LY6E impairs coronavirus fusion and confers immune control of viral disease

• Published in: Nature microbiology Vol. 5; no. 11; pp. 1330 - 1339
• Main Authors: Pfaender, Stephanie, Mar, Katrina B., Michailidis, Eleftherios, Kratzel, Annika, Boys, Ian N., V’kovski, Philip, Fan, Wenchun, Kelly, Jenna N., Hirt, Dagny, Ebert, Nadine, Stalder, Hanspeter, Kleine-Weber, Hannah, Hoffmann, Markus, Hoffmann, Hans-Heinrich, Saeed, Mohsan, Dijkman, Ronald, Steinmann, Eike, Wight-Carter, Mary, McDougal, Matthew B., Hanners, Natasha W., Pöhlmann, Stefan, Gallagher, Tom, Todt, Daniel, Zimmer, Gert, Rice, Charles M., Schoggins, John W., Thiel, Volker
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.11.2020; Nature Publishing Group
• Subjects: 631/250/262; 631/326/596/2555; 631/326/596/2556; 631/326/596/4130; 692/699/255/2514; Angiotensin-Converting Enzyme 2; Animals; Antigens; Antigens, Surface - genetics; Antigens, Surface - immunology; Antigens, Surface - metabolism; Betacoronavirus - immunology; Betacoronavirus - physiology; Biomedical and Life Sciences; Coronaviridae; Coronavirus - immunology; Coronavirus - physiology; Coronavirus Infections - immunology; Coronavirus Infections - virology; Coronaviruses; COVID-19; Dendritic cells; Female; Fusion protein; GPI-Linked Proteins - genetics; GPI-Linked Proteins - immunology; GPI-Linked Proteins - metabolism; Hepatitis; Infections; Infectious Diseases; Interferon; Letter; Life Sciences; Liver diseases; Lymphocytes B; Male; Medical Microbiology; Membrane fusion; Membrane proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Microbiology; Middle East respiratory syndrome; Middle East Respiratory Syndrome Coronavirus - immunology; Middle East Respiratory Syndrome Coronavirus - physiology; Pandemics; Parasitology; Pathogenesis; Peptidyl-Dipeptidase A - metabolism; Pneumonia, Viral - immunology; Pneumonia, Viral - virology; Public health; Respiratory diseases; SARS-CoV-2; Severe acute respiratory syndrome coronavirus 2; Severe acute respiratory syndrome-related coronavirus - immunology; Severe acute respiratory syndrome-related coronavirus - physiology; Spike protein; Spleen; Viral diseases; Virology; Virus Internalization; Zoonoses
• ISSN: 2058-5276; 2058-5276
• DOI: 10.1038/s41564-020-0769-y

Zoonotic coronaviruses (CoVs) are substantial threats to global health, as exemplified by the emergence of two severe acute respiratory syndrome CoVs (SARS-CoV and SARS-CoV-2) and Middle East respiratory syndrome CoV (MERS-CoV) within two decades 1 – 3 . Host immune responses to CoVs are complex and regulated in part through antiviral interferons. However, interferon-stimulated gene products that inhibit CoVs are not well characterized 4 . Here, we show that lymphocyte antigen 6 complex, locus E (LY6E) potently restricts infection by multiple CoVs, including SARS-CoV, SARS-CoV-2 and MERS-CoV. Mechanistic studies revealed that LY6E inhibits CoV entry into cells by interfering with spike protein-mediated membrane fusion. Importantly, mice lacking Ly6e in immune cells were highly susceptible to a murine CoV—mouse hepatitis virus. Exacerbated viral pathogenesis in Ly6e knockout mice was accompanied by loss of hepatic immune cells, higher splenic viral burden and reduction in global antiviral gene pathways. Accordingly, we found that constitutive Ly6e directly protects primary B cells from murine CoV infection. Our results show that LY6E is a critical antiviral immune effector that controls CoV infection and pathogenesis. These findings advance our understanding of immune-mediated control of CoV in vitro and in vivo—knowledge that could help inform strategies to combat infection by emerging CoVs. Here, the authors identify lymphocyte antigen 6E (LY6E) as a coronavirus (CoV) restriction factor that prevents infection of B cells and dendritic cells. LY6E inhibits both human and mouse CoV entry into cells by interfering with viral spike protein-mediated membrane fusion. It facilitates an antiviral immune response that prevents liver disease and reduces death in the mouse model of MHV-A59 CoV infection.