ABSTRACT
C3A is a sub-clone of human hepatoblastoma HepG2 cell line with the strong contact inhibition of growth. We fortuitously found that C3A was more susceptible to human coronavirus HCoV-OC43 infection than HepG2, which was attributed to the increased efficiency of virus entry into C3A cells. In an effort to search for the host cellular protein(s) mediating the differential susceptibility of the two cell lines to HCoV-OC43 infection, we found that ADAP2, GILT and LY6E, three cellular proteins with known activity of interfering virus entry, expressed at significantly higher levels in HepG2 cells. Functional analyses revealed that ectopic expression of LY6E, but not GILT or ADAP2, in HEK 293 cells inhibited the entry of HCoV-OC43. While overexpression of LY6E in C3A and A549 cells efficiently inhibited the infection of HCoV-OC43, knockdown of LY6E expression in HepG2 significantly increased its susceptibility to HCoV-OC43 infection. Moreover, we found that LY6E also efficiently restricted the entry mediated by the envelope spike proteins of other human coronaviruses, including the currently pandemic SARS-CoV-2. Interestingly, overexpression of serine protease TMPRSS2 or amphotericin treatment significantly neutralized the IFITM3 restriction of human coronavirus entry, but did not compromise the effect of LY6E on the entry of human coronaviruses. The work reported herein thus demonstrates that LY6E is a critical antiviral immune effector that controls CoV infection and pathogenesis via a distinct mechanism. ImportanceVirus entry into host cells is one of the key determinants of host range and cell tropism and is subjected to the control by host innate and adaptive immune responses. In the last decade, several interferon inducible cellular proteins, including IFITMs, GILT, ADAP2, 25CH and LY6E, had been identified to modulate the infectious entry of a variety of viruses. Particularly, LY6E was recently identified as host factors to facilitate the entry of several human pathogenic viruses, including human immunodeficiency virus, influenza A virus and yellow fever virus. Identification of LY6E as a potent restriction factor of coronaviruses expands the biological function of LY6E and sheds new light on the immunopathogenesis of human coronavirus infection.
ABSTRACT
Treatment of chronic hepatitis B virus (HBV) infection with the viral DNA polymerase inhibitors or pegylated alpha-interferon has led to a significant retardation in HBV-related disease progression and reduction in mortality related to chronic hepatitis B associated liver decompensation and hepatocellular carcinoma. However, chronic HBV infection remains not cured. The reasons for the failure to eradicate HBV infection by long-term antiviral therapy are not completely understood. However, clinical studies suggest that the intrinsic stability of the nuclear form of viral genome, the covalently closed circular (ccc) DNA, sustained low level viral replication under antiviral therapy and homeostatic proliferation of hepatocytes are the critical virological and pathophysiological factors that affect the persistence and therapeutic outcomes of HBV infection. More importantly, despite potent suppression of HBV replication in livers of the treated patients, the dysfunction of HBV-specific antiviral immunity persists. The inability of the immune system to recognize cells harboring HBV infection and to cure or eliminate cells actively producing virus is the biggest challenge to finding a cure. Unraveling the complex virus-host interactions that lead to persistent infection should facilitate the rational design of antivirals and immunotherapeutics to cure chronic HBV infection.
