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Oropharyngeal Candidiasis in HIV Infection: Analysis of Impaired Mucosal Immune Response to Candida albicans in Mice Expressing the HIV-1 Transgene.

de Repentigny L, Goupil M, Jolicoeur P - Pathogens (2015)

Bottom Line: IL-17-producing Th17 cells are of critical importance in host defense against oropharyngeal candidiasis (OPC).Innate phagocytes were quantitatively and functionally intact, and individually dispensable for control of OPC and to prevent systemic dissemination of Candida to deep organs.Therefore, the immunopathogenesis of OPC in the context of HIV infection involves defective T-cell-mediated immunity, failure of crosstalk with innate mucosal immune effector mechanisms, and compensatory cell responses, which limit Candida infection to the oral mucosa and prevent systemic dissemination.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, Infectious Diseases and Immunology, Faculty of Medicine, University of Montreal, C.P. 6128, succursale Centre-Ville, Montreal, PQ H3C 3J7, Canada. louis.de.repentigny@umontreal.ca.

ABSTRACT
IL-17-producing Th17 cells are of critical importance in host defense against oropharyngeal candidiasis (OPC). Speculation about defective Th17 responses to oral C. albicans infection in the context of HIV infection prompted an investigation of innate and adaptive immune responses to Candida albicans in transgenic mice expressing the genome of HIV-1 in immune cells and displaying an AIDS-like disease. Defective IL-17 and IL-22-dependent mucosal responses to C. albicans were found to determine susceptibility to OPC in these transgenic mice. Innate phagocytes were quantitatively and functionally intact, and individually dispensable for control of OPC and to prevent systemic dissemination of Candida to deep organs. CD8+ T-cells recruited to the oral mucosa of the transgenic mice limited the proliferation of C. albicans in these conditions of CD4+ T-cell deficiency. Therefore, the immunopathogenesis of OPC in the context of HIV infection involves defective T-cell-mediated immunity, failure of crosstalk with innate mucosal immune effector mechanisms, and compensatory cell responses, which limit Candida infection to the oral mucosa and prevent systemic dissemination.

No MeSH data available.


Related in: MedlinePlus

The protective Th17 cell-mediated mucosal immune response to Candida albicans is perturbed (red color) in CD4C/HIV Mut transgenic mice. Dendritic cells display an immature phenotype and defective antigen presentation. Naïve CD4+ T cells, and differentiated CD4+ T-cell subsets, including Th17 cells, are all depleted in these transgenic mice, which fail to up-regulate oral mucosal expression of IL17, IL22 and S100a8 in response to oral C. albicans infection. CLRs, C-type lectin receptors; RNIs, reactive nitrogen intermediates; ROIs, reactive oxygen intermediates; and TLRs, toll-like receptors.
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pathogens-04-00406-f002: The protective Th17 cell-mediated mucosal immune response to Candida albicans is perturbed (red color) in CD4C/HIV Mut transgenic mice. Dendritic cells display an immature phenotype and defective antigen presentation. Naïve CD4+ T cells, and differentiated CD4+ T-cell subsets, including Th17 cells, are all depleted in these transgenic mice, which fail to up-regulate oral mucosal expression of IL17, IL22 and S100a8 in response to oral C. albicans infection. CLRs, C-type lectin receptors; RNIs, reactive nitrogen intermediates; ROIs, reactive oxygen intermediates; and TLRs, toll-like receptors.

