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Nat Biotechnol. 2019 Aug 26. doi: 10.1038/s41587-019-0225-9. [Epub ahead of print]

Precision mouse models with expanded tropism for human pathogens.

Author information

1
Division of Infectious Diseases, International Center for the Advancement of Translational Science, Center for AIDS Research, University of North Carolina, School of Medicine, Chapel Hill, NC, USA. angela_wahl@med.unc.edu.
2
Division of Infectious Diseases, International Center for the Advancement of Translational Science, Center for AIDS Research, University of North Carolina, School of Medicine, Chapel Hill, NC, USA.
3
Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC, USA.
4
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.
5
Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA.
6
Joint Department of Biomedical Engineering, University of North Carolina and North Carolina State University, Chapel Hill, NC, USA.
7
BD Life Sciences, San Jose, CA, USA.
8
Marsico Lung Institute, University of North Carolina, Chapel Hill, NC, USA.
9
Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
10
UNC HIV Cure Center, University of North Carolina, Chapel Hill, NC, USA.
11
Division of Infectious Diseases, International Center for the Advancement of Translational Science, Center for AIDS Research, University of North Carolina, School of Medicine, Chapel Hill, NC, USA. victor_garcia@med.unc.edu.

Abstract

A major limitation of current humanized mouse models is that they primarily enable the analysis of human-specific pathogens that infect hematopoietic cells. However, most human pathogens target other cell types, including epithelial, endothelial and mesenchymal cells. Here, we show that implantation of human lung tissue, which contains up to 40 cell types, including nonhematopoietic cells, into immunodeficient mice (lung-only mice) resulted in the development of a highly vascularized lung implant. We demonstrate that emerging and clinically relevant human pathogens such as Middle East respiratory syndrome coronavirus, Zika virus, respiratory syncytial virus and cytomegalovirus replicate in vivo in these lung implants. When incorporated into bone marrow/liver/thymus humanized mice, lung implants are repopulated with autologous human hematopoietic cells. We show robust antigen-specific humoral and T-cell responses following cytomegalovirus infection that control virus replication. Lung-only mice and bone marrow/liver/thymus-lung humanized mice substantially increase the number of human pathogens that can be studied in vivo, facilitating the in vivo testing of therapeutics.

PMID:
31451733
DOI:
10.1038/s41587-019-0225-9

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