Chitin Recognition via Chitotriosidase Promotes Pathologic Type-2 Helper T Cell Responses to Cryptococcal Infection

Wiesner, Darin L.; Specht, Charles A.; Lee, Chrono K.; Smith, Kyle D.; Mukaremera, Liliane; Lee, S. Thera; Lee, Chun G.; Elias, Jack A.; Nielsen, Judith N.; Boulware, David R.; Bohjanen, Paul R.; Jenkins, Marc K.; Levitz, Stuart M.; Nielsen, Kirsten

doi:10.1371/journal.ppat.1004701

Cited by 214Fungal Infections and StudiesStudies on Chitinases and ChitosanasesImmune responses and vaccinations

Chitin Recognition via Chitotriosidase Promotes Pathologic Type-2 Helper T Cell Responses to Cryptococcal Infection

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Wiesner, Darin L., Specht, Charles A., Lee, Chrono K., Smith, Kyle D., Mukaremera, Liliane, Lee, S. Thera, Lee, Chun G., Elias, Jack A. +6 more·2015·PLOS Pathogens

DOI 10.1371/journal.ppat.1004701PMC PMC4357429

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Abstract

Pulmonary mycoses are often associated with type-2 helper T (Th2) cell responses. However, mechanisms of Th2 cell accumulation are multifactorial and incompletely known. To investigate Th2 cell responses to pulmonary fungal infection, we developed a peptide-MHCII tetramer to track antigen-specific CD4+ T cells produced in response to infection with the fungal pathogen Cryptococcus neoformans. We noted massive accruement of pathologic cryptococcal antigen-specific Th2 cells in the lungs following infection that was coordinated by lung-resident CD11b+ IRF4-dependent conventional dendritic cells. Other researchers have demonstrated that this dendritic cell subset is also capable of priming protective Th17 cell responses to another pulmonary fungal infection, Aspergillus fumigatus. Thus, higher order detection of specific features of fungal infection by these dendritic cells must direct Th2 cell lineage commitment. Since chitin-containing parasites commonly elicit Th2 responses, we hypothesized that recognition of fungal chitin is an important determinant of Th2 cell-mediated mycosis. Using C. neoformans mutants or purified chitin, we found that chitin abundance impacted Th2 cell accumulation and disease. Importantly, we determined Th2 cell induction depended on cleavage of chitin via the mammalian chitinase, chitotriosidase, an enzyme that was also prevalent in humans experiencing overt cryptococcosis. The data presented herein offers a new perspective on fungal disease susceptibility, whereby chitin recognition via chitotriosidase leads to the initiation of harmful Th2 cell differentiation by CD11b+ conventional dendritic cells in response to pulmonary fungal infection.

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On titan cell formation, the polysaccharide capsule becomes condensed and highly crosslinked; the cell wall can increase in thickness from 50-100 nm to 2-3 μm; and cell wall composition is altered through an increase in chitin content and a decrease in glucan.
“On titan cell formation, the polysaccharide capsule surrounding Cryptococcus cells becomes condensed and highly crosslinked151; the cell wall can increase in thickness from 50–100 nm to 2–3 µm (ref.147), and the cell wall composition is altered through an increase in chitin content and a decrease in glucan152.”
From Treatment strategies for cryptococcal infection: challenges, advances and future outlook (2021) · cites this paper as [152]
The increase in chitin induces a T helper 2-type allergic response and cytokine release, rather than a protective T helper 1-type response, which leads to increased mortality in infected mice.
“This increase in chitin induces a T helper 2-type allergic response and cytokine release, rather than a protective T helper 1-type response, which leads to increased mortality in infected mice152.”
From Treatment strategies for cryptococcal infection: challenges, advances and future outlook (2021) · cites this paper as [152]

