Mucosal Immunity and the Role of TH1 Cytokines in a Model of Cryptosporidiosis

粘膜免疫和 TH1 细胞因子在隐孢子虫病模型中的作用

基本信息

  • 批准号:
    8045925
  • 负责人:
  • 金额:
    --
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2010
  • 资助国家:
    美国
  • 起止时间:
    2010-10-01 至 2014-09-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Every year outbreaks of cryptosporidiosis are reported in the US, mainly due to ingestion of water that has been contaminated by the chlorine-resistant pathogen Cryptosporidium. Currently, limited therapeutic agents are available for cryptosporidiosis among immunocompromised patients, which is an important concern since Cryptosporidium parvum infections in immunocompromised individuals often develop into chronic, severe cryptosporidiosis that can become life threatening. Thus there is a need for a more effective therapy and a better understanding of host immune responses to this infection. Experimental Cryptosporidium infections in mice have been used to understand how cell-mediated immunity develops and to specifically define the factors driving Th1 or Th2 responses. A major factor in resistance to C. parvum infection is the production of IFN-3. Several cytokines are inducers of IFN-3; these include IL-12, and IL-18. Both of these cytokines play a role in infection as evidenced by the fact that IL-12 knockout (KO) and IL-18 KO mice are highly susceptible to C. parvum infection. Limited information exists about IL-12 in C. parvum infections; even less is known about the role of IL-18, a cytokine produced by epithelial cells and other immune cells. We have found that IL-18 is up- regulated in response to C. parvum infection and that rIL-18 is protective, even in the absence of IL-12. It is hypothesized that IL-18 has a significant role in C. parvum infection through 1) innate responses in the epithelial cells and 2) rapidly polarizing the response to a Th1 direction by inducing IFN-3 in NK cells, dendritic cells, and intestinal intraepithelial lymphocytes (IELs). Specifically, IL-18 augments the production of S7+ IELs, a population of 'high-responder' effector cells that produce much higher amounts of IFN-3 and are highly lytic. IL-18 acts either directly on IELs or by activating dendritic cells that activate IELs. In addition, dendritic cells may be a key generator of IL-18 in the intestinal tract. We plan to identify the IL-18 expressing mucosal cell populations in the intestinal tract and determine their expression levels. We will determine the impact of IL-18 on infection using murine models of infection that discern IL-12 and IFN-3 independent and innate immune mechanisms. Specifically, we will investigate its role (IL-18) in the activation of NK, dendritic cells, and IELs and determine if these same cell types may act as both responders and generators of this cytokine. This proposal aims to define the role IL-18 plays in resistance to C. parvum and to determine its effect alone and in conjunction with other cytokines, primarily IL-12, that are key inducers of IFN-3. In immunocompromised patients, such as HIV-infected individuals, there is an increase in Th2 cytokines, which may increase patient susceptibility and/or severity of infections that require strong Th1 responses. PUBLIC HEALTH RELEVANCE: Cryptosporidium is a significant cause of diarrheal illness and is particularly severe in immunocompromised and older Americans (a significant portion of Veterans are > 55). The VA is the single largest provider of HIV care in the US (~20,000 HIV+ patients seen annually). AIDS is of extreme importance to the VA patient care mission and to general medical science. Despite a 36-96% success rate, HAART treatment for AIDS patients can fail due to drug resistance or malabsorption. Susceptibility to opportunistic infections may persist despite increased CD4 levels, due to dysregulated cytokines or effector CD4 functions. Antiretroviral failure is higher in certain groups, such as African-Americans, even when equal access to care is provided (Hartzell et al., 2006). Since anticryptosporidial therapy in immunocompromised individuals is limited and often ineffective, understanding the immune response to cryptosporidiosis should facilitate the development of immunomodulating therapies that augment immune responses in order to prevent and control C. parvum and other opportunistic infections.
描述(由申请人提供): 美国每年都有隐孢子虫病爆发的报告,主要是由于摄入了被耐氯病原体隐孢子虫污染的水。目前,针对免疫受损患者的隐孢子虫病的治疗药物有限,这是一个重要的问题,因为免疫受损患者的微小隐孢子虫感染通常会发展成慢性、严重的隐孢子虫病,可能会危及生命。因此,需要一种更有效的治疗方法,更好地了解宿主对这种感染的免疫反应。隐孢子虫在小鼠体内的实验感染已被用来了解细胞免疫是如何发展的,并专门定义驱动Th1或Th2反应的因素。抵抗微小弧菌感染的一个主要因素是产生干扰素-3。几种细胞因子是干扰素-3的诱导者,包括IL-12和IL-18。IL-12基因敲除(KO)和IL-18基因敲除(KO)小鼠对微小弧菌感染高度易感,证明了这两种细胞因子在感染中的作用。关于IL-12在微小弧菌感染中的作用的信息有限,对IL-18的作用更是知之甚少,IL-18是一种由上皮细胞和其他免疫细胞产生的细胞因子。我们已经发现,IL-18在应对微小弧菌感染时上调,并且rIL-18具有保护性,即使在没有IL-12的情况下也是如此。据推测,IL-18通过1)上皮细胞的先天反应和2)通过在NK细胞、树突状细胞和肠道上皮内淋巴细胞(IEL)中诱导IFN-3而迅速极化对Th1方向的反应,在微小弧菌感染中发挥重要作用。具体地说,IL-18增加了S7+IEL的产生,S7+IEL是一群高反应性的效应细胞,产生更多的干扰素-3,具有高度的裂解能力。IL-18可以直接作用于IELs,也可以通过激活树突状细胞来激活IELs。此外,树突状细胞可能是肠道中IL-18的关键生成者。我们计划鉴定肠道中表达IL-18的粘膜细胞群,并确定其表达水平。我们将使用小鼠感染模型来确定IL-18对感染的影响,该模型识别IL-12和干扰素-3的独立和先天免疫机制。具体地说,我们将研究其在NK、树突状细胞和IEL激活中的作用,并确定这些相同类型的细胞是否既是该细胞因子的反应者,又是该细胞因子的生成者。这项建议旨在确定IL-18在抵抗微小弧菌中所起的作用,并确定其单独和与其他细胞因子,主要是IL-12,是干扰素-3的关键诱导者的效果。在免疫功能低下的患者中,如艾滋病毒感染者,Th2细胞因子增加,这可能会增加患者的易感性和/或需要强烈Th1反应的感染的严重程度。 公共卫生相关性: 隐孢子虫是腹泻疾病的一个重要原因,在免疫功能低下的美国人和老年人中尤其严重(很大一部分退伍军人是55岁以下的人)。退伍军人管理局是美国最大的艾滋病毒护理提供者(每年约有20,000名艾滋病毒+患者就诊)。艾滋病对退伍军人管理局的病人护理任务和普通医学都是极其重要的。尽管HAART治疗艾滋病患者的成功率为36%-96%,但由于耐药性或吸收不良,HAART治疗可能会失败。尽管CD4水平升高,但由于细胞因子或效应器CD4功能失调,机会性感染的易感性仍可能存在。在某些群体中,抗逆转录病毒失败率更高,例如非裔美国人,即使在提供平等的护理机会时也是如此(Hartzell等人,2006年)。由于免疫受损个体的抗隐孢子虫治疗是有限的,而且往往无效,了解隐孢子虫病的免疫应答将有助于开发增强免疫应答的免疫调节疗法,以预防和控制微小隐孢子虫和其他机会性感染。

