Non-invasive administration of AAV to target lung parenchymal cells and develop SARS-CoV-2-susceptible mice

Adeno-associated virus (AAV)-mediated gene delivery holds great promise for gene therapy. However, the non-invasive delivery of AAV for lung tissues has not been adequately es-tablished. Here, we revealed that the intratracheal adminis-tration of an appropriate amount of AAV2/8 predominantly targets lung tissue. AAV-mediated gene delivery that we used in this study induced the expression of the desired pro-tein in lung parenchymal cells, including alveolar type II cells. We harnessed the technique to develop severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-suscepti-ble mice. Three kinds of immune function-relevant gene knockout (KO) mice were transduced with AAV encoding human angiotensin-converting enzyme 2 (hACE2) and then injected with SARS-CoV-2. Among these mice, type I inter-feron receptor (IFNAR) KO mice showed increased viral titer in the lungs compared to that in the other KO mice. Moreover, nucleocapsid protein of SARS-CoV-2 and multi-ple lesions in the trachea and lung were observed in AAV-hACE2-transduced, SARS-CoV-2-infected IFNAR KO mice, indicating the involvement of type I interferon signaling in the protection of SARS-CoV-2. In this study, we demon-strate the ease and rapidness of the intratracheal administra-tion of AAV for targeting lung tissue in mice, and this can be used to study diverse pulmonary diseases.

Automated summary

In this study, the researchers demonstrated that intratracheal administration of an appropriate amount of AAV2/8 can effectively target lung tissue. The AAV-mediated gene delivery induced the expression of the desired protein in lung parenchymal cells, and this technique was used to develop a SARS-CoV-2 susceptible mouse model. The study also showed the involvement of type I interferon signaling in the protection against SARS-CoV-2.