Distinct Roles of Type I and Type III Interferons during a Native Murine β Coronavirus Lung Infection

• Published in: Journal of virology Vol. 96; no. 2; p. e0124121
• Main Authors: Sharma, Lokesh, Peng, Xiaohua, Qing, Hua, Hilliard, Brandon K., Kim, Jooyoung, Swaminathan, Anush, Tian, Justin, Israni-Winger, Kavita, Zhang, Cuiling, Habet, Victoria, Wang, Lin, Gupta, Gayatri, Tian, Xuefei, Ma, Yina, Shin, Hyeon-Jun, Kim, Sang-Hun, Kang, Min-Jong, Ishibe, Shuta, Young, Lawrence H., Kotenko, Sergei, Compton, Susan, Wilen, Craig B., Wang, Andrew, Dela Cruz, Charles S.
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 26.01.2022
• Subjects: Animals; Coronavirus Infections - immunology; Female; Immunology; Interferon Lambda; Interferon Type I - immunology; Interferons - immunology; Lung - immunology; Lung - virology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Pathogenesis and Immunity; type III interferons; coronavirus; lung defense; antiviral agents; type I interferons
• ISSN: 0022-538X; 1098-5514; 1098-5514
• DOI: 10.1128/JVI.01241-21

The antiviral and pathological potential of type I and type III interferons during coronavirus infection remains poorly defined, and opposite findings have been reported. We report that both type I and type III interferons have anticoronaviral activities, but their potency and organ specificity differ. Coronaviruses are a major health care threat to humankind. Currently, the host factors that contribute to limit disease severity in healthy young patients are not well defined. Interferons are key antiviral molecules, especially type I and type III interferons. The role of these interferons during coronavirus disease is a subject of debate. Here, using mice that are deficient in type I (IFNAR1 −/− ), type III (IFNLR1 −/− ), or both (IFNAR1/LR1 −/− ) interferon signaling pathways and murine-adapted coronavirus (MHV-A59) administered through the intranasal route, we define the role of interferons in coronavirus infection. We show that type I interferons play a major role in host survival in this model, while a minimal role of type III interferons was manifested only in the absence of type I interferons or during a lethal dose of coronavirus. IFNAR1 −/− and IFNAR1/LR1 −/− mice had an uncontrolled viral burden in the airways and lung and increased viral dissemination to other organs. The absence of only type III interferon signaling had no measurable difference in the viral load. The increased viral load in IFNAR1 −/− and IFNAR1/LR1 −/− mice was associated with increased tissue injury, especially evident in the lung and liver. Type I but not type III interferon treatment was able to promote survival if treated during early disease. Further, we show that type I interferon signaling in macrophages contributes to the beneficial effects during coronavirus infection in mice. IMPORTANCE The antiviral and pathological potential of type I and type III interferons during coronavirus infection remains poorly defined, and opposite findings have been reported. We report that both type I and type III interferons have anticoronaviral activities, but their potency and organ specificity differ. Type I interferon deficiency rendered the mice susceptible to even a sublethal murine coronavirus infection, while the type III interferon deficiency impaired survival only during a lethal infection or during a sublethal infection in the absence of type I interferon signaling. While treatment with both type I and III interferons promoted viral clearance in the airways and lung, only type I interferons promoted the viral clearance in the liver and improved host survival upon early treatment (12 h postinfection). This study demonstrates distinct roles and potency of type I and type III interferons and their therapeutic potential during coronavirus lung infection.