Aspergillus fumigatus corneal infection is regulated by chitin synthases and by neutrophil–derived acidic mammalian chitinase. Issue 6 (14th May 2019)

• Record Type: Journal Article
• Authors: de Jesus Carrion, Steven; Abbondante, Serena; Clark, Heather L.; Marshall, Michaela E.; Mouyna, Isabelle; Beauvais, Anne; Sun, Yan; Taylor, Patricia R.; Leal, Sixto M.; Armstrong, Brittany; Carrera, William; Latge, Jean‐Paul; Pearlman, Eric
• Is Part Of: European journal of immunology. Volume 49:Issue 6(2019)
• Page Start: 918
• Page End: 927
• Publication Date: 2019-05-14
• Subjects: Acidic mammalian chitinase -- Aspergillus fumigatus -- Corneal infection -- Chitin synthase -- Keratitis -- Neutrophil; Immunology -- Periodicals; 616.079
• DOI: 10.1002/eji.201847851
• Languages: English
• ISSNs: 0014-2980

Abstract

Abstract: 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. Abstract : Graphical Abstract: Neutrophils are an important source of Acidic Mammalian Chitinase (AMCase), which is required to kill A. fumigatus hyphae in vitro and in a murine model of corneal infection where hyphae grow throughout the corneal stroma. Conversely, A. fumigatus chitin synthases are required for fungal survival in the presence of neutrophils in vitro and in vivo.