Project description:There is an urgent need for humanized mouse models of viral respiratory diseases to study immunopathogenesis and therapeutic interventions. Although mice with a functional human immune system (HIS) permit analysis in real time of human immune responses in vivo, evolutionary divergences preclude their usefulness for studies of respiratory viruses that do not infect mouse lungs. Here, we sought to use HIS mice with human lung tissue xenografts (referred to as HISL mice) to address this issue. The grafted human lung tissue was found survived for over 30 weeks, maintained histologically normal structure, and populated with human tissue-resident immune cells, including CD11c+ DCs and CD4+ and CD8+ tissue-resident memory T cells (TRMs). HISL mice showed a marked expansion of TRMs and generation of viral antigen-specific T cells in the human lung xenografts, and production of antiviral IgM and class-switched IgG antibodies upon infection of the human lung xenograft by H1N1 influenza viruses. RNA-seq analysis on H1N1-infected and control human lung xenografts identified a total of 5089 differentially expressed genes (DEGs) with enrichments for genes involved in respiratory tract and lung diseases, viral infections and associated immune responses. Furthermore, prophylactic viral exposures resulted in protection against subsequent lethal challenge by intranasal viral inoculation, leading to reduced disease severity and mortality. This study supports the usefulness of this preclinical model in exploring the immunopathology and therapies of respiratory viral diseases.