Mentions: Demonstration of the critical role of Th17 cells in mucosal protection against OPC [16] led us to analyse CD4+ T-cell subsets and to seek direct evidence for a defective IL-17-dependent response to oral C. albicans in the CD4C/HIVMutA Tg mice [88] (Figure 2). As expected, naïve CD4+ T-cells and the differentiated Th1, Th2, Th17, Th1Th17 and Treg lineages were all profoundly depleted in cervical lymph nodes of the Tg mice. To determine if this subset depletion is caused by a lack of naïve cells and/or inability of naïve cells to respond to differentiating cytokines, identical numbers of naïve cells from Tg and non-Tg mice were incubated in vitro with cocktails of differentiating cytokines specific to each CD4+ T-cell subset [88]. It turned out that naïve CD4+ T-cells from Tg mice maintained the capacity to differentiate into the specific lineages in response to polarizing cytokines and to produce the critical cytokines, including IL-17A in the case of Th17 differentiating conditions, required for a protective adaptive immune response to C. albicans. These findings indicated that depletion of polarized CD4+ T-cell subsets in the Tg mice is most likely caused by the marked diminution of naïve CD4+ cells, rather than any potential downstream defects in CD4+ cell differentiation [88].We next showed that oral infection with C. albicans induced expression of S100a8, Ccl20, Il17 and Il22 in tongue tissues of non-Tg mice, but that this mucosal immune response to C. albicans infection was completely abrogated in the Tg mice. Furthermore, treatment of infected Tg mice with the combination of IL-17 and IL-22 significantly reduced oral burdens of C. albicans, markedly decreased the density of C. albicans on histopathology of the oral epithelium, and restored the expression of S100a8 and Ccl20 [88]. Therefore, in the context of HIV-expression, cause-and-effect was established between defective IL-17 and IL-22 responses, perturbed antimicrobial peptide gene expression, and susceptibility to oral C. albicans infection. Interestingly, Il-17 and Il-22 alone did not significantly reduce oral loads of C. albicans, showing that neither cytokine is dispensable for protection against OPC in this animal model [88]. Furthermore, untreated Tg mice displayed a progressive reduction in oral burdens of C. albicans from day 5 to 17 after oral infection, suggesting the participation of IL-17-producing cell populations other than Th17 cells in the response to OPC in the Tg mice, which could potentially include γδ T-cells, NKT cells, Tc17 CD8 T-cells, and ILCs.


Oropharyngeal Candidiasis in HIV Infection: Analysis of Impaired Mucosal Immune Response to Candida albicans in Mice Expressing the HIV-1 Transgene.

de Repentigny L, Goupil M, Jolicoeur P - Pathogens (2015)

The protective Th17 cell-mediated mucosal immune response to Candida albicans is perturbed (red color) in CD4C/HIV Mut transgenic mice. Dendritic cells display an immature phenotype and defective antigen presentation. Naïve CD4+ T cells, and differentiated CD4+ T-cell subsets, including Th17 cells, are all depleted in these transgenic mice, which fail to up-regulate oral mucosal expression of IL17, IL22 and S100a8 in response to oral C. albicans infection. CLRs, C-type lectin receptors; RNIs, reactive nitrogen intermediates; ROIs, reactive oxygen intermediates; and TLRs, toll-like receptors.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4493482&req=5