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The Fungal Cell Wall: Candida, Cryptococcus, and Aspergillus Species
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Titan cells formation in Cryptococcus neoformans is finely tuned by environmental conditions and modulated by positive and negative genetic regulators
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Titan cell production in Cryptococcus neoformans reshapes the cell wall and capsule composition during infection
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A titanic drug resistance threat in Cryptococcus neoformans
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Disarming Fungal Pathogens: Bacillus safensis Inhibits Virulence Factor Production and Biofilm Formation by Cryptococcus neoformans and Candida albicans
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Immunity to fungi in the lung
Heung, L. J., Wiesner, D. L., Wang, K., Rivera, A., & Hohl, T. M. (2023) · Seminars in Immunology · doi:10.1016/j.smim.2023.101728 · Cited by 72 · see citing works
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PAMPs of the Fungal Cell Wall and Mammalian PRRs
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Mechanisms of Pulmonary Escape and Dissemination by Cryptococcus neoformans
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Glycoside hydrolase family 18 and 20 enzymes are novel targets of the traditional medicine berberine
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Immunomodulatory Effects of Chitotriosidase Enzyme
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A chitinase from pacific white shrimp Litopenaeus vannamei involved in immune regulation
Niu, S., Yang, L., Zuo, H., Zheng, J., Weng, S., He, J., & Xu, X. (2018) · Developmental & Comparative Immunology · doi:10.1016/j.dci.2018.04.013 · Cited by 61 · see citing works
Inflammatory monocytes are detrimental to the host immune response during acute infection with Cryptococcus neoformans
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Safety and immunogenicity evaluation of recombinant BCG vaccine against respiratory syncytial virus in a randomized, double-blind, placebo-controlled phase I clinical trial
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Resistance and Tolerance to Cryptococcal Infection: An Intricate Balance That Controls the Development of Disease
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Does HIV infection contribute to increased beta-amyloid synthesis and plaque formation leading to neurodegeneration and Alzheimer’s disease?
Fülöp, T., Witkowski, J. M., Larbi, A., Khalil, A., Herbein, G., & Frost, E. H. (2019) · Journal of NeuroVirology · doi:10.1007/s13365-019-00732-3 · Cited by 59 · see citing works
Acidic chitinase primes the protective immune response to gastrointestinal nematodes
Vannella, K. M., Ramalingam, T. R., Hart, K. M., Prado, R. D. Q., Sciurba, J. C., Barron, L., Borthwick, L. A., Smith, A. D., Mentink‐Kane, M. M., White, S., et al. (2016) · Nature Immunology · doi:10.1038/ni.3417 · Cited by 57 · see citing works
Defects in intracellular trafficking of fungal cell wall synthases lead to aberrant host immune recognition
Esher, S. K., Ost, K. S., Kohlbrenner, M. A., Pianalto, K. M., Telzrow, C. L., Campuzano, A., Nichols, C. B., Munro, C. A., Wormley, F. L., & Alspaugh, J. A. (2018) · PLoS Pathogens · doi:10.1371/journal.ppat.1007126 · Cited by 54 · see citing works
Regulatory T Cell Induction and Retention in the Lungs Drives Suppression of Detrimental Type 2 Th Cells During Pulmonary Cryptococcal Infection
Wiesner, D. L., Smith, K. D., Kotov, D. I., Nielsen, J. N., Bohjanen, P. R., & Nielsen, K. (2015) · The Journal of Immunology · doi:10.4049/jimmunol.1501871 · Cited by 55 · see citing works
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Morphology Changes in Human Fungal Pathogens upon Interaction with the Host
Li, Z., & Nielsen, K. (2017) · Journal of Fungi · doi:10.3390/jof3040066 · Cited by 52 · see citing works
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N-acetylglucosamine Regulates Virulence Properties in Microbial Pathogens
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Piehler, D., Eschke, M., Schulze, B., Protschka, M., Müller, U., Grahnert, A., Richter, T., Heyen, L., Köhler, G., Brombacher, F., et al. (2015) · Mucosal Immunology · doi:10.1038/mi.2015.106 · Cited by 49 · see citing works
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Ost, K. S., Esher, S. K., Wager, C. M. L., Walker, L. A., Wagener, J., Munro, C. A., Wormley, F. L., & Alspaugh, J. A. (2017) · mBio · doi:10.1128/mbio.02290-16 · Cited by 47 · see citing works
