RESUMO
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.
Assuntos
Infecções por Coronavirus/virologia , Modelos Animais de Doenças , Pulmão/fisiologia , Infecção por Zika virus/virologia , Animais , Anticorpos Antivirais , Células Apresentadoras de Antígenos , Infecções por Coronavirus/imunologia , Citocinas/genética , Citocinas/metabolismo , Citomegalovirus/fisiologia , Feminino , Regulação da Expressão Gênica , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Camundongos SCID , Coronavírus da Síndrome Respiratória do Oriente Médio/imunologia , Tropismo/imunologia , Replicação Viral , Zika virus/imunologia , Infecção por Zika virus/imunologiaRESUMO
HIV has a very limited species tropism that prevents the use of most conventional small animal models for AIDS research. The in vivo analysis of HIV/AIDS has benefited extensively from novel chimeric animal models that accurately recapitulate key aspects of the human condition. Specifically, immunodeficient mice that are systemically repopulated with human hematolymphoid cells offer a viable alternative for the study of a multitude of highly relevant aspects of HIV replication, pathogenesis, therapy, transmission, prevention, and eradication. This article summarizes some of the multiple contributions that humanized mouse models of HIV infection have made to the field of AIDS research. These models have proven to be highly informative and hold great potential for accelerating multiple aspects of HIV research in the future.