Contrasting roles of MERS-CoV and SARS-CoV-2 internal proteins in pathogenesis in mice

Lok-Yin Roy Wong; Abby Odle; Emma Luhmann; Douglas C Wu; Yiquan Wang; Qi Wen Teo; Celeste Ptak; Alan Sariol; Shea Lowery; Matthias Mack; David K Meyerholz; Nicholas C Wu; Lilliana Radoshevich; Stanley Perlman

doi:10.1128/mbio.02476-23

Contrasting roles of MERS-CoV and SARS-CoV-2 internal proteins in pathogenesis in mice

mBio. 2023 Oct 26;14(6):e0247623. doi: 10.1128/mbio.02476-23. Online ahead of print.

Authors

Lok-Yin Roy Wong^{1

2}, Abby Odle^{1

2}, Emma Luhmann^{1

2}, Douglas C Wu³, Yiquan Wang³, Qi Wen Teo³, Celeste Ptak^{1

2}, Alan Sariol^{1

2}, Shea Lowery^{1

2}, Matthias Mack⁴, David K Meyerholz⁵, Nicholas C Wu^{3

6}, Lilliana Radoshevich^{1

2}, Stanley Perlman^{1

2

7}

Affiliations

¹ Department of Microbiology, University of Iowa, Iowa City, Iowa, USA.
² Department of Immunology, University of Iowa, Iowa City, Iowa, USA.
³ Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
⁴ Department of Internal Medicine, University Hospital Regensburg, Regensburg, Germany.
⁵ Department of Pathology, University of Iowa, Iowa City, Iowa, USA.
⁶ Carle Illinois College of Medicine, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
⁷ Department of Pediatrics, University of Iowa, Iowa City, Iowa, USA.

Abstract

Betacoronaviruses encode an internal (I) gene via an alternative reading frame within the nucleocapsid gene, called ORF8b for Middle-East respiratory syndrome coronavirus (MERS-CoV) and ORF9b for severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2. Previous reports suggested that proteins 8b and 9b are involved in evading multiple innate immune signaling pathways. However, their roles in mediating pathogenesis in infected animals have not been determined. In this study, we abrogated the expression of protein 8b in MERS-CoV and protein 9b in SARS-CoV-2. Using mouse models of MERS-CoV and SARS-CoV-2 infection, we found that MERS-CoV lacking protein 8b expression was more virulent, while SARS-CoV-2 lacking protein 9b expression was attenuated compared with the respective wild-type viruses. Upon further analysis, we detected increased levels of type I interferon and enhanced infiltration of immune cells to the lungs of mice infected with MERS-CoV lacking protein 8b expression. These data suggest that the I protein of MERS-CoV plays a role in limiting pathogenesis while that of SARS-CoV-2 enhances disease severity. IMPORTANCE The function of betacoronavirus internal protein has been relatively understudied. The earliest report on the internal protein of mouse hepatitis virus suggested that the internal protein is a structural protein without significant functions in virus replication and virulence. However, the internal proteins of severe acute respiratory syndrome coronavirus (SARS-CoV), Middle-East respiratory syndrome coronavirus, and SARS-CoV-2 have been shown to evade immune responses. Despite the reported functions of the internal protein in these highly pathogenic human coronaviruses, its role in mediating pathogenesis in experimentally infected animals has not been characterized. Our data indicated that despite the similar genomic location and expression strategy of these internal proteins, their effects on virulence are vastly different and virus specific, highlighting the complexity between host-virus interaction and disease outcome.

Keywords: MERS-CoV; SARS-CoV-2; immune response; pathogenesis.

Abstract

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