Potent NKT cell ligands overcome SARS-CoV-2 immune evasion to mitigate viral pathogenesis in mouse models

Abstract

One of the major pathogenesis mechanisms of SARS-CoV-2 is its potent suppression of innate immunity, including blocking the production of type I interferons. However, it is unknown whether and how the virus interacts with different innate-like T cells, including NKT, MAIT and γδ T cells. Here we reported that upon SARS-CoV-2 infection, invariant NKT (iNKT) cells rapidly trafficked to infected lung tissues from the periphery. We discovered that the envelope (E) protein of SARS-CoV-2 efficiently down-regulated the cell surface expression of the antigen-presenting molecule, CD1d, to suppress the function of iNKT cells. E protein is a small membrane protein and a viroporin that plays important roles in virion packaging and envelopment during viral morphogenesis. We showed that the transmembrane domain of E protein was responsible for suppressing CD1d expression by specifically reducing the level of mature, post-ER forms of CD1d, suggesting that it suppressed the trafficking of CD1d proteins and led to their degradation. Point mutations demonstrated that the putative ion channel function was required for suppression of CD1d expression and inhibition of the ion channel function using small chemicals rescued the CD1d expression. Importantly, we discovered that among seven human coronaviruses, only E proteins from highly pathogenic coronaviruses including SARS-CoV-2, SARS-CoV and MERS suppressed CD1d expression, whereas the E proteins of human common cold coronaviruses, HCoV-OC43, HCoV-229E, HCoV-NL63 and HCoV-HKU1, did not. These results suggested that E protein-mediated evasion of NKT cell function was likely an important pathogenesis factor, enhancing the virulence of these highly pathogenic coronaviruses. Remarkably, activation of iNKT cells with their glycolipid ligands, both prophylactically and therapeutically, overcame the putative viral immune evasion, significantly mitigated viral pathogenesis and improved host survival in mice. Our results suggested a novel NKT cell-based anti-SARS-CoV-2 therapeutic approach.

SARS-COV-2 induces blood-brain barrier and choroid plexus barrier impairments and vascular inflammation in mice

“…The SARS-CoV-2 (Isolate USA-WA1/2020) was obtained from Biodefense and Emerging Infections Research Resources Repository (BEI Resources), propagated and titered in Vero-E6 cells as we previously described 23 , and was used for all in vivo studies. K18-hACE2-Tg ( B6.Cg-Tg(K18-ACE2) 2Prlmn/J ) mice were purchased from the Jackson Laboratory (Stock #034860) and bred locally.…”

“…K18-hACE2 transgene was maintained at hemizygous status in experimental mice. For SARS-CoV-2 infection, 1×10 4 pfu virus were inoculated intranasally per mouse, as we recently reported 23 . Mice were monitored every day for weight loss and survival.…”

SARS‐CoV‐2 induces blood‐brain barrier and choroid plexus barrier impairments and vascular inflammation in mice

“…For SARS-CoV-2 infection, 1 × 10 4 pfu virus was inoculated intranasally per mouse, as we recently reported. 23 Mice were monitored every day for weight loss and survival. All animal procedures were performed at the ABSL3 facility at the University of Southern California and approved by the Institutional Animal Care and Use Committee at the University of Southern California.…”

Initial immune response after exposure to Mycobacterium tuberculosis or to SARS-COV-2: similarities and differences

“…CD1d-restricted NKT cells are other types of innate lymphocytes that are involved in antiviral immunity ( 169 ). To counteract their function, the envelope (E) protein of SARS-CoV-2 reduces the expression of the antigen-presenting molecule CD1d thus inhibiting the activation of innate NKT cells and enhancing SARS-CoV-2 virulence ( 76 ).…”