项目成果

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JAN R MEAD其他文献

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{{ truncateString('JAN R MEAD', 18)}}的其他基金

Microbiome Impact on the Susceptibility and Severity to Cryptosporidium Infection
微生物组对隐孢子虫感染的易感性和严重程度的影响
  • 批准号:
    10252399
  • 财政年份:
    2021
  • 资助金额:
    --
  • 项目类别:
Microbiome Impact on the Susceptibility and Severity to Cryptosporidium Infection
微生物组对隐孢子虫感染的易感性和严重程度的影响
  • 批准号:
    10338198
  • 财政年份:
    2021
  • 资助金额:
    --
  • 项目类别:
Mucosal Immunity and the Role of TH1 Cytokines in a Model of Cryptosporidiosis
粘膜免疫和 TH1 细胞因子在隐孢子虫病模型中的作用
  • 批准号:
    8391629
  • 财政年份:
    2010
  • 资助金额:
    --
  • 项目类别:
Mucosal Immunity and the Role of TH1 Cytokines in a Model of Cryptosporidiosis
粘膜免疫和 TH1 细胞因子在隐孢子虫病模型中的作用
  • 批准号:
    8597404
  • 财政年份:
    2010
  • 资助金额:
    --
  • 项目类别:
Mucosal Immunity and the Role of TH1 Cytokines in a Model of Cryptosporidiosis
粘膜免疫和 TH1 细胞因子在隐孢子虫病模型中的作用
  • 批准号:
    8198365
  • 财政年份:
    2010
  • 资助金额:
    --
  • 项目类别:
IMMUNODOMINANT TARGETS OF CMI TO CRYPTOSPORIDIUM
CMI 对隐孢子虫的免疫显性靶点
  • 批准号:
    6532705
  • 财政年份:
    1996
  • 资助金额:
    --
  • 项目类别:
IMMUNODOMINANT TARGETS OF CMI TO CRYPTOSPORIDIUM
CMI 对隐孢子虫的免疫显性靶点
  • 批准号:
    7198162
  • 财政年份:
    1996
  • 资助金额:
    --
  • 项目类别:
IMMUNODOMINANT TARGETS OF CMI TO CRYPTOSPORIDIUM
CMI 对隐孢子虫的免疫显性靶点
  • 批准号:
    7091583
  • 财政年份:
    1996
  • 资助金额:
    --
  • 项目类别:
IMMUNODOMINANT TARGETS OF CMI TO CRYPTOSPORIDIUM
CMI 对隐孢子虫的免疫显性靶点
  • 批准号:
    7585748
  • 财政年份:
    1996
  • 资助金额:
    --
  • 项目类别:
IMMUNODOMINANT TARGETS OF CMI TO CRYPTOSPORIDIUM
CMI 对隐孢子虫的免疫显性靶点
  • 批准号:
    2073113
  • 财政年份:
    1996
  • 资助金额:
    --
  • 项目类别:

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    10541028
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    2022
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A multidimensional Digital Approach to Address Vaccine Hesitancy and Increase COVID-19 Vaccine Uptake among African American Young Adults in the South
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减少非裔美国男性的高血压:解决健康差异的移动压力管理干预措施
  • 批准号:
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Reducing Hypertension among African American Men: A Mobile Stress Management Intervention to Address Health Disparities
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    10245326
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    2021
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Building a Multidisciplinary Research Program to Address Hypertension Disparities:Exploring the Neurocognitive Mechanisms of a Self-Management Intervention for African American Women with Hypertension
建立一个多学科研究计划来解决高血压差异:探索非裔美国高血压女性自我管理干预的神经认知机制
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