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Jagunal homolog 1 is a critical regulator of neutrophil function in fungal host defense.

ABSTRACT: Neutrophils are key innate immune effector cells that are essential to fighting bacterial and fungal pathogens. Here we report that mice carrying a hematopoietic lineage-specific deletion of Jagn1 (encoding Jagunal homolog 1) cannot mount an efficient neutrophil-dependent immune response to the human fungal pathogen Candida albicans. Global glycobiome analysis identified marked alterations in the glycosylation of proteins involved in cell adhesion and cytotoxicity in Jagn1-deficient neutrophils. Functional analysis confirmed marked defects in neutrophil migration in response to Candida albicans infection and impaired formation of cytotoxic granules, as well as defective myeloperoxidase release and killing of Candida albicans. Treatment with granulocyte/macrophage colony-stimulating factor (GM-CSF) protected mutant mice from increased weight loss and accelerated mortality after Candida albicans challenge. Notably, GM-CSF also restored the defective fungicidal activity of bone marrow cells from humans with JAGN1 mutations. These data directly identify Jagn1 (JAGN1 in humans) as a new regulator of neutrophil function in microbial pathogenesis and uncover a potential treatment option for humans.

SUBMITTER: Wirnsberger G

PROVIDER: S-EPMC6245568 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Jagunal homolog 1 is a critical regulator of neutrophil function in fungal host defense.

Wirnsberger Gerald G Zwolanek Florian F Stadlmann Johannes J Tortola Luigi L Liu Shang Wan SW Perlot Thomas T Järvinen Päivi P Dürnberger Gerhard G Kozieradzki Ivona I Sarao Renu R De Martino Alba A Boztug Kaan K Mechtler Karl K Kuchler Karl K Klein Christoph C Elling Ulrich U Penninger Josef M JM

Nature genetics 20140817 9

Neutrophils are key innate immune effector cells that are essential to fighting bacterial and fungal pathogens. Here we report that mice carrying a hematopoietic lineage-specific deletion of Jagn1 (encoding Jagunal homolog 1) cannot mount an efficient neutrophil-dependent immune response to the human fungal pathogen Candida albicans. Global glycobiome analysis identified marked alterations in the glycosylation of proteins involved in cell adhesion and cytotoxicity in Jagn1-deficient neutrophils. ...[more]

PMID: 25129145

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Project description:Microorganisms typically maintain cellular homeostasis despite facing large fluctuations in their surroundings. Microbes that reside on human mucosal surfaces may experience significant variations in nutrient and ion availability as well as pH. Whether the mechanisms employed by these microbial cells to sustain homeostasis directly impact on the interplay with the host's mucosae remains unclear. Here, we report that the previously uncharacterized transcription regulator ZCF8 in the human-associated yeast Candida albicans maintains vacuole homeostasis when the fungus faces fluctuations in nitrogen. Genome-wide identification of genes directly regulated by Zcf8p followed by fluorescence microscopy to define their subcellular localization uncovered the fungal vacuole as a top target of Zcf8p regulation. Deletion and overexpression of ZCF8 resulted in alterations in vacuolar morphology and luminal pH and rendered the fungus resistant or susceptible to nigericin and brefeldin A, two drugs that impair vacuole and associated functions. Furthermore, we establish that the regulator modulates C. albicans attachment to epithelial cells in a manner that depends on the status of the fungal vacuole. Our findings, therefore, suggest that fungal vacuole physiology regulation is intrinsically linked to, and shapes to a significant extent, the physical interactions that Candida cells establish with mammalian mucosal surfaces. IMPORTANCE Candida albicans is a fungus that resides on various human mucosal surfaces. Individuals with debilitated immune systems are prone to develop C. albicans infections, which can range in severity from mucosal disease (e.g., oral thrush in AIDS patients) to life-threatening conditions (e.g., deep-seated, disseminated infections in patients undergoing organ transplants). Understanding the cellular and molecular mechanisms that this eukaryotic microbe employs to colonize different parts of the human body and to cause disease will lay the foundation for the development of novel strategies for preventing and treating C. albicans infections. This report establishes the fungal vacuole, a key organelle to the overall fungal physiology, as a key determinant of the interplay between C. albicans and mammalian mucosal surfaces.

Dataset Information

Jagunal homolog 1 is a critical regulator of neutrophil function in fungal host defense.

Publications

Jagunal homolog 1 is a critical regulator of neutrophil function in fungal host defense.

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