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A Candida albicans Strain Expressing Mammalian Interleukin-17A Results in Early Control of Fungal Growth during Disseminated Infection.

ABSTRACT: Candida albicans is normally a commensal fungus of the human mucosae and skin, but it causes life-threatening systemic infections in hospital settings in the face of predisposing conditions, such as indwelling catheters, abdominal surgery, or antibiotic use. Immunity to C. albicans involves various immune parameters, but the cytokine interleukin-17A (IL-17A) (also known as IL-17) has emerged as a centrally important mediator of immune defense against both mucosal and systemic candidiasis. Conversely, IL-17A has been suggested to enhance the virulence of C. albicans, indicating that it may exert detrimental effects on pathogenesis. In this study, we hypothesized that a C. albicans strain expressing IL-17A would exhibit reduced virulence in vivo. To that end, we created a Candida-optimized expression cassette encoding murine IL-17A, which was transformed into the DAY286 strain of C. albicans. Candida-derived IL-17A was indistinguishable from murine IL-17A in terms of biological activity and detection in standard enzyme-linked immunosorbent assays (ELISAs). Expression of IL-17A did not negatively impact the growth of these strains in vitro. Moreover, the IL-17A-expressing C. albicans strains showed significantly reduced pathogenicity in a systemic model of Candida infection, mainly evident during the early stages of disease. Collectively, these findings suggest that IL-17A mitigates the virulence of C. albicans.

SUBMITTER: Huppler AR

PROVIDER: S-EPMC4534662 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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A Candida albicans Strain Expressing Mammalian Interleukin-17A Results in Early Control of Fungal Growth during Disseminated Infection.

Huppler Anna R AR Whibley Natasha N Woolford Carol A CA Childs Erin E EE He Jie J Biswas Partha S PS McGeachy Mandy J MJ Mitchell Aaron P AP Gaffen Sarah L SL

Infection and immunity 20150706 9

Candida albicans is normally a commensal fungus of the human mucosae and skin, but it causes life-threatening systemic infections in hospital settings in the face of predisposing conditions, such as indwelling catheters, abdominal surgery, or antibiotic use. Immunity to C. albicans involves various immune parameters, but the cytokine interleukin-17A (IL-17A) (also known as IL-17) has emerged as a centrally important mediator of immune defense against both mucosal and systemic candidiasis. Conver ...[more]

PMID: 26150537

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Project description:The association between Candida albicans (C. albicans) and oral cancer (OC) has been noticed for a long time, but the mechanisms for C. albicans promoting OC are rarely explored. In this study, we determined that C. albicans infection promoted OC incidence in a 4-nitroquinoline 1-oxide (4NQO)-induced mouse tongue carcinogenesis model as well as promoted OC progression in a tongue tumor-bearing mouse model (C3H/HeN-SCC VII). We then demonstrated that tumor-associated macrophage (TAMs) infiltration was elevated during C. albicans infection. Meanwhile, the attracted TAMs polarized into M2-like macrophages with high expression of programmed death ligand 1 (PD-L1) and galectin-9 (GAL-9). Further analysis suggested that the interleukin (IL)-17A/IL-17RA pathway activated in OC cells was a contributor to the excessive TAMs infiltration in C. albicans-infected mice. Thus, we constructed IL-17A neutralization and macrophage depletion experiments in C3H/HeN-SCC VII mice to explore the role of IL-17A/IL-17RA and TAMs in OC development caused by C. albicans infection. The results showed that both IL-17A neutralization and macrophage depletion tended to reduce the TAMs number and tumor size in mice with C. albicans infection. Collectively, our finding revealed that C. albicans promoted OC development via the IL-17A/IL-17RA-macrophage axis, opening perspectives for revealing C. albicans-tumor immune microenvironment links. IMPORTANCE The relationship between fungi and cancer is gradually receiving attention. Among them, some clinical evidence has shown that Candida may be a contributor to gastrointestinal cancers, especially oral cancer. However, the underlying mechanisms for Candida promoting oral cancer need to be explored. For this reason, this study demonstrated the role of C. albicans in oral cancer development. Moreover, this study revealed the underlying mechanisms for C. albicans promoting oral cancer from the perspective of the tumor immune microenvironment.

Project description:PurposeThe aim of this study was to investigate the role of genetic background in determining the development or prognosis of experimental fungal keratitis by comparing the disease courses and related molecules of experimental Candida albicans in two common mouse strains.MethodsAfter intrastromal inoculation of 1 × 10(5)C. albicans blastospores into corneas of Balb/c and C57BL/6 mice, all mice developed typical keratitis. The disease was monitored using a slit lamp microscope and scored for comparison of symptoms. At desired time points, blood was collected and corneal homogenates were prepared for enzyme-linked immunosorbent assay measurement of interferon (IFN)γ or interleukin (IL)17. Other corneas were processed for histological evaluation, pathogen load measurement, or total RNA extraction, the last of which was subjected to reverse transcription in conjunction with real-time PCR to measure genes of interest in terms of collagens, matrix metalloproteinases (MMPs), and the tissue inhibitors of MMPs (TIMPs).ResultsThe infected corneas from the two strains presented different manifestations. Corneal transparency was less affected in Balb/c mice than in C57BL/6 mice, and Balb/c corneas contained fewer pathogens than C57BL/6 corneas during the measured period (10 days). In both strains, keratitis started to resolve around days 7-10, but C57BL/6 mice healed slower than Balb/c mice as indicated by disease presentation, histology, and pathogen burden assay. By day 7 post infection, pseudohyphae were rare but cellular infiltration remained intensive in both strains. The surface of the Balb/c corneas remained relatively intact and smooth, and C57BL/6 corneal lesions produced open erosion areas. Perforation was never seen in the current study setting. In both sera and corneas, IL17 expression increased earlier than IFNγ, and C57BL/6 mice produced higher IL17 levels and lower IFNγ levels than Balb/c mice. Compared with C57BL/6 mice, Balb/c corneas produced more MMP-2, Col3a1, and Col4a1, and less or equivalent TIMP-2 at all detected time points. They also produced more MMP-13, less MMP-8, MMP-9, and TIMP-1 at day 3 post infection, but less MMP-13, basically equivalent MMP-8, and more MMP-9 at later time points.ConclusionsThe disease course of experimental C. albicans keratitis depends on the genetic background of the host animals. The balance between IL17 and IFNγ, as well as among the common injury- and wound healing-related proteins, may contribute to the pathogenesis of C. albicans keratitis. This study suggests that great variance of disease presentation should be expected for human subjects with Candida keratitis.

Dataset Information

A Candida albicans Strain Expressing Mammalian Interleukin-17A Results in Early Control of Fungal Growth during Disseminated Infection.

Publications

A Candida albicans Strain Expressing Mammalian Interleukin-17A Results in Early Control of Fungal Growth during Disseminated Infection.

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