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）：结核病引起的结核病在包括美国在内的许多国家中仍然是一个公共卫生问题，因为它在HIV感染的患者中的兴趣以及由于多药耐药性（MDR）的出现而引起的，并且是抗药性（XDR）的（XDR）菌株（XDR）。据估计，世界三分之一的人口感染了结核分枝杆菌。 Bovis BCG M.是目前可用于预防结核病的疫苗。但是，在临床试验中，BCG疫苗的疗效已有很高的变化。大多数受感染的个体在对生物体产生强大的免疫反应时控制感染，但是，许多人一生都携带了残留的杆菌，没有疾病的临床表现。重新激活结核病可能会在某些个体中在几年后发展，因为其免疫系统受到HIV感染，营养不良或使用免疫抑制剂的损害。从流行病学研究中可以明显看出，潜在感染的重新激活是导致结核病发病率高的因素之一。有令人信服的证据表明，紫外线辐射（UVR）在人类和实验动物中都会引起免疫抑制。我们假设UVR可能有助于潜在的结核分枝杆菌感染。我们先前的研究表明，暴露于UVR会导致免疫抑制和实验感染的发病机理增加。这些研究的目的是研究UVR在低剂量豚鼠肺结核模型中持续的结核分枝杆菌感染期间的宿主 - 寄生虫相互作用是否改变。 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.第二个特定目的将通过检查UVR诱导的MRNA产生的MRNA来阐明UV诱导的作用的机制，用于通过表皮细胞（通过实时RT-PCR）和从T细胞和巨噬细胞功能的UV型表皮细胞上获得的紫外线辐射表皮细胞获得的培养上清液的作用。这些研究对于了解高度相关的动物模型中UVR，免疫抑制和结核分枝杆菌感染的重新激活之间的相互作用至关重要。此外，结果将提供对调节持久性和重新激活过程中调节分枝杆菌生长的宿主因子的见解，并作为设计未来的流行病学研究对UVR对结核病的影响的基础。公共卫生相关性：由于艾滋病毒感染的患者的盛行以及由于多药耐药（MDR）的出现和大细胞杆菌的抗药性（XDR）菌株的出现，结核病仍然是许多国家的公共卫生问题。潜在结核病的重生是人类结核病高发病率的原因之一。这些研究的目的是确定每天遇到的环境毒素（例如阳光的紫外线辐射）是否通过重新激活潜在感染而导致结核病的高发病率。这些研究将在肺结核的低剂量豚鼠模型中解决，因为这些动物中的疾病与人类疾病非常相似。