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

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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.