Year: 2026
Type: preprint
Abstract: As highly pathogenic human coronaviruses continue to emerge from zoonotic sources, understanding how host intrinsic immune responses control infection is critical for preventing severe disease. The interferon (IFN) pathway induces antiviral effectors, including the interferon-stimulated gene (ISG) Shiftless (SHFL), which restricts −1 programmed ribosomal frameshifting during SARS-CoV-2 infection. Here, we investigate a novel proviral mechanism for SHFL using loss-of-function and gain-of-function approaches. Despite its established antiviral activity, SHFL enhanced infection by SARS-CoV-2 and the seasonal coronavirus HCoV-229E by increasing cellular susceptibility to infection. SHFL further promoted coronavirus infection by reducing cellular sensitivity to IFNα, through IFN signaling. Finally, we demonstrate that SHFL’s proviral effect is not completely dependent on the −1 programmed ribosomal frameshifting domain. In contrast, SHFL-mediated regulation of IFN signaling is independent of this domain. Together, these findings establish SHFL as a dual-function ISG with distinct proviral and antiviral activities, highlighting the complex roles of innate immune effectors during coronavirus infection. Importance Highly pathogenic human coronaviruses have emerged three times since 2002, and spillovers are likely to continue as human contact with animal habitats increases. Against a novel pathogen, the innate immune response is the host’s first line of defense, and interferon-stimulated genes (ISGs) are its main effectors. ISGs are canonically antiviral, but growing evidence suggests that viruses may co-opt them for proviral functions. Here we describe a novel, proviral function of the ISG, Shiftless (SHFL), during infection by SARS-CoV-2 and the seasonal coronavirus HCoV-229E. Our findings show that an IFN-induced gene is not necessarily an antiviral factor. For human coronaviruses, SHFL expression initially benefits the virus although it may act as an antiviral factor at a later step. Knowing which ISGs have dual functions, and in which cells, is a prerequisite for interpreting context-dependent IFN responses and for understanding the balance between host defense and viral persistence.
Authors: Taylor M. Shue, Georgios Mourtzouchos, Dar-Yin Li, Yee T. Ong, Antonis Athanasiadis, Maria Bousali, Madeleine K. Sanders, Sophie N. Spector, Christopher Rivera-Bonilla, Khadija Ndoye, Kenneth C. Levenson, Jens Cuba, Jayden Harris, Kelly Mieck, Shuiyun Lan, Volker Kinast, Julia LeCher, Jérémie Le Pen, Stefan G. Sarafianos, Eleftherios Michailidis
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7222879773