Insights on interferon-independent induction of interferon-stimulated genes shaping the lung's response in early SARS-CoV-2 infection

Sung-Dong Cho; Haeun Shin; Sujin Kim; Hyun Jik Kim

doi:10.1016/j.heliyon.2023.e22997

Insights on interferon-independent induction of interferon-stimulated genes shaping the lung's response in early SARS-CoV-2 infection

Heliyon. 2023 Nov 28;9(12):e22997. doi: 10.1016/j.heliyon.2023.e22997. eCollection 2023 Dec.

Authors

Sung-Dong Cho¹, Haeun Shin², Sujin Kim², Hyun Jik Kim^{2

3}

Affiliations

¹ Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, South Korea.
² Department of Otorhinolaryngology, Seoul National University College of Medicine, Seoul, South Korea.
³ Sensory Organ Research Institute, Seoul National University Medical Research Center, Seoul, Korea.

Abstract

While mRNA vaccine efficacy against the 2019 coronavirus disease (COVID-19) outbreak remains high, research on antiviral innate immune responses in the early stages of infection is essential to develop strategies to prevent the dissemination of SARS-CoV-2. In this study, we investigated the induction of both interferon (IFN)-stimulated genes (ISGs) and IFN-independently upregulated ISGs following SARS-CoV-2 infection in Syrian golden hamsters. The viral titers were highest at 3 days post-infection (dpi). Over time, the viral titer gradually decreased while ISGs such as Mx1, Ifit2, Ifit3, Ifi44, and Rsad2 were markedly induced in the lung. The transcription of ISGs significantly increased from 2 dpi, and SARS-CoV-2-induced ISGs were maintained in the hamster lung until 7 dpi. The transcription of Ifnb and Ifng was minimally elevated, while Ifnl_2/3 was significantly induced in the lung at 5 days after SARS-CoV-2 infection. RNA sequencing results also showed that at 3 dpi, SARS-CoV-2 initiated the activation of ISGs, with lesser increases of Ifnl₂ and Ifnl₃ transcription. In addition, Ddx58 and cGAS, which encode factors for virus sensing, Stat1, Stat2, and IFN regulatory factor 7 and 9 mRNA levels were also induced at the initial stage of infection. Our data demonstrate that ISGs might be upregulated in the lung in response to SARS-CoV-2 during the early stages of infection, and the rapid induction of ISGs was not associated with the activation of IFNs. Elucidation of IFN-independent induction of ISGs could further our understanding of alternative defense mechanisms employed by the lungs against SARS-CoV-2 and provide more effective antiviral strategies for patients with severe COVID-19.

Keywords: Innate immune responses; Interferon-independent pathway; Interferon-stimulated genes; SARS-CoV-2.