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 White Paper

The Large High Altitude Air Shower Observatory (LHAASO) project is a new generation multi-component instrument, to be built at 4410 meters of altitude in the Sichuan province of China, with the aim to study with unprecedented sensitivity the spec trum, the composition and the anisotropy of cosmic rays in the energy range between 10$^{12}$ and 10$^{18}$ eV, as well as to act simultaneously as a wide aperture (one stereoradiant), continuously-operated gamma ray telescope in the energy range between 10$^{11}$ and $10^{15}$ eV. The experiment will be able of continuously surveying the TeV sky for steady and transient sources from 100 GeV to 1 PeV, t hus opening for the first time the 100-1000 TeV range to the direct observations of the high energy cosmic ray sources. In addition, the different observables (electronic, muonic and Cherenkov/fluorescence components) that will be measured in LHAASO will allow to investigate origin, acceleration and propagation of the radiation through a measurement of energy spec trum, elemental composition and anisotropy with unprecedented resolution. The remarkable sensitivity of LHAASO in cosmic rays physics and gamma astronomy would play a key-role in the comprehensive general program to explore the High Energy Universe. LHAASO will allow important studies of fundamental physics (such as indirect dark matter search, Lorentz invariance violation, quantum gravity) and solar and heliospheric physics. In this document we introduce the concept of LHAASO and the main science goals, providing an overview of the project