Altered TMPRSS2 usage by SARS-CoV-2 Omicron impacts infectivity and fusogenicity

The SARS-CoV-2 Omicron BA.1 variant emerged in 20211 and has multiple mutations in its spike protein2. Here we show that the spike protein of Omicron has a higher affinity for ACE2 compared with Delta, and a marked change in its antigenicity increases Omicron’s evasion of therapeutic monoclonal and vaccine-elicited polyclonal neutralizing antibodies after two doses. mRNA vaccination as a third vaccine dose rescues and broadens neutralization. Importantly, the antiviral drugs remdesivir and molnupiravir retain efficacy against Omicron BA.1. Replication was similar for Omicron and Delta virus isolates in human nasal epithelial cultures. However, in lung cells and gut cells, Omicron demonstrated lower replication. Omicron spike protein was less efficiently cleaved compared with Delta. The differences in replication were mapped to the entry efficiency of the virus on the basis of spike-pseudotyped virus assays. The defect in entry of Omicron pseudotyped virus to specific cell types effectively correlated with higher cellular RNA expression of TMPRSS2, and deletion of TMPRSS2 affected Delta entry to a greater extent than Omicron. Furthermore, drug inhibitors targeting specific entry pathways3 demonstrated that the Omicron spike inefficiently uses the cellular protease TMPRSS2, which promotes cell entry through plasma membrane fusion, with greater dependency on cell entry through the endocytic pathway. Consistent with suboptimal S1/S2 cleavage and inability to use TMPRSS2, syncytium formation by the Omicron spike was substantially impaired compared with the Delta spike. The less efficient spike cleavage of Omicron at S1/S2 is associated with a shift in cellular tropism away from TMPRSS2-expressing cells, with implications for altered pathogenesis

The Large High Altitude Air Shower Observatory (LHAASO) Science Book (2021 Edition)

International audienceSince the science white paper of the Large High Altitude Air Shower Observatory (LHAASO) published on arXiv in 2019 [e-Print: 1905.02773 (astro-ph.HE)], LHAASO has completed the transition from a project to an operational gamma-ray astronomical observatory LHAASO is a new generation multi-component facility located in Daocheng, Sichuan province of China, at an altitude of 4410 meters. It aims at measuring with unprecedented sensitivity the spectrum, composition, and anisotropy of cosmic rays in the energy range between 10$^{12}$ and 10$^{18}$~eV, and acting simultaneously as a wide aperture (one stereoradiant) continuously operating gamma-ray telescope in the energy range between 10$^{11}$ and $10^{15}$~eV with the designed sensitivity of 1.3% of the Crab Unit (CU) above 100 TeV. LHAASO's capability of measuring simultaneously different shower components (electrons, muons, and Cherenkov/fluorescence light), will allow it to investigate the origin, acceleration, and propagation of CR through measurement of the energy spectrum, elemental composition, and anisotropy with unprecedented resolution. The remarkable sensitivity of LHAASO will play a key role in CR physics and gamma-ray astronomy for a general and comprehensive exploration of the high energy universe and will allow important studies of fundamental physics (such as indirect dark matter search, Lorentz invariance violation, quantum gravity) and solar and heliospheric physics. The LHAASO Collaboration organized an editorial working group and finished all editorial work of this science book, to summarize the instrumental features and outline the prospects of scientific researches with the LHAASO experiment