Effect Ultraviolet Radiation on Latent M. tuberculosis Infection in Guinea Pigs

紫外线辐射对豚鼠潜伏结核分枝杆菌感染的影响

• 批准号: 7660077
• 负责人: Amminikutty Jeevan
• 金额: $ 21.98万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-22 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7660077
• 关键词: Address; Affect; Animal Model; Animals; Antigens; BCG Vaccine; Bacillus (bacterium); Bacteria; CCL2 gene; Cavia; Cells; Clinical; Clinical Trials; Country; Disease; Dose; Epidemiologic Studies; Equilibrium; Event; Extreme drug resistant tuberculosis; Future; Granuloma; Growth; HIV; HIV Infections; Human; Hydrocortisone; Immune; Immune response; Immune system; Immunosuppressive Agents; In Vitro; Incidence; Individual; Infection; Infection Control; Integration Host Factors; Interleukin-10; Interleukin-4; Leucocytic infiltrate; Life; Lung; MHC Class II Genes; Malnutrition; Mediating; Mediator of activation protein; Messenger RNA; Modeling; Multi-Drug Resistance; Mus; Mycobacterium tuberculosis; Organ; Organism; Parasites; Pathogenesis; Patients; Population; Prevalence; Prevention; Process; Production; Public Health; Pulmonary Tuberculosis; Research; Residual state; Respiratory physiology; Reverse Transcriptase Polymerase Chain Reaction; Spleen; Sunlight; T-Cell Activation; T-Lymphocyte; Testing; Time; Toxic Environmental Substances; Tuberculosis; UV Radiation Exposure; UV induced; Ultraviolet B Radiation; Ultraviolet Rays; United States; Up-Regulation; Vaccines; base; chemokine; cytokine; design; human disease; in vivo; insight; keratinocyte; laser capture microdissection; latent infection; mRNA Expression; macrophage; mycobacterial; public health relevance; pulmonary granuloma; reactive oxygen intermediate; research study; response; ultraviolet irradiation; vaccination against tuberculosis

DESCRIPTION (provided by applicant): Tuberculosis, caused by Mycobacterium tuberculosis, continues to be a public health problem in many countries including the United States because of its prevalence in HIV-infected patients and also due to the emergence of multi-drug resistant (MDR) and extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis. It is estimated that one third of the world's population is infected with M. tuberculosis. M. bovis BCG is the only vaccine currently available for the prevention of tuberculosis; however, the efficacy of BCG vaccine has been highly variable in clinical trials. The majority of the infected individuals control the infection as they develop a robust immune response to the organism, however, many harbor residual bacilli throughout their life with no clinical manifestations of disease. Reactivation tuberculosis may develop years later in some individuals as their immune system is compromised by HIV infection, malnutrition or the use of immunosuppressive agents. It is clear from epidemiological studies that reactivation of latent infection is one of the contributing factors for the high incidence of tuberculosis. There is compelling evidence that ultraviolet radiation (UVR) causes immune suppression in both humans and experimental animals. We hypothesize that UVR might contribute to the reactivation of latent M. tuberculosis infection. Our previous studies indicated that exposure to UVR caused immune suppression and increased pathogenesis in experimental infections. The purpose of these studies is to investigate whether UVR alters the host-parasite interactions during persistent M. tuberculosis infection in the low-dose guinea pig model of pulmonary tuberculosis. In the first specific aim, we will determine the effect of UVR on persistent infection by examining the number of viable bacteria in the organs of infected guinea pigs and the cytokine and chemokine responses in lung granulomas by laser capture microdissection and real-time RT-PCR as well as whole spleen and lung digest cells following antigen stimulation by real time RT-PCR. The second specific aim will elucidate the mechanism of UV-induced effects by examining UVR-induced production of mRNA for immunosuppressive cytokines by epidermal cells (by real-time RT-PCR) and the effect of culture supernatants obtained from UV-irradiated epidermal cells on T cell and macrophage functions. These studies are crucial in understanding the interaction between UVR, immune suppression and reactivation of M. tuberculosis infection in a highly relevant animal model. Moreover, the results will provide insight into the host-factors that regulate mycobacterial growth during persistence and reactivation as well as serve as a basis for designing future epidemiological studies on the effect of UVR on tuberculosis. PUBLIC HEALTH RELEVANCE: Tuberculosis continues to be a public health problem in many countries because of its prevalence in HIV-infected patients and also due to the emergence of multi-drug resistant (MDR) and extensively drug- resistant (XDR) strains of Mycobacterium tuberculosis. Reactivation of latent tuberculosis is one of the contributing factors for the high incidence of tuberculosis in humans. The purpose of these studies is to determine whether an environmental toxin such as ultraviolet radiation from sunlight that is encountered on a daily basis contributes to the high incidence of tuberculosis by reactivating a latent infection. These studies will be addressed in the low-dose guinea pig model of pulmonary tuberculosis as the disease in these animals closely resembles the human disease.

