LY6E impairs coronavirus fusion and confers immune control of viral disease

Nat Microbiol. 2020 Nov;5(11):1330-1339. doi: 10.1038/s41564-020-0769-y. Epub 2020 Jul 23.

Abstract

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 decades1-3. 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 characterized4. 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Angiotensin-Converting Enzyme 2
  • Animals
  • Antigens, Surface / genetics
  • Antigens, Surface / immunology
  • Antigens, Surface / metabolism*
  • Betacoronavirus / immunology
  • Betacoronavirus / physiology
  • COVID-19
  • Coronavirus / immunology
  • Coronavirus / physiology*
  • Coronavirus Infections / immunology*
  • Coronavirus Infections / virology*
  • Female
  • GPI-Linked Proteins / genetics
  • GPI-Linked Proteins / immunology
  • GPI-Linked Proteins / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle East Respiratory Syndrome Coronavirus / immunology
  • Middle East Respiratory Syndrome Coronavirus / physiology
  • Pandemics
  • Peptidyl-Dipeptidase A / metabolism
  • Pneumonia, Viral / immunology
  • Pneumonia, Viral / virology
  • SARS Virus / immunology
  • SARS Virus / physiology
  • SARS-CoV-2
  • Virus Internalization

Substances

  • Antigens, Surface
  • GPI-Linked Proteins
  • Ly6e protein, mouse
  • Peptidyl-Dipeptidase A
  • ACE2 protein, human
  • Ace2 protein, mouse
  • Angiotensin-Converting Enzyme 2

Grant support