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
• 负责人: JAN R MEAD
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/8198365
• 关键词: Acquired Immunodeficiency Syndrome; Address; African American; American; Anti-Retroviral Agents; Antigen Presentation Pathway; Antigens; Automobile Driving; Caring; Cell physiology; Cells; Cellular Immunity; Chlorine; Chronic; Cryptosporidiosis; Cryptosporidium; Cryptosporidium parvum; Dendritic Cells; Development; Disease Outbreaks; Drug resistance; Effector Cell; Epithelial Cells; Failure; HIV; Health Services Accessibility; Highly Active Antiretroviral Therapy; Immune; Immune response; Immunocompromised Host; Individual; Infection; Ingestion; Interferon Type II; Interferons; Interleukin-12; Interleukin-13; Interleukin-18; Interleukin-4; Intestines; Knock-out; Knockout Mice; Life; Lymphocyte; Lymphocyte Activation; Lymphocyte Subset; Lytic; Malabsorption Syndromes; Medical; Mission; Modeling; Mucosal Immune Responses; Mucosal Immunity; Mucous Membrane; Mus; NK Cell Activation; Natural Immunity; Natural Killer Cells; Opportunistic Infections; Patient Care; Patients; Play; Population; Predisposition; Production; Provider; Recovery; Reporting; Resistance; Resistance to infection; Role; Science; Severities; Source; T-Lymphocyte; Therapeutic Agents; Tumor Necrosis Factor-alpha; Veterans; Water; cell type; cytokine; cytotoxicity; effective therapy; human TNF protein; intraepithelial; pathogen; prevent; public health relevance; receptor expression; response; success

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）： 美国每年都会报告隐孢子虫病的爆发，主要原因是摄入了被耐氯病原体隐孢子虫污染的水。目前，针对免疫功能低下患者的隐孢子虫病可用的治疗药物有限，这是一个重要的问题，因为免疫功能低下个体的微小隐孢子虫感染常常发展为慢性、严重的隐孢子虫病，可能危及生命。因此，需要一种更有效的治疗方法并更好地了解宿主对此感染的免疫反应。小鼠实验性隐孢子虫感染已被用来了解细胞介导的免疫如何发展，并具体确定驱动 Th1 或 Th2 反应的因素。抵抗微小念珠菌感染的一个主要因素是 IFN-3 的产生。多种细胞因子是 IFN-3 的诱导剂；这些包括 IL-12 和 IL-18。这两种细胞因子在感染中都发挥着作用，IL-12 敲除 (KO) 和 IL-18 KO 小鼠对微小念珠菌感染高度敏感的事实证明了这一点。有关微小念珠菌感染中 IL-12 的信息有限；人们对 IL-18 的作用知之甚少，IL-18 是一种由上皮细胞和其他免疫细胞产生的细胞因子。我们发现，IL-18 在应对微小念珠菌感染时上调，并且即使在不存在 IL-12 的情况下，rIL-18 也具有保护作用。据推测，IL-18 通过 1) 上皮细胞的先天反应和 2) 通过诱导 NK 细胞、树突状细胞和肠上皮内淋巴细胞 (IEL) 中的 IFN-3 使反应快速极化至 Th1 方向，从而在微小念珠菌感染中发挥重要作用。具体而言，IL-18 增强了 S7+ IEL 的产生，S7+ IEL 是一群“高反应”效应细胞，可产生更高量的 IFN-3 并且具有高度裂解性。 IL-18 直接作用于 IEL，或通过激活树突状细胞来激活 IEL。此外，树突状细胞可能是肠道中 IL-18 的关键产生者。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，该模型可识别 IL-12 和 IFN-3 独立的先天免疫机制。具体来说，我们将研究其 (IL-18) 在 NK、树突状细胞和 IEL 激活中的作用，并确定这些相同的细胞类型是否可以充当该细胞因子的应答者和生成者。该提案旨在确定 IL-18 在抵抗微小念珠菌中所起的作用，并确定其单独作用以及与其他细胞因子（主要是 IFN-3 的关键诱导剂 IL-12）联合作用的作用。在免疫功能低下的患者中，例如 HIV 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年龄 > 55 岁）。退伍军人管理局是美国最大的艾滋病毒护理服务提供者（每年接待约 20,000 名艾滋病毒+患者）。艾滋病对于退伍军人管理局的患者护理使命和普通医学极其重要。尽管HAART治疗的成功率为36-96%，但艾滋病患者的HAART治疗可能会因耐药性或吸收不良而失败。尽管 CD4 水平升高，但由于细胞因子或效应 CD4 功能失调，机会性感染的易感性可能持续存在。即使提供平等的护理机会，某些群体（例如非洲裔美国人）的抗逆转录病毒治疗失败率也较高（Hartzell 等，2006）。由于免疫功能低下个体的抗隐孢子虫治疗有限且常常无效，了解对隐孢子虫病的免疫反应应有助于开发增强免疫反应的免疫调节疗法，以预防和控制微小隐孢子虫和其他机会性感染。