A Humanized Mouse Model of Tuberculosis

被引:85
作者
Calderon, Veronica E. [1 ]
Valbuena, Gustavo [1 ]
Goez, Yenny [1 ]
Judy, Barbara M. [1 ]
Huante, Matthew B. [2 ]
Sutjita, Putri [2 ]
Johnston, R. Katie [2 ]
Estes, D. Mark [3 ]
Hunter, Robert L. [4 ]
Actor, Jeffrey K. [4 ]
Cirillo, Jeffrey D. [5 ]
Endsley, Janice J. [1 ,2 ]
机构
[1] Univ Texas Med Branch, Dept Pathol, Galveston, TX 77555 USA
[2] Univ Texas Med Branch, Dept Microbiol & Immunol, Galveston, TX 77555 USA
[3] Univ Georgia, Athens, GA 30602 USA
[4] Univ Texas Houston, Hlth Sci Ctr, Dept Pathol, Houston, TX USA
[5] Texas A&M Hlth Sci Ctr, Dept Microbial & Mol Pathogenesis, College Stn, TX USA
基金
美国国家卫生研究院;
关键词
RESTRICTED IMMUNE-RESPONSES; MYCOBACTERIUM-BOVIS BCG; T-CELL DEPLETION; TREHALOSE 6,6'-DIMYCOLATE; LATENT TUBERCULOSIS; HIV LATENCY; MICE; GRANULYSIN; INFECTION; PATHOLOGY;
D O I
10.1371/journal.pone.0063331
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Mycobacterium tuberculosis (M.tb) is the second leading infectious cause of death worldwide and the primary cause of death in people living with HIV/AIDS. There are several excellent animal models employed to study tuberculosis (TB), but many have limitations for reproducing human pathology and none are amenable to the direct study of HIV/M.tb co-infection. The humanized mouse has been increasingly employed to explore HIV infection and other pathogens where animal models are limiting. Our goal was to develop a small animal model of M.tb infection using the bone marrow, liver, thymus (BLT) humanized mouse. NOD-SCID/gamma(null)(c) mice were engrafted with human fetal liver and thymus tissue, and supplemented with CD34(+) fetal liver cells. Excellent reconstitution, as measured by expression of the human CD45 pan leukocyte marker by peripheral blood populations, was observed at 12 weeks after engraftment. Human T cells (CD3, CD4, CD8), as well as natural killer cells and monocyte/macrophages were all observed within the human leukocyte (CD45(+)) population. Importantly, human T cells were functionally competent as determined by proliferative capacity and effector molecule (e.g. IFN-gamma, granulysin, perforin) expression in response to positive stimuli. Animals infected intranasally with M.tb had progressive bacterial infection in the lung and dissemination to spleen and liver from 2-8 weeks post infection. Sites of infection in the lung were characterized by the formation of organized granulomatous lesions, caseous necrosis, bronchial obstruction, and crystallization of cholesterol deposits. Human T cells were distributed throughout the lung, liver, and spleen at sites of inflammation and bacterial growth and were organized to the periphery of granulomas. These preliminary results demonstrate the potential to use the humanized mouse as a model of experimental TB.
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页数:12
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