Browsing by Author "Xu, Guang"
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Item Elucidation of Mechanisms of Host Immunity against Orientia tsutsugamushi in a Newly Developed Murine ModelXu, GuangScrub typhus, caused by a Gram-negative obligately intracellular coccobacillus, Orientia tsutsugamushi, is a long neglected but important tropical disease. Orientia tsutsugamushi causes illness in one million people each year, with an additional 1 billion people at risk. Without appropriate diagnosis and treatment, the disease can cause severe multiorgan failure with a case fatality rate of 7-15%. The current gaps in the knowledge of immunity include the unknown mechanisms of host immunity to O. tsutsugamushi. Using an intravenous (i.v.) disseminated infection mouse model, we observed that more CD8+ T cells than CD4+ T cells were present in the spleens of infected mice at 12 days post infection (dpi). We also determined that Treg cells and the proportion of T cells producing IL-10 were significantly increased from 6 dpi, which correlated with the onset of illness, body weight loss, and increased bacterial loads. We further studied CD8-/-, MHC I-/- and wild type control (WT) C57BL/6J mice to determine the importance of CD8+ T cells and MHC I molecules. After infection with an ordinarily sub-lethal dose of O. tsutsugamushi, all CD8-/- and MHC I-/- mice expired between 12 and 15 dpi, whereas all WT mice survived. Bacterial loads in the lung, kidney, liver and spleen of CD8-/- and MHC I-/- mice were significantly greater than those in WT mice. Interferon-γ (IFN-γ) and granzyme B mRNA levels in the liver of CD8-/- and MHC I-/- mice were significantly greater than in WT mice. In addition, more severe histopathologic lesions were observed in CD8-/- mice. Finally, adoptive transfer confirmed a major role of activated CD8+ T cells, as well as a less effective contribution by activated CD8 T cell-depleted splenocytes, in protection against O. tsutsugamushi infection. These studies demonstrated the critical importance of CD8+ T cells in the host immune response during O. tsutsugamushi infection.Item Scrub typhus: Epidemiology, Diagnosis, Treatment, Prevention and Control in the Asia-Pacific Area and WorldwideXu, Guang; Arcari, Christine M; Melby, Peter C; Jupiter, DanielThe long term goal of this study is to develop effective measures to control and even eradicate scrub typhus and other related infectious diseases. Scrub typhus is a serious public health problem in the Asia-Pacific area. It threatens one billion people globally, and causes illness in one million people each year. It can cause severe multiorgan failure with a case fatality rate up to 30% without appropriate treatment. The antigenic heterogeneity of Orientia tsutsugamushi results in reinfection with scrub typhus. As a neglected disease, there is still a large gap in our knowledge of the disease, as evidenced by the sporadic epidemiology data and other related public health data regarding scrub typhus in its endemic areas. Our objective is to provide a systematic analysis of current epidemiology, diagnosis, treatment, prevention and control of scrub typhus in its endemic area and the rest of the world. We first described the epidemiology of scrub typhus through a thorough review of the epidemiology and public health impacts of the disease. This specific aim helps us understand the disease, and provides a foundation for disease prevention and control. We then described the diagnosis and treatment of scrub typhus, which will facilitate the development of the next generation of diagnostics and treatment. The last part of the capstone focused on the prevention and control of scrub typhus in the Asia-Pacific region, and worldwide. This analysis will aid in the control of the disease and promotion of public health. This project helps better understand the epidemiology, diagnosis, treatment, and control of scrub typhus. It can aid in the identification of effective new approaches to prevent and control the endemic disease. The research also provides strategies that could be applicable to combat other infectious diseases and public health threats.