Neutrophil Responses to <italic toggle="yes">Candida</italic> Species
title_fullStr	Spleen Tyrosine Kinase Is a Critical Regulator of Neutrophil Responses to <italic toggle="yes">Candida</italic> Species
title_full_unstemmed	Spleen Tyrosine Kinase Is a Critical Regulator of Neutrophil Responses to <italic toggle="yes">Candida</italic> Species
title_sort	spleen tyrosine kinase is a critical regulator of neutrophil responses to <italic toggle="yes">candida</italic> species
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/8ea9d37e9ee144ada176ccd4590e9d2d
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Spleen Tyrosine Kinase Is a Critical Regulator of Neutrophil Responses to <italic toggle="yes">Candida</italic> Species

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