Experimental tuberculosis in the humanized mouse (43.28)

Abstract

Abstract Currently there is no animal model of HIV/Mtb co-infection, limiting our understanding of how HIV-induced defects in immune function promote the dramatic susceptibility to Mtb. The humanized mouse is contributing to discoveries relevant to HIV/AIDS, but the model has not been further developed for opportunistic infection. The goal of this project was to develop the humanized mouse as a small animal model of Mtb infection to determine the potential use for HIV/Mtb co-infection research. NOD-SCID/γcnull mice were engrafted with human fetal liver and thymus tissue, and injected intravenously with CD34+ fetal liver cells. At 12 weeks following engraftment in this model we observe that on average, 40% of the total leukocytes in mouse peripheral blood are human CD45+ cells. These human leukocytes include human T cells (CD4 and CD8), as well as NK cells, and antigen presenting cells (macrophages, DC). Importantly, the circulating human T cells and NK cells respond to specific antigen and/or positive stimuli as measured by proliferation and expression of effector molecules (e.g. IFN-γ, granulysin). Animals infected intranasally with Mtb have progressive bacterial infection in the lung, dissemination of bacteria to spleen and liver, and formation of organized granulomatous lesions at sites of infection. The results demonstrate the utility of the humanized mouse as a model of experimental TB and suggest promise as a small animal model of HIV/Mtb co-infection.