Rim Pathway-Mediated Alterations in the Fungal Cell Wall Influence Immune Recognition and Inflammation
Abstract
Compared to other fungal pathogens,Cryptococcus neoformansis particularly adept at avoiding detection by innate immune cells. To explore fungal cellular features involved in immune avoidance, we characterized cell surface changes of theC. neoformans rim101Δ mutant, a strain that fails to organize and shield immunogenic epitopes from host detection. These cell surface changes are associated with an exaggerated, detrimental inflammatory response in mouse models of infection. We determined that the disorganized strainrim101Δ cell wall increases macrophage detection in a contact-dependent manner. Using biochemical and microscopy methods, we demonstrated that therim101Δ strain shows a modest increase in the levels of both cell wall chitin and chitosan but that it shows a more dramatic increase in chito-oligomer exposure, as measured by wheat germ agglutinin staining. We also created a series of mutants with various levels of cell wall wheat germ agglutinin staining, and we demonstrated that the staining intensity correlates with the degree of macrophage activation in response to each strain. To explore the host receptors responsible for recognizing therim101Δ mutant, we determined that both the MyD88 and CARD9 innate immune signaling proteins are involved. Finally, we characterized the immune response to therim101Δ mutantin vivo, documenting a dramatic and sustained increase in Th1 and Th17 cytokine responses. These results suggest that the Rim101 transcription factor actively regulates theC. neoformanscell wall to prevent the exposure of immune stimulatory molecules within the host. These studies further explored the ways in which immune cells detectC. neoformansand other fungal pathogens by mechanisms that include sensing N-acetylglucosamine-containing structures, such as chitin and chitosan.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Mar 08, 2017
- Source ID
- 10.1128/mbio.02290-16
Entities
People
- Carol Munro
- Chrissy M. Leopold Wager
- Floyd L. Wormley Jr.
- J. Andrew Alspaugh
- Jeanette Wagener
- Kyla S. Ost
- Louise Walker
- Shannon K. Esher
Organizations
- Army Research Office
- Duke University
- MRC Centre for Medical Mycology
- National Institute of Allergy and Infectious Diseases
- University of Aberdeen
- University of Texas at San Antonio
- Wellcome