Rickettsial infection of humanized mice

我们的长期目标是阐明复杂的免疫和病理机制

Our long-term goal is to elucidate the complex immunological and pathological mechanisms of humans in response to agents, such as Rickettsia, whose pathogenesis involves the cells lining the vasculature (endothelial cells). These arthropod-borne obligately intracellular bacteria include the agents of Rocky Mountain spotted fever (Rickettsia rickettsii) and epidemic typhus (R. prowazekii). They are among the most lethal pathogens known to man (case fatality rate of 20-30% in untreated cases), and they are designated select agents with potential use for bioterrorism. Relevant data from humans have lagged behind those derived from the animal models due mainly to the difficulty in correctly identifying cases of rickettsioses. This gap in knowledge has prevented the discovery of novel targets of intervention. Our objective is to develop a humanized mouse model of epidemic typhus as a paradigm for other infectious diseases in which endothelial cells are involved in the pathogenesis. The hypothesis is that humanized mice develop rickettsia- triggered vascular lesions and adaptive immune responses against rickettsiae. The specific aims are: 1) to identify the types of human leukocytes that infiltrate rickettsia-infected human vascular beds in humanized mice; and 2) to measure the human B-cell and T cell-mediated anti-rickettsial immune responses in humanized mice. The experimental approaches are: a) identification of infiltrating leukocytes in humanized mice infected with R. prowazekii or R. rickettsii and measurement of rickettsial loads in synthetic human vascular beds; and b) determination of human immunoglobulin subtypes of anti-rickettsiae antibodies and antigen-specific human T cell proliferation, cytokine production, and cytotoxicity in humanized mice infected with rickettsiae. The humanized mice will allow: i) the identification of targets of therapeutic intervention and of protective antigens recognized by humans for vaccine development; ii) the study of the in vivo interactions between human leukocytes and rickettsia-infected endothelial cells; iii) the determination of the mechanism(s) of vascular leakage, a central feature of the pathogenesis of these diseases; iv) the evaluation of natural and vaccine-induced immune responses; and v) testing of immunogenicity and protection of candidate vaccines.