LY6E impairs coronavirus fusion and confers immune control of viral disease

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 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. Coronaviruses (CoVs) are enveloped RNA viruses with broad host tropism and documented capability to cross the species barrier to infect humans 5. The mammalian innate immune response controls CoV infection partly through the action of interferons (IFNs) 4,6,7. IFNs inhibit viral infection by inducing hundreds of genes, many of which encode antiviral effectors 8. The IFN-stimulated genes (ISGs) that inhibit CoV infection are not well

Syncytia formation by SARS‐CoV‐2‐infected cells

“…IFITMs inhibit SARS‐CoV, 229E, and MERS‐CoV entry, but promote infection by HCoV‐OC43, a coronavirus that causes the common cold (Huang et al , 2011; Bertram et al , 2013; Warren et al , 2014; Wrensch et al , 2014; Zhao et al , 2014; Zhao et al , 2018). IFITMs, as well as other ISGs, including LY6E and Cholesterol 25‐hydrolase (CH25H), impair SARS‐CoV‐2 replication by blocking the fusion of virions (Pfaender et al , 2020; preprint: Zang et al , 2020; Zhao et al , 2020). Most of the experiments regarding these ISGs have been performed with single‐cycle viral pseudotypes.…”

Nucleic Acid-Sensing Pathways During SARS-CoV-2 Infection: Expectations versus Reality

“…Lymphocyte antigen 6 complex, locus E (LY6E), was found to impair the cellular fusion of multiple CoVs, including SARS-CoV-2, SARS-CoV-1, and MERS-CoV, by interfering with the S protein-mediated membrane fusion. 108 This suggests that IFN-induced transmembrane (IFITM) protein family members, such as LY6E, could potentially restrict the entry of SARS-CoV-2 and their replication, as was previously shown in the case of SARS-CoV-1. 109 However, IFITM proteins have also been implicated in promoting infection by other human CoVs, such as HCoV-OC43.…”

Novel Method for Detection of Genes With Altered Expression Caused by Coronavirus Infection and Screening of Candidate Drugs for SARS-CoV-2

“…× u 1j u 2k u 3m u 4n u 5p u 6 i (1) where G( 1 2 3 4 5 6 ) ∈ R N ×2×2×3×3×2 is a core tensor, and u 1j ∈ R 2×2 , u 2 k ∈ R 2×2 , u 3m ∈ R 3×3 , u 4n ∈ R 3×3 , u 5 p ∈ R 2×2 , and u 6 i ∈ R N ×N are singular values vectors, which can be obtained via the higher-order singular value decomposition (HOSVD) algorithm [2]. To select u 6 i , attributed to selected genes, we need to select u 1j attributed to the genotype, u 2 k attributed to the tissue, u 3m attributed to the treatment, u 4n attributed to the biological replicate, and u 5p attributed to the technical replicate, associated with desired properties.…”

“…To achieve this goal, it is essential to understand the mechanism by which SARS-CoV-2 successfully invades human cells. Recently, Pfaender et al [1] demonstrated that host lymphocyte antigen 6 (LY6E) complex impairs coronavirus fusion and confers immune control of viral disease. The authors also used a transcriptome approach to evaluate the effect of infection of mouse hepatitis virus (MHV), a natural mouse pathogen that causes hepatitis and encephalomyelitis, which is a well-studied model of coronavirus infection.…”