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.
A low-jitter delay-locked loop (DLL) for high-resolution time-to-digital converter (TDC) is proposed in this study. The generated high accurate and low-jitter outputs with uniformly distributed multiphase clocks directly from the voltage-controlled delay line (VCDL) in DLL are applied to two-segment TDC. For reducing the static phase offset in locked state, the charge pump with interior feedback loop is used to achieve a better current matching between the charging and discharging currents. An improved phase detector as well as a differential VCDL excellent in linearity property and noise suppression is utilised for reducing the output clock jitter. Fabricated by TSMC 0.35 μm complementary metal-oxide-semiconductor process, the measurement results show that DLL's frequency locking range is 60-240 MHz, the output clock jitters at 125 MHz are 3.6 ps for root mean square and 35.07 ps for peak-to-peak. By clock period counting and eight-phase discrimination, the resolution of <1 ns and maximum range of around 1 μs as well as the differential non-linearity <0.68 LSB and the integration non-linearity within −0.97 to 1.24 LSB are obtained for two-segment TDC.
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