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

Myeon-Sik Yang; Min-Jung Park; Junhyeong Lee; Byungkwan Oh; Kyung Won Kang; Yeonhwa Kim; Sang-Myeong Lee; Je-Oh Lim; Tae-Yang Jung; Jong-Hwan Park; Seok-Chan Park; Yun-Sook Lim; Soon B Hwang; Kwang-Soo Lyoo; Dong-Il Kim; Bumseok Kim

doi:10.1016/j.ymthe.2022.01.010

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

Mol Ther. 2022 May 4;30(5):1994-2004. doi: 10.1016/j.ymthe.2022.01.010. Epub 2022 Jan 7.

Authors

Myeon-Sik Yang¹, Min-Jung Park², Junhyeong Lee², Byungkwan Oh¹, Kyung Won Kang³, Yeonhwa Kim⁴, Sang-Myeong Lee⁴, Je-Oh Lim⁵, Tae-Yang Jung⁵, Jong-Hwan Park⁶, Seok-Chan Park¹, Yun-Sook Lim⁷, Soon B Hwang⁷, Kwang-Soo Lyoo⁷, Dong-Il Kim⁸, Bumseok Kim⁹

Affiliations

¹ Biosafety Research Institute and Laboratory of Veterinary Pathology, College of Veterinary Medicine, Jeonbuk National University, Iksan 54596, Korea.
² Department of Veterinary Physiology, College of Veterinary Medicine, Chonnam National University, Gwangju 61186, Korea; College of Veterinary Medicine and BK21 FOUR Program, Chonnam National University, Gwangju 61186, Korea.
³ Division of Biotechnology, College of Environmental and Bioresources, Jeonbuk National University, Iksan 54596, Korea.
⁴ College of Veterinary Medicine, Chungbuk National University, Cheongju 28644, Korea.
⁵ College of Veterinary Medicine and BK21 FOUR Program, Chonnam National University, Gwangju 61186, Korea.
⁶ College of Veterinary Medicine and BK21 FOUR Program, Chonnam National University, Gwangju 61186, Korea; Laboratory Animal Medicine, College of Veterinary Medicine, Chonnam National University, Gwangju 61186, Korea.
⁷ Korea Zoonosis Research Institute, Jeonbuk National University, Iksan 54531, Korea.
⁸ Department of Veterinary Physiology, College of Veterinary Medicine, Chonnam National University, Gwangju 61186, Korea; College of Veterinary Medicine and BK21 FOUR Program, Chonnam National University, Gwangju 61186, Korea. Electronic address: kimdi@chonnam.ac.kr.
⁹ Biosafety Research Institute and Laboratory of Veterinary Pathology, College of Veterinary Medicine, Jeonbuk National University, Iksan 54596, Korea; Korea Zoonosis Research Institute, Jeonbuk National University, Iksan 54531, Korea. Electronic address: bskims@jbnu.ac.kr.

Abstract

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 established. Here, we revealed that the intratracheal administration 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 protein in lung parenchymal cells, including alveolar type II cells. We harnessed the technique to develop severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-susceptible 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 interferon 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 multiple 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 demonstrate the ease and rapidness of the intratracheal administration of AAV for targeting lung tissue in mice, and this can be used to study diverse pulmonary diseases.

Keywords: AAV; AAV2/8; AT1; AT2; SARS-CoV-2; hACE2; intratracheal injection; lung targeting.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
COVID-19* / therapy
Dependovirus / genetics
Disease Models, Animal
Disease Susceptibility
Lung / pathology
Mice
Mice, Transgenic
SARS-CoV-2* / genetics