pathogens-04-00406-f002: The protective Th17 cell-mediated mucosal immune response to Candida albicans is perturbed (red color) in CD4C/HIV Mut transgenic mice. Dendritic cells display an immature phenotype and defective antigen presentation. Naïve CD4+ T cells, and differentiated CD4+ T-cell subsets, including Th17 cells, are all depleted in these transgenic mice, which fail to up-regulate oral mucosal expression of IL17, IL22 and S100a8 in response to oral C. albicans infection. CLRs, C-type lectin receptors; RNIs, reactive nitrogen intermediates; ROIs, reactive oxygen intermediates; and TLRs, toll-like receptors.
Mentions: Demonstration of the critical role of Th17 cells in mucosal protection against OPC [16] led us to analyse CD4+ T-cell subsets and to seek direct evidence for a defective IL-17-dependent response to oral C. albicans in the CD4C/HIVMutA Tg mice [88] (Figure 2). As expected, naïve CD4+ T-cells and the differentiated Th1, Th2, Th17, Th1Th17 and Treg lineages were all profoundly depleted in cervical lymph nodes of the Tg mice. To determine if this subset depletion is caused by a lack of naïve cells and/or inability of naïve cells to respond to differentiating cytokines, identical numbers of naïve cells from Tg and non-Tg mice were incubated in vitro with cocktails of differentiating cytokines specific to each CD4+ T-cell subset [88]. It turned out that naïve CD4+ T-cells from Tg mice maintained the capacity to differentiate into the specific lineages in response to polarizing cytokines and to produce the critical cytokines, including IL-17A in the case of Th17 differentiating conditions, required for a protective adaptive immune response to C. albicans. These findings indicated that depletion of polarized CD4+ T-cell subsets in the Tg mice is most likely caused by the marked diminution of naïve CD4+ cells, rather than any potential downstream defects in CD4+ cell differentiation [88].We next showed that oral infection with C. albicans induced expression of S100a8, Ccl20, Il17 and Il22 in tongue tissues of non-Tg mice, but that this mucosal immune response to C. albicans infection was completely abrogated in the Tg mice. Furthermore, treatment of infected Tg mice with the combination of IL-17 and IL-22 significantly reduced oral burdens of C. albicans, markedly decreased the density of C. albicans on histopathology of the oral epithelium, and restored the expression of S100a8 and Ccl20 [88]. Therefore, in the context of HIV-expression, cause-and-effect was established between defective IL-17 and IL-22 responses, perturbed antimicrobial peptide gene expression, and susceptibility to oral C. albicans infection. Interestingly, Il-17 and Il-22 alone did not significantly reduce oral loads of C. albicans, showing that neither cytokine is dispensable for protection against OPC in this animal model [88]. Furthermore, untreated Tg mice displayed a progressive reduction in oral burdens of C. albicans from day 5 to 17 after oral infection, suggesting the participation of IL-17-producing cell populations other than Th17 cells in the response to OPC in the Tg mice, which could potentially include γδ T-cells, NKT cells, Tc17 CD8 T-cells, and ILCs.

Bottom Line: IL-17-producing Th17 cells are of critical importance in host defense against oropharyngeal candidiasis (OPC).Innate phagocytes were quantitatively and functionally intact, and individually dispensable for control of OPC and to prevent systemic dissemination of Candida to deep organs.Therefore, the immunopathogenesis of OPC in the context of HIV infection involves defective T-cell-mediated immunity, failure of crosstalk with innate mucosal immune effector mechanisms, and compensatory cell responses, which limit Candida infection to the oral mucosa and prevent systemic dissemination.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, Infectious Diseases and Immunology, Faculty of Medicine, University of Montreal, C.P. 6128, succursale Centre-Ville, Montreal, PQ H3C 3J7, Canada. louis.de.repentigny@umontreal.ca.

ABSTRACT
IL-17-producing Th17 cells are of critical importance in host defense against oropharyngeal candidiasis (OPC). Speculation about defective Th17 responses to oral C. albicans infection in the context of HIV infection prompted an investigation of innate and adaptive immune responses to Candida albicans in transgenic mice expressing the genome of HIV-1 in immune cells and displaying an AIDS-like disease. Defective IL-17 and IL-22-dependent mucosal responses to C. albicans were found to determine susceptibility to OPC in these transgenic mice. Innate phagocytes were quantitatively and functionally intact, and individually dispensable for control of OPC and to prevent systemic dissemination of Candida to deep organs. CD8+ T-cells recruited to the oral mucosa of the transgenic mice limited the proliferation of C. albicans in these conditions of CD4+ T-cell deficiency. Therefore, the immunopathogenesis of OPC in the context of HIV infection involves defective T-cell-mediated immunity, failure of crosstalk with innate mucosal immune effector mechanisms, and compensatory cell responses, which limit Candida infection to the oral mucosa and prevent systemic dissemination.

No MeSH data available.


Related in: MedlinePlus