Skip to main content

Rim Pathway-Mediated Alterations in the Fungal Cell Wall Influence Immune Recognition and Inflammation.

Publication ,  Journal Article
Ost, KS; Esher, SK; Leopold Wager, CM; Walker, L; Wagener, J; Munro, C; Wormley, FL; Alspaugh, JA
Published in: mBio
January 31, 2017

UNLABELLED: Compared to other fungal pathogens, Cryptococcus neoformans is particularly adept at avoiding detection by innate immune cells. To explore fungal cellular features involved in immune avoidance, we characterized cell surface changes of the C. 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 strain rim101Δ cell wall increases macrophage detection in a contact-dependent manner. Using biochemical and microscopy methods, we demonstrated that the rim101Δ 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 the rim101Δ mutant, we determined that both the MyD88 and CARD9 innate immune signaling proteins are involved. Finally, we characterized the immune response to the rim101Δ mutant in vivo, documenting a dramatic and sustained increase in Th1 and Th17 cytokine responses. These results suggest that the Rim101 transcription factor actively regulates the C. neoformans cell wall to prevent the exposure of immune stimulatory molecules within the host. These studies further explored the ways in which immune cells detect C. neoformans and other fungal pathogens by mechanisms that include sensing N-acetylglucosamine-containing structures, such as chitin and chitosan. IMPORTANCE: Infectious microorganisms have developed many ways to avoid recognition by the host immune system. For example, pathogenic fungi alter their cell surfaces to mask immunogenic epitopes. We have created a fungal strain with a targeted mutation in a pH response pathway that is unable to properly organize its cell wall, resulting in a dramatic immune reaction during infection. This mutant cell wall is defective in hiding important cell wall components, such as the chito-oligomers chitin and chitosan. By creating a series of cell wall mutants, we demonstrated that the degree of chito-oligomer exposure correlates with the intensity of innate immune cell activation. This activation requires a combination of host receptors to recognize and respond to these infecting microorganisms. Therefore, these experiments explored host-pathogen interactions that determine the degree of the subsequent inflammatory response and the likely outcome of infection.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

mBio

DOI

EISSN

2150-7511

Publication Date

January 31, 2017

Volume

8

Issue

1

Location

United States

Related Subject Headings

  • Transcription Factors
  • Th17 Cells
  • Th1 Cells
  • Mice
  • Macrophages
  • Inflammation
  • Immune Evasion
  • Gene Deletion
  • Fungal Proteins
  • Disease Models, Animal
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Ost, K. S., Esher, S. K., Leopold Wager, C. M., Walker, L., Wagener, J., Munro, C., … Alspaugh, J. A. (2017). Rim Pathway-Mediated Alterations in the Fungal Cell Wall Influence Immune Recognition and Inflammation. MBio, 8(1). https://doi.org/10.1128/mBio.02290-16
Ost, Kyla S., Shannon K. Esher, Chrissy M. Leopold Wager, Louise Walker, Jeanette Wagener, Carol Munro, Floyd L. Wormley, and J Andrew Alspaugh. “Rim Pathway-Mediated Alterations in the Fungal Cell Wall Influence Immune Recognition and Inflammation.MBio 8, no. 1 (January 31, 2017). https://doi.org/10.1128/mBio.02290-16.
Ost KS, Esher SK, Leopold Wager CM, Walker L, Wagener J, Munro C, et al. Rim Pathway-Mediated Alterations in the Fungal Cell Wall Influence Immune Recognition and Inflammation. mBio. 2017 Jan 31;8(1).
Ost, Kyla S., et al. “Rim Pathway-Mediated Alterations in the Fungal Cell Wall Influence Immune Recognition and Inflammation.MBio, vol. 8, no. 1, Jan. 2017. Pubmed, doi:10.1128/mBio.02290-16.
Ost KS, Esher SK, Leopold Wager CM, Walker L, Wagener J, Munro C, Wormley FL, Alspaugh JA. Rim Pathway-Mediated Alterations in the Fungal Cell Wall Influence Immune Recognition and Inflammation. mBio. 2017 Jan 31;8(1).

Published In

mBio

DOI

EISSN

2150-7511

Publication Date

January 31, 2017

Volume

8

Issue

1

Location

United States

Related Subject Headings

  • Transcription Factors
  • Th17 Cells
  • Th1 Cells
  • Mice
  • Macrophages
  • Inflammation
  • Immune Evasion
  • Gene Deletion
  • Fungal Proteins
  • Disease Models, Animal