Dear Editor, Accumulating clinical data suggest the main causes of death by COVID-19 include respiratory failure and the onset of sepsis. 1 Importantly, sepsis has been observed in nearly all deceased patients. 2-5 It remains elusive how SARS-CoV-2 infection results in viral sepsis in humans. Toll-like receptor 4 (TLR4) mediates antigram-negative bacterial immune responses by recognizing lipopolysaccharide (LPS) from bacteria. 6 We recently found that SARS-CoV-2 infection provoked an anti-bacterial like response at the very early stage of infection via TLR4. However, the identity of the original trigger initiating these abnormal immune responses during SARS-CoV-2 infection is unknown. Previous in silico studies predicted cell surface TLRs, especially TLR4, are most likely to be involved in recognizing molecular patterns, probably spike protein, from SARS-CoV-2 to induce inflammatory responses. 7,8 Consistently, we found that the induction of IL1B by SARS-CoV-2 was completely blocked by TLR4-specific inhibitor Resatorvid (Fig. 1a). Combined with our recent data that TLR4 signaling was activated by SARS-CoV-2, we hypothesized that spike protein could activate TLR4 pathway. A recent study has reported that trimeric SARS-CoV-2 spike proteins are high quality antigens. 9 To this end, we purified the trimeric spike protein (1-1208 aa) (Fig. 1b; Supplementary information, Fig. S1a), as this form of spike protein presents on the surface of viral particle, which most likely interacts with the proteins on the cell surface. Results of the surface plasmon resonance (SPR) assay showed that SARS-CoV-2 spike trimer directly bound to TLR4 with an affinity of~300 nM (Fig. 1b), comparable to many virus-receptor interactions. We then treated THP-1 cells, a cell line of human monocytes, with purified spike protein. IL1B was robustly induced by spike protein in a dose-dependent manner (Fig. 1c), which was comparable to LPS (Supplementary information, Fig. S1b). IL6 was also induced by spike protein (Supplementary information, Fig. S1c). As IL1B induction was much more robust than that of IL6, we chose IL1B production as a marker of immune activation. Moreover, the pseudovirus expressing spike protein can also induce IL1B production (Fig. 1d). Neutrophils also express TLR4 on their cell surface and play an important role in the development of sepsis. We utilized all-trans retinoic acid (ATRA) to treat HL-60 cell (a promyelocytic leukemia cell line), which directed those cells to differentiate into neutrophils. Spike proteins significantly induced IL1B production in HL-60 cells after ATRA treatment (Fig. 1e; Supplementary information, Fig. S1d). We treated THP-1 cells with the N-terminal domain (NTD) or the receptor-binding domain (RBD) of spike protein. Only the trimeric protein could induce IL1B and IL6 (Fig. 1f; Supplementary information, Fig. S1e). To examine if this activation was mediated by TLR4, we treated cells with Resatorvid. Resatorvid greatly blocked induction of IL1B by spike protein and LPS (Fig. 1g). Moreover, spike pro...

The SARS-CoV-2 pandemic poses an unprecedented public health crisis. Evidence suggests that SARS-CoV-2 infection causes dysregulation of the immune system. However, the unique signature of early immune responses remains elusive. We characterized the transcriptome of rhesus macaques and mice infected with SARS-CoV-2. Alarmin S100A8 was robustly induced in SARS-CoV-2 infected animal models as well as in COVID-19 patients. Paquinimod, a specific inhibitor of S100A8/A9, could rescue the pneumonia with substantial reduction of viral loads in SARS-CoV-2 infected mice. Remarkably, Paquinimod treatment resulted in almost 100% survival in a lethal model of mouse coronavirus infection using the mouse hepatitis virus (MHV). A group of neutrophils that contributes to the uncontrolled pathological damage and onset of COVID-19 were dramatically induced by coronavirus infection. Paquinimod treatment could reduce these neutrophils and regain antiviral responses, unveiling key roles of S100A8/A9 and aberrant neutrophils in the pathogenesis of COVID-19, highlighting new opportunities for therapeutic intervention.

The detailed spatial distributions and diurnal variations of low-level jets (LLJs) during early summer (May–July) in China are documented using 2006–11 hourly model data from the Weather Research and Forecasting (WRF) Model with a 9-km horizontal resolution. It was found that LLJs frequently occur in the following regions of China: the Tarim basin, northeastern China, the Tibetan Plateau (TP), and southern China. The LLJs over China are classified into two types: boundary layer jets (BLJs, below 1 km) and synoptic-system-related LLJs (SLLJs, within 1–4 km). The LLJs in the Tarim basin and the TP are mainly BLJs. The SLLJs over southern China and northeastern China are associated with the mei-yu front and northeast cold vortex (NECV), respectively. The BLJs in all regions show pronounced diurnal variations with maximum occurrences at nighttime or in the early morning, whereas diurnal variations of SLLJs vary, depending on the location. From the analysis of model data, the diurnal variation of BLJs is mainly caused by inertial oscillation at nighttime and vertical mixing in the boundary layer during daytime. Over northeastern China, SLLJ occurrences show little diurnal variation. Over southern China, two diurnal modes of SLLJs, propagation and stationary, exist and have seasonal variations, which is generally consistent with diurnal variations of precipitation.

Peptide modulators targeting protein-protein interactions (PPIs) exhibit greater potential than small-molecule drugs in several important aspects including facile modification and relative large contact surface area. Stabilized peptides constructed by variable chemistry methods exhibit improved peptide stability and cell permeability compared to that of the linears. Herein, we designed a stabilized peptide-based proteolysis-targeting chimera (PROTAC) targeting estrogen receptor α (ERα) by tethering an N-terminal aspartic acid cross-linked stabilized peptide ERα modulator (TD-PERM) with a pentapeptide that binds the Von Hippel-Lindau (VHL) E3 ubiquitin ligase complex. The resulting heterobifunctional peptide (TD-PROTAC) selectively recruits ERα to the VHL E3 ligase complex, leading to the degradation of ERα in a proteasome-dependent manner. Compared with the control peptides, TD-PROTAC shows significantly enhanced activities in reducing the transcription of the ERα-downstream genes and inhibiting the proliferation of ERα-positive breast cancer cells. In addition, in vivo experiments indicate that TD-PROTAC leads to tumor regression in the MCF-7 mouse xenograft model. This work is a successful attempt to construct PROTACs based on cell-permeable stabilized peptides, which significantly broadens the chemical space of PROTACs and stabilized peptides.

Highlights d The nuclear matrix protein SAFA is required for antiviral immunity in cells and mice d SAFA directly senses viral RNA in the nucleus d SAFA facilitates antiviral immunity through interacting with chromatin remodelers d Oligomerized SAFA mediates IFNB1 transcription by activating its distal enhancers