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Cited by 26Antifungal resistance and susceptibilityFungal and yeast genetics researchFungal Infections and Studies

Caspofungin-induced β(1,3)-glucan exposure in Candida albicans is driven by increased chitin levels

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Wagner, Andrew S., Lumsdaine, Stephen W., Mangrum, Mikayla M., Reynolds, Todd B.·2023·mBio
DOI 10.1128/mbio.00074-23PMC PMC10470516
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Abstract

To successfully induce disease, Candida albicans must effectively evade the host immune system. One mechanism used by C. albicans to achieve this is to mask immunogenic β(1,3)-glucan epitopes within its cell wall under an outer layer of mannosylated glycoproteins. Consequently, induction of β(1,3)-glucan exposure (unmasking) via genetic or chemical manipulation increases fungal recognition by host immune cells in vitro and attenuates disease during systemic infection in mice. Treatment with the echinocandin caspofungin is one of the most potent drivers of β(1,3)-glucan exposure. Several reports using murine infection models suggest a role for the immune system, and specifically host β(1,3)-glucan receptors, in mediating the efficacy of echinocandin treatment in vivo . However, the mechanism by which caspofungin-induced unmasking occurs is not well understood. In this report, we show that foci of unmasking co-localize with areas of increased chitin within the yeast cell wall in response to caspofungin, and that inhibition of chitin synthesis via nikkomycin Z attenuates caspofungin-induced β(1,3)-glucan exposure. Furthermore, we find that both the calcineurin and Mkc1 mitogen-activated protein kinase pathways work synergistically to regulate β(1,3)-glucan exposure and chitin synthesis in response to drug treatment. When either of these pathways are interrupted, it results in a bimodal population of cells containing either high or low chitin content. Importantly, increased unmasking correlates with increased chitin content within these cells. Microscopy further indicates that caspofungin-induced unmasking correlates with actively growing cells. Collectively, our work presents a model in which chitin synthesis induces unmasking within the cell wall in response to caspofungin in growing cells. IMPORTANCE: Systemic candidiasis has reported mortality rates ranging from 20% to 40%. The echinocandins, including caspofungin, are first-line antifungals used to treat systemic candidiasis. However, studies in mice have shown that echinocandin efficacy relies on both its cidal impacts on Candida albicans , as well as a functional immune system to successfully clear invading fungi. In addition to direct C. albicans killing, caspofungin increases exposure (unmasking) of immunogenic β(1,3)-glucan moieties. To evade immune detection, β(1,3)-glucan is normally masked within the C. albicans cell wall. Consequently, unmasked β(1,3)-glucan renders these cells more visible to the host immune system and attenuates disease progression. Therefore, discovery of how caspofungin-induced unmasking occurs is needed to elucidate how the drug facilitates host immune system-mediated clearance in vivo . We report a strong and consistent correlation between chitin deposition and unmasking in response to caspofungin and propose a model in which altered chitin synthesis drives increased unmasking during drug exposure.

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  • Echinocandin treatment often results only in partial inhibition of β-1,3-glucan synthesis.

    “However, echinocandin treatment often results only in partial inhibition of β−1,3-glucan synthesis22–24.”

    From Distinct echinocandin responses of Candida albicans and Candida auris cell walls revealed by solid-state NMR (2025) · cites this paper as [24]

    The Introduction (page not provided) says echinocandins inhibit the β(1,3)-glucan synthase enzymes Fks1 and Fks2. It does not say that inhibition is often only partial; its findings about glucan exposure during caspofungin treatment do not establish how much synthesis remains. (LLM, conf=0.78)

    Experimental — accuracy not yet measured

  • Cell wall adaptation to echinocandins is characterized by increased levels and exposure of chitin following depletion of a substantial portion of β-glucan.

    “These effects have been associated with cell wall adaptation to echinocandins, characterized by increased levels and exposure of chitin following the depletion of a substantial portion of β-glucan; however, our understanding of echinocandin-induced remodeling mechanism of Candida cell wall architecture remains limited24,27–29.”

    From Distinct echinocandin responses of Candida albicans and Candida auris cell walls revealed by solid-state NMR (2025) · cites this paper as [24]

    The Introduction and Discussion (pages unavailable) describe increased chitin deposition during caspofungin treatment of Candida albicans and link it to cell-wall remodeling. They identify the exposed material as β(1,3)-glucan, not chitin. The Introduction says echinocandins inhibit β(1,3)-glucan synthesis, but does not establish depletion of a substantial portion of cell-wall β-glucan. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Wagner, A. S., Lumsdaine, S. W., Mangrum, M. M., & Reynolds, T. B.
Affiliations
University of Tennessee at Knoxville (US)
Corresponding author
Reynolds, Todd B.
ORCID
Venue
mBio
Publisher
American Society for Microbiology
Published
2023-06-28
Volume
14
Issue
4
Pages
e0007423-e0007423
ISSN
2150-7511 (ISSN-L)
DOI
10.1128/mbio.00074-23
PMC
PMC10470516
OpenAlex
W4382344891
Cited by
26
References
16
Citations by year
2026: 10 · 2025: 8 · 2024: 6 · 2023: 2
FWCI
5.35
Type
journal article
Language
en
Open access
Licence
Locations
  • mBio (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
HHS | NIH | National Institute of Allergy and Infectious Diseases (1R01AI153599)
Topics
  • Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
  • Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
Keywords
caspofungin, echinocandins, Candida albicans, chitin synthesis, nikkomycin Z, calcineurin pathway, systemic candidiasis, antifungal resistance, cell wall, fungal immune evasion, cell growth state, antifungal susceptibility testing
MeSH terms
Caspofungin, Animals, Antifungal Agents, Candida albicans, Candidiasis, Cell Wall, Chitin, Glucans, Mice, Echinocandins, Lipopeptides

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