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. 2024 Nov 21;9(11):e0073424.
doi: 10.1128/msphere.00734-24. Epub 2024 Oct 30.

Cell aggregation mediated by ACE2 deletion in Candida auris modulates fungal colonization and host immune responses in the skin

Abishek Balakumar  1 , Abigail Cox  1 , Shankar Thangamani  1   2
Affiliations

Cell aggregation mediated by ACE2 deletion in Candida auris modulates fungal colonization and host immune responses in the skin

Abishek Balakumar et al. mSphere. .

Abstract

Candida auris is an emerging multi-drug-resistant fungal pathogen that colonizes the skin and causes invasive infections in hospitalized patients. Multi-cellular aggregative phenotype is widely reported in the C. auris isolates, but its role in skin colonization and host immune response is not yet known. In this study, we generated aggregative phenotype by deleting the ACE2 gene in C. auris and determined the fungal colonization and host immune response using an intradermal mouse model of C. auris skin infection. Our results indicate that mice infected with ace2Δ strain had significantly lower fungal load after 3 and 14 days post-infections compared to the non-aggregative wild-type and the ACE2 reintegrated strain. The colonization of ace2Δ is associated with increased recruitment of CD11b+ Ly6G+ neutrophils and decreased accumulation of CD11b+ Ly6 Chi inflammatory monocytes and CD11b+ MHCII+ CD64+ macrophages. Furthermore, Th17 cells and type 3 innate lymphoid cells (ILCs) were significantly increased in the skin tissue of ace2Δ infected mice. Our findings suggest that aggregative phenotype mediated by ACE2 deletion in C. auris induces potent neutrophil and IL-17-mediated immune response and reduces fungal colonization in the skin.IMPORTANCEC. auris is a rapidly emerging fungal pathogen that can colonize hospitalized patients, especially in skin tissue, and cause invasive infections. C. auris isolates exhibit morphological heterogeneity, and the multicellular aggregative phenotype of C. auris is reported frequently in clinical settings. Understanding the role of fungal morphotypes in colonization, persistence, and immune response in the skin microenvironment will have potential applications in clinical diagnosis and novel preventive and therapeutic measures. Here, we utilized the murine model of intradermal infection and determined that the aggregative phenotype of C. auris as the result of ACE2 gene deletion elicits potential innate and adaptive immune responses in mice. These observations will help explain the differences in the skin colonization and immune responses of the aggregative morphotype of C. auris and open the door to developing novel antifungal therapeutics.

Keywords: Candida auris; cell aggregation; colonization; skin immune response.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig 1
Fig 1
In vitro growth and in vivo skin colonization regulated by ACE2 deletion in C. auris. (A) Microscopy of C. auris AR0387 (WT) ace2Δ and ace2Δ + ACE2 strains in differential interference contrast. Cells were grown in YPD at 30°C for 16 h, and images were taken under 400 × magnification. Bars, 100 µm. (B) Standard curve of the 107, 106, 105, and 104 fungal cells of WT, ace2Δ, and ace2Δ + ACE2 strains quantified using qPCR. The x-axis represents the colony forming units, and the y-axis represents the cycle threshold values. (C) Fungal load of murine skin infected with either WT or ace2Δ or ace2Δ + ACE2 after days 3 and 14. The bar graph represents the relative quantity of fungal DNA in murine skin tissue quantified in 25 grams of tissue weight in the WT, ace2Δ, and ace2Δ + ACE2 infected groups compared using Mann-Whitney U test, *P ≤ 0.05, **P ≤ 0.01. (D) Growth curve of C. auris WT, ace2Δ, and ace2Δ + ACE2 strains after 0 h, 6 h, 18 h, and 24 h. The strains were grown in RPMI-MOPS at 300 C. The growth curve of the three groups was analyzed using one-way ANOVA, and there was no statistical significance between the groups.
Fig 2
Fig 2
The ace2Δ aggregative strain induces a potent neutrophil response in the murine skin after 3 days post-infection. Representative flow plots, percentage, and absolute number of (A) CD11b+ Ly6G+ neutrophils, (B) CD11b+ Ly6CHi monocytes, and (C) CD11b+ MHC-II+ CD64+ macrophages in C. auris WT or ace2Δ infected murine skin after 3 days post-infection. Data are represented in a bar graph as mean ± SEM for each group obtained from 12 infected mice compared using the Mann-Whitney U test. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001, ****P ≤ 0.0001.
Fig 3
Fig 3
The ace2Δ aggregative strain induces a potent type 3 ILCs response in the murine skin after 14 days post-infection. Percentage and absolute number of (A) IL-17A+ ILCs, (B) IL-17F+ ILCs, and (C) IL-22+ ILCs in C. auris WT or ace2Δ infected mice skin tissue after 14 days post-infection. The samples from the different groups were processed independently for the intracellular staining and were gated with respect to their controls. Data are represented in a bar graph as mean ± SEM for each group obtained from eight infected mice compared using the Mann-Whitney U test. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001.
Fig 4
Fig 4
The ace2Δ aggregative strain induces a potent IL-17-producing CD4+ T helper response in the murine skin after 14 days post-infection. Percentage and absolute number of (A-D) total γδ+ cells, γδ+ IFN-γ+, γδ+ IL-17A+, and γδ+ IL-17F+. (E-H) Total CD4+ cells, CD4+ IFN-γ+, CD4+ IL-17A+, and CD4+ IL-17F+ T cells. (I-L) Total CD8+ cells, CD8+ IFN-γ+, CD8+ IL-17A+, and CD8+ IL-17F+ T cells in C. auris WT or ace2Δ infected mice skin tissue after 14 days post-infection. Data are represented in a bar graph as mean ± SEM for each group obtained from 8 to 10 infected mice compared using the Mann-Whitney U test. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001.
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