描述（由申请人提供）：由结核分枝杆菌引起的结核病仍然是包括美国在内的许多国家的公共卫生问题，因为它在艾滋病毒感染者中普遍存在，而且还由于结核分枝杆菌的多重耐药（MDR）和广泛耐药（XDR）菌株的出现。据估计，世界上三分之一的人口感染了结核分枝杆菌。牛分枝杆菌卡介苗是目前唯一可用于预防结核病的疫苗；然而，卡介苗疫苗的功效在临床试验中差异很大。大多数感染者在对微生物产生强大的免疫反应时控制了感染，然而，许多人一生中都携带残留的杆菌，没有疾病的临床表现。由于艾滋病毒感染、营养不良或使用免疫抑制剂的免疫系统受到损害，某些人可能会在数年后出现结核病再激活。流行病学研究清楚地表明，潜伏感染的重新激活是结核病高发的因素之一。有令人信服的证据表明，紫外线辐射 (UVR) 会导致人类和实验动物的免疫抑制。我们假设紫外线可能有助于潜伏结核分枝杆菌感染的重新激活。我们之前的研究表明，暴露于紫外线会导致免疫抑制并增加实验感染的发病机制。这些研究的目的是调查低剂量豚鼠肺结核模型中结核分枝杆菌持续感染期间，UVR 是否会改变宿主与寄生虫的相互作用。在第一个具体目标中，我们将通过激光捕获显微切割和实时 RT-PCR 检查受感染豚鼠器官中的活细菌数量和肺肉芽肿中的细胞因子和趋化因子反应，以及通过实时 RT-PCR 进行抗原刺激后的整个脾脏和肺消化细胞，以确定 UVR 对持续感染的影响。第二个具体目标将通过检查 UVR 诱导表皮细胞产生免疫抑制细胞因子 mRNA（通过实时 RT-PCR）以及从 UV 照射的表皮细胞获得的培养上清液对 T 细胞和巨噬细胞功能的影响来阐明 UV 诱导效应的机制。这些研究对于了解高度相关的动物模型中紫外线辐射、免疫抑制和结核分枝杆菌感染再激活之间的相互作用至关重要。此外，这些结果将提供对在持久性和重新激活过程中调节分枝杆菌生长的宿主因素的深入了解，并作为设计未来关于紫外线对结核病影响的流行病学研究的基础。公共卫生相关性：结核病在许多国家仍然是一个公共卫生问题，因为它在艾滋病毒感染者中流行，而且还因为结核分枝杆菌多重耐药（MDR）和广泛耐药（XDR）菌株的出现。潜伏结核病的再激活是人类结核病高发的因素之一。这些研究的目的是确定日常遇到的环境毒素（例如阳光中的紫外线辐射）是否会通过重新激活潜伏感染而导致结核病的高发病率。这些研究将在低剂量豚鼠肺结核模型中进行，因为这些动物的疾病与人类疾病非常相似。