Precision mouse models with expanded tropism for human pathogens

Wahl, Angela; De, Chandrav; Fernandez, Maria Abad; 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; Garcia, J. Victor

A major limitation of current humanized mouse models is that they primarily permit 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, that contains up to 40 cell types including non-hematopoietic cells, into immunodeficient mice (lung-only mice [LoM]) 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 (BLT) humanized mice (BLT-L 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. LoM and BLT-L mice dramatically increase the number of human pathogens that can be studied in vivo facilitating the in vivo testing of therapeutics.