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THE ROLE OF IL-17 IN THE INNATE IMMUNE RESPONSE TO OROPHARYNGEAL CANDIDIASIS

Peterson, Alanna C. (2011) THE ROLE OF IL-17 IN THE INNATE IMMUNE RESPONSE TO OROPHARYNGEAL CANDIDIASIS. Master's Thesis, University of Pittsburgh.

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    Abstract

    Oropharyngeal candidiasis (OPC; thrush) is an opportunistic oral infection caused by the commensal fungus Candida albicans that afflicts immunosuppressed and immunocompromised individuals. Although patients with HIV/AIDS are the prototypical population associated with development of thrush, there are a host of conditions that lead to susceptibility to OPC, including Hyper-IgE Syndrome (HIES). The autosomal dominant form of HIES (AD-HIES) is characterized by inherited dominant negative mutations in the STAT3 transcription factor, which is crucial for physiologic homeostasis and development in many tissues, including immune cells. Due to the ubiquitous nature of STAT3, mutations in this gene lead to a highly varied set of clinical sequelae, including oral thrush. Numerous cytokines utilize STAT3 to mediate downstream signaling, including IL-6 and IL-23, which are crucial for the differentiation and expansion of T helper 17 (Th17) cells, respectively. IL-23 is necessary for 1) in vivo expansion of Th17 cells, and 2) the secretion of IL-17 and other proinflammatory cytokines. Recently, the Th17 lineage has been shown to play a major role in host defense against OPC. Our lab has previously shown that mice deficient in the IL-17 receptor (IL-17RAKO) and IL-23p19 (IL-23KO) are susceptible to OPC. Furthermore, saliva from both AD-HIES patients and IL-23KO mice exhibits reduced ability to kill C. albicans ex vivo. However, despite the requirement for both IL-17 and IL-23 in protecting against OPC, we found that CD4-specific STAT3 knockout (CD4(stat3KO)) mice are not susceptible to our model of OPC. These data suggested that STAT3 mediates the initial response to oral C. albicans challenge by inducing an IL-17-producing subset other than Th17. Experiments carried out in this study revealed that the initial source of IL-17 is lymphocytic, and is likely multifactorial, involving both γδ and αβ T cells. Furthermore, in this study, natural killer and natural killer T cells were shown to have no apparent role in IL-17 secretion in response to C. albicans challenge in the oral cavity. In addition, while a memory or rechallenge response may involve CD4+ Th17 cells, this lineage appears to be unessential for the initial response to C. albicans in the oral cavity. Although we also attempted to examine the immune response to OPC using a mouse model of HIES harboring a transgenic STAT3 mutation, these mice proved resistant to C. albicans challenge at the buccal mucosa. However, despite the OPC resistance, they did exhibit a skin phenotype consistent with STAT3 deficiency, including eczematous lesions and delayed wound healing. These findings suggest that this mouse model may be used to study the role of STAT3 in both eczema as well as the immune response to cutaneous Staphylococcus aureus and C. albicans skin infections in the context of STAT3.


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    Item Type: University of Pittsburgh ETD
    ETD Committee:
    ETD Committee TypeCommittee MemberEmail
    Committee ChairKane, Lawrence Plkane@pitt.edu
    Committee CoChairGaffen, Sarah Lsig65@pitt.edu
    Committee MemberClancy, Cornelius Jcjc76@pitt.edu
    Committee MemberSteinman, Richardsteinman@pitt.edu
    Committee MemberKhader, Shabaanakhadersa@upmc.edu
    Title: THE ROLE OF IL-17 IN THE INNATE IMMUNE RESPONSE TO OROPHARYNGEAL CANDIDIASIS
    Status: Unpublished
    Abstract: Oropharyngeal candidiasis (OPC; thrush) is an opportunistic oral infection caused by the commensal fungus Candida albicans that afflicts immunosuppressed and immunocompromised individuals. Although patients with HIV/AIDS are the prototypical population associated with development of thrush, there are a host of conditions that lead to susceptibility to OPC, including Hyper-IgE Syndrome (HIES). The autosomal dominant form of HIES (AD-HIES) is characterized by inherited dominant negative mutations in the STAT3 transcription factor, which is crucial for physiologic homeostasis and development in many tissues, including immune cells. Due to the ubiquitous nature of STAT3, mutations in this gene lead to a highly varied set of clinical sequelae, including oral thrush. Numerous cytokines utilize STAT3 to mediate downstream signaling, including IL-6 and IL-23, which are crucial for the differentiation and expansion of T helper 17 (Th17) cells, respectively. IL-23 is necessary for 1) in vivo expansion of Th17 cells, and 2) the secretion of IL-17 and other proinflammatory cytokines. Recently, the Th17 lineage has been shown to play a major role in host defense against OPC. Our lab has previously shown that mice deficient in the IL-17 receptor (IL-17RAKO) and IL-23p19 (IL-23KO) are susceptible to OPC. Furthermore, saliva from both AD-HIES patients and IL-23KO mice exhibits reduced ability to kill C. albicans ex vivo. However, despite the requirement for both IL-17 and IL-23 in protecting against OPC, we found that CD4-specific STAT3 knockout (CD4(stat3KO)) mice are not susceptible to our model of OPC. These data suggested that STAT3 mediates the initial response to oral C. albicans challenge by inducing an IL-17-producing subset other than Th17. Experiments carried out in this study revealed that the initial source of IL-17 is lymphocytic, and is likely multifactorial, involving both γδ and αβ T cells. Furthermore, in this study, natural killer and natural killer T cells were shown to have no apparent role in IL-17 secretion in response to C. albicans challenge in the oral cavity. In addition, while a memory or rechallenge response may involve CD4+ Th17 cells, this lineage appears to be unessential for the initial response to C. albicans in the oral cavity. Although we also attempted to examine the immune response to OPC using a mouse model of HIES harboring a transgenic STAT3 mutation, these mice proved resistant to C. albicans challenge at the buccal mucosa. However, despite the OPC resistance, they did exhibit a skin phenotype consistent with STAT3 deficiency, including eczematous lesions and delayed wound healing. These findings suggest that this mouse model may be used to study the role of STAT3 in both eczema as well as the immune response to cutaneous Staphylococcus aureus and C. albicans skin infections in the context of STAT3.
    Date: 19 August 2011
    Date Type: Completion
    Defense Date: 26 July 2011
    Approval Date: 19 August 2011
    Submission Date: 02 August 2011
    Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
    Patent pending: No
    Institution: University of Pittsburgh
    Thesis Type: Master's Thesis
    Refereed: Yes
    Degree: MS - Master of Science
    URN: etd-08022011-115749
    Uncontrolled Keywords: eczema; fungal biology; inherited immunodeficiencies; innate immunity; Job's syndrome; microbiology; mucosal immunology
    Schools and Programs: School of Medicine > Immunology
    Date Deposited: 10 Nov 2011 14:56
    Last Modified: 11 Jun 2012 10:12
    Other ID: http://etd.library.pitt.edu/ETD/available/etd-08022011-115749/, etd-08022011-115749

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