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Adoptive transfer of Trichinella spiralis-activated macrophages can ameliorate both Th1- and Th2-activated inflammation in murine models
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Immunomodulation of Host Chitinase 3-Like 1 During a Mammary Pathogenic Escherichia coli Infection
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The cause and effect of Cryptococcus interactions with the host
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The 2 micron plasmid: a selfish genetic element with an optimized survival strategy within Saccharomyces cerevisiae
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The Cyclin Cln1 Controls Polyploid Titan Cell Formation following a Stress-Induced G2 Arrest in Cryptococcus
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Different Lymphocyte Populations Direct Dichotomous Eosinophil or Neutrophil Responses to Pulmonary Cryptococcus Infection
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Cytomegalovirus Viremia Associated With Increased Mortality in Cryptococcal Meningitis in Sub-Saharan Africa
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A Novel Scaffold for Developing Specific or Broad-Spectrum Chitinase Inhibitors
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Chitotriosidase inhibits allergic asthmatic airways via regulation of TGF ‐β expression and Foxp3+ Treg cells
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RESEARCH ARTICLE Chitin Recognition via Chitotriosidase Promotes Pathologic Type-2 Helper T Cell Responses to Cryptococcal Infection
Wiesner, D. L., Specht, C. A., Lee, C. K., Smith, K. D., Mukaremera, L., Lee, S. T., Lee, C. G., Elias, J. A., & Nielsen, J. N. (2016)
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Authors: Wiesner, D. L., Specht, C. A., Lee, C. K., Smith, K. D., Mukaremera, L., Lee, S. T., Lee, C. G., Elias, J. A., Nielsen, J. N., Boulware, D. R., Bohjanen, P. R., Jenkins, M. K., Levitz, S. M., & Nielsen, K.
Affiliations: University of Minnesota (US)
University of Massachusetts Chan Medical School (US)
Brown University (US)
University of North Carolina at Chapel Hill (US)
Corresponding author: Nielsen, Kirsten
ORCID: Specht, Charles A.
Smith, Kyle D.
Mukaremera, Liliane
Lee, Chun G.
Elias, Jack A.
Boulware, David R.
Bohjanen, Paul R.
Jenkins, Marc K.
Levitz, Stuart M.
Nielsen, Kirsten
Venue: PLOS Pathogens
Publisher: Public Library of Science (PLoS)
Published: 2015-03-12
Volume: 11
Issue: 3
Pages: e1004701
ISSN: 1553-7366 (ISSN-L)
1553-7374
DOI: 10.1371/journal.ppat.1004701
PMC: PMC4357429
OpenAlex: W2005361432
Cited by: 214
References: 83
Citations by year: 2026: 8 · 2025: 17 · 2024: 17 · 2023: 12 · 2022: 18 · 2021: 9 · 2020: 18 · 2019: 26 · 2018: 30 · 2017: 27 · 2016: 20 · 2015: 12
FWCI: 23.30
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (vor)
Locations: PLoS Pathogens (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, cc-by)
PubMed (publishedVersion)
The Journal of the American Medical Association (JAMA) Network (American Medical Association) (submittedVersion, cc-by)
Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Figshare (submittedVersion, cc-by)
UNC Libraries
Funders: Pfizer
University of Minnesota
National Institutes of Health (UL1TR000114, NIH T32)
National Heart, Lung, and Blood Institute (R01HL112671, HL112671)
National Cancer Institute (P30CA077598)
National Institute of Allergy and Infectious Diseases (AI072195, AI025780, R21AI093302, AI 007313, R01AI025780, R01AI080275, R01AI039614, AI093302, AI089067, K24AI096925, AI039614, R01AI072195, AI080275, T32AI007313)
National Center for Advancing Translational Sciences
Topics: Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Studies on Chitinases and Chitosanases
Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
Keywords: chitin recognition, chitotriosidase, Th2 differentiation, Cryptococcus neoformans, pulmonary cryptococcosis, fungal lung infection, IRF4, fungal chitin, Th17 cells, Aspergillus fumigatus
MeSH terms: Animals, Antigens, Fungal, Chitin, Cryptococcosis, Cryptococcus neoformans, Dendritic Cells, Disease Models, Animal, Flow Cytometry, Hexosaminidases, Lung Diseases, Fungal, Lymphocyte Activation, Mice, Inbred C57BL, Microscopy, Fluorescence, Th2 Cells, Mice

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Chitin Recognition via Chitotriosidase Promotes Pathologic Type-2 Helper T Cell Responses to Cryptococcal Infection

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