1. Aspergillus fumigatus corneal infection is regulated by chitin synthases and by neutrophil-derived acidic mammalian chitinase
- Author
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Patricia R. Taylor, Anne Beauvais, William Carrera, Eric Pearlman, Steven de Jesus Carrion, Sixto M. Leal, Yan Sun, Brittany A. Armstrong, Heather L. Clark, Serena Abbondante, Isabelle Mouyna, Michaela E. Marshall, Jean-Paul Latgé, Case Western Reserve University [Cleveland], University of California [Irvine] (UC Irvine), University of California (UC), Aspergillus, Institut Pasteur [Paris] (IP), This work was supported by R01 EY18612 (EP), by core grant P30 EY11373, and by the Research to Prevent Blindness Foundation., The authors greatly appreciate the outstanding technical assistance of the Visual Sciences Research Center core facilities at CWRU, especially Scott Howell, Catherine Doller, and Dawn Smith. We also thank Michaela Marshall at UCI for outstanding technical support and Stuart Levitz and Charles Specht at UMASS for sending the AMCase−/− mice., University of California [Irvine] (UCI), University of California, and Institut Pasteur [Paris]
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0301 basic medicine ,Hyphal growth ,Corneal Infection ,Neutrophils ,Inbred C57BL ,[SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity ,Aspergillus fumigatus ,Mice ,chemistry.chemical_compound ,0302 clinical medicine ,[SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases ,Acidic mammalian chitinase ,2.2 Factors relating to the physical environment ,2.1 Biological and endogenous factors ,Immunology and Allergy ,Aetiology ,[SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology ,Virulence ,Chitinases ,Neutrophil ,Chitin synthase ,3. Good health ,Infectious Diseases ,Infection ,Immunology ,Biology ,Article ,Microbiology ,03 medical and health sciences ,Immune system ,Chitin ,Animals ,Aspergillosis ,Humans ,[SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs ,Eye Disease and Disorders of Vision ,Chitin Synthase ,Keratitis ,Aspergillus ,biology.organism_classification ,Mice, Inbred C57BL ,Emerging Infectious Diseases ,030104 developmental biology ,chemistry ,Corneal infection ,biology.protein ,030215 immunology - Abstract
International audience; Aspergillus fumigatus is an important cause of pulmonary and systemic infections in immune compromised individuals, and of corneal ulcers and blindness in immune competent patients. To examine the role of chitin synthases in Aspergillus corneal infection, we analyzed Aspergillus mutants of chitin synthase family 1 and family 2, and found that compared with the parent strain, the quadruple mutants from both families were more readily killed by neutrophils in vitro, and that both also exhibited impaired hyphal growth in the cornea. Further, inhibition of chitin synthases using Nikkomycin Z enhanced neutrophil killing in vitro and in vivo in a murine model of A. fumigatus corneal infection. Acidic mammalian chitinase (AMCase) is mostly produced by macrophages in asthmatic lungs; however, we now demonstrate that neutrophils are a major source of AMCase, which inhibits hyphal growth. In A. fumigatus corneal infection, neutrophils are the major source of AMCase, and addition of AMCase inhibitors or adoptive transfer of neutrophils from AMCase −/− mice resulted in impaired hyphal killing. Together, these findings identify chitin synthases as important fungal virulence factors and neutrophil-derived AMCase as an essential mediator of host defense.
- Published
- 2019
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