Precision mouse models with expanded tropism for human pathogens

• Published in: Nature biotechnology Vol. 37; no. 10; pp. 1163 - 1173
• Main Authors: Wahl, Angela, De, Chandrav, Abad Fernandez, Maria, Lenarcic, Erik M., Xu, Yinyan, Cockrell, Adam S., Cleary, Rachel A., Johnson, Claire E., Schramm, Nathaniel J., Rank, Laura M., Newsome, Isabel G., Vincent, Heather A., Sanders, Wes, Aguilera-Sandoval, Christian R., Boone, Allison, Hildebrand, William H., Dayton, Paul A., Baric, Ralph S., Pickles, Raymond J., Braunstein, Miriam, Moorman, Nathaniel J., Goonetilleke, Nilu, Victor Garcia, J.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-10-2019; Nature Publishing Group
• Subjects: 631/1647/767/1424; 631/326; Agriculture; Analysis; Animal models; Animals; Antibodies, Viral; Antigen-Presenting Cells; Antigens; Autografts; Bioinformatics; Biomedical and Life Sciences; Biomedical Engineering/Biotechnology; Biomedical materials; Biomedicine; Biotechnology; Bone implants; Bone marrow; Coronaviridae; Coronavirus Infections - immunology; Coronavirus Infections - virology; Coronaviruses; Cytokines - genetics; Cytokines - metabolism; Cytomegalovirus; Cytomegalovirus - physiology; Disease Models, Animal; Female; Gene Expression Regulation; Growth; Humans; Immune response; Immunodeficiency; Immunohistochemistry; Implantation; In vivo methods and tests; Life Sciences; Liver; Lung - physiology; Lung diseases; Lungs; Lymphocytes T; Male; Mesenchyme; Mice; Mice, SCID; Middle East Respiratory Syndrome Coronavirus - immunology; Pathogenic microorganisms; Pathogens; Respiratory syncytial virus; Surgical implants; Thymus; Transplants & implants; Tropism; Tropism - immunology; Tropisms; Vector-borne diseases; Virus Replication; Viruses; Zika Virus - immunology; Zika Virus Infection - immunology; Zika Virus Infection - virology; United States
• ISSN: 1087-0156; 1546-1696
• DOI: 10.1038/s41587-019-0225-9

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.
Implantation of lung tissue into humanized mice enables in vivo study of the human immune response to pathogens.