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Nat Genet. 2014 Sep;46(9):1028-33. doi: 10.1038/ng.3070. Epub 2014 Aug 17.

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

Author information

1
Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna, Austria.
2
Department of Medical Biochemistry, Max F. Perutz Laboratories, Medical University of Vienna, Vienna, Austria.
3
1] Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna, Austria. [2] Institute for Molecular Pathology (IMP), Vienna, Austria.
4
Department of Pediatrics, Dr. Von Hauner Children's Hospital, Ludwig Maximilians University, Munich, Germany.
5
Campus Science Support Facility (CSF), Vienna, Austria.
6
1] Research Center for Molecular Medicine of the Austrian Academy of Sciences (CeMM), Vienna, Austria. [2] Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.

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.

PMID:
25129145
PMCID:
PMC6245568
DOI:
10.1038/ng.3070
[Indexed for MEDLINE]
Free PMC Article

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