Graphical AbstractHighlights d SARS-CoV-2 uses the SARS-CoV receptor ACE2 for host cell entry d The spike protein of SARS-CoV-2 is primed by TMPRSS2 d Antibodies against SARS-CoV spike may offer some protection against SARS-CoV-2

Coronavirus disease 2019 (COVID -19) is an acute infection of the respiratory tract that emerged in late 2019 1,2 . Initial outbreaks in China involved 13.8% of cases with severe courses, and 6.1% of cases with critical courses 3 . This severe presentation may result from the virus using a virus receptor that is expressed predominantly in the lung 2,4 ; the same receptor tropism is thought to have determined the pathogenicity-but also aided in the control-of severe acute respiratory syndrome (SARS) in 2003 5 . However, there are reports of cases of COVID-19 in which the patient shows mild upper respiratory tract symptoms, which suggests the potential for pre-or oligosymptomatic transmission 6-8 . There is an urgent need for information on virus replication, immunity and infectivity in specific sites of the body. Here we report a detailed virological analysis of nine cases of COVID-19 that provides proof of active virus replication in tissues of the

Most human coronaviruses cause mild upper respiratory tract disease but may be associated with more severe pulmonary disease in immunocompromised individuals. However, SARS coronavirus caused severe lower respiratory disease with nearly 10% mortality and evidence of systemic spread. Recently, another coronavirus (human coronavirus-Erasmus Medical Center (hCoV-EMC)) was identified in patients with severe and sometimes lethal lower respiratory tract infection. Viral genome analysis revealed close relatedness to coronaviruses found in bats. Here we identify dipeptidyl peptidase 4 (DPP4; also known as CD26) as a functional receptor for hCoV-EMC. DPP4 specifically co-purified with the receptor-binding S1 domain of the hCoV-EMC spike protein from lysates of susceptible Huh-7 cells. Antibodies directed against DPP4 inhibited hCoV-EMC infection of primary human bronchial epithelial cells and Huh-7 cells. Expression of human and bat (Pipistrellus pipistrellus) DPP4 in non-susceptible COS-7 cells enabled infection by hCoV-EMC. The use of the evolutionarily conserved DPP4 protein from different species as a functional receptor provides clues about the host range potential of hCoV-EMC. In addition, it will contribute critically to our understanding of the pathogenesis and epidemiology of this emerging human coronavirus, and may facilitate the development of intervention strategies.

a new coronavirus emerged in China and caused an acute respiratory disease now known as coronavirus disease 2019 (COVID-19) (1). The virus was identified to be a betacoronavirus related to severe acute respiratory syndrome coronavirus (SARS-CoV) and thus was named SARS-CoV-2 (2). In <2 decades, this virus is the third known coronavirus to cross the species barrier and cause severe respiratory infections in humans after SARS-CoV in 2003 and Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012, yet with unprecedented spread compared with the earlier 2 viruses.Because of the rapid increase in number of cases and uncontrolled and vast spread worldwide, the World Health Organization has declared SARS-CoV-2 a pandemic. As of March 14, 2020, the virus had infected >130,000 persons in 122 countries, 3.7% of whom had died. (3). Rapid identification of the etiology and sharing of the genetic sequence of the virus, followed by international collaborative efforts initiated because of emergence of SARS-CoV-2, has led to rapid availability of real-time PCR diagnostic assays that support case ascertainment and tracking of the outbreak (4). Availability of these assays has helped in patient detection and efforts to contain the virus. However, validated serologic assays are still lacking and are urgently needed.Validated serologic assays are crucial for patient contact tracing, identifying the viral reservoir hosts, and epidemiologic studies. Epidemiologic studies are urgently needed to help uncover the burden of disease, in particular the rate of asymptomatic infections, and to get better estimates on illness and death. In ad-

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The spike (S) protein of the severe acute respiratory syndrome coronavirus (SARS-CoV) can be proteolytically activated by cathepsins B and L upon viral uptake into target cell endosomes. In contrast, it is largely unknown whether host cell proteases located in the secretory pathway of infected cells and/or on the surface of target cells can cleave SARS S. We along with others could previously show that the type II transmembrane protease TMPRSS2 activates the influenza virus hemagglutinin and the human metapneumovirus F protein by cleavage. Here, we assessed whether SARS S is proteolytically processed by TMPRSS2. Western blot analysis revealed that SARS S was cleaved into several fragments upon coexpression of TMPRSS2 (cis-cleavage) and upon contact between SARS S-expressing cells and TMPRSS2-positive cells (trans-cleavage). cis-cleavage resulted in release of SARS S fragments into the cellular supernatant and in inhibition of antibody-mediated neutralization, most likely because SARS S fragments function as antibody decoys. trans-cleavage activated SARS S on effector cells for fusion with target cells and allowed efficient SARS S-driven viral entry into targetstreated with a lysosomotropic agent or a cathepsin inhibitor. Finally, ACE2, the cellular receptor for SARSCoV, and TMPRSS2 were found to be coexpressed by type II pneumocytes, which represent important viral target cells, suggesting that SARS S is cleaved by TMPRSS2 in the lung of SARS-CoV-infected individuals. In summary, we show that TMPRSS2 might promote viral spread and pathogenesis by diminishing viral recognition by neutralizing antibodies and by activating SARS S for cell-cell and virus-cell fusion.

The emergence of a novel, highly pathogenic coronavirus, 2019-nCoV, in China, 24 and its rapid national and international spread pose a global health emergency. 25Coronaviruses use their spike proteins to select and enter target cells and insights into 26 nCoV-2019 spike (S)-driven entry might facilitate assessment of pandemic potential and 27 reveal therapeutic targets. Here, we demonstrate that 2019-nCoV-S uses the SARS-28 coronavirus receptor, ACE2, for entry and the cellular protease TMPRSS2 for 2019-nCoV-29 S priming. A TMPRSS2 inhibitor blocked entry and might constitute a treatment option. 30 Finally, we show that the serum form a convalescent SARS patient neutralized 2019-nCoV-31 S-driven entry. Our results reveal important commonalities between 2019-nCoV and 32 SARS-coronavirus infection, which might translate into similar transmissibility and disease 33 pathogenesis. Moreover, they identify a target for antiviral intervention.34 35 One sentence summary: The novel 2019 coronavirus and the SARS-coronavirus share central 36 biological properties which can guide risk assessment and intervention. 37 38 39 40 41 42 43 44 45 46 author/funder. All rights reserved. No reuse allowed without permission.

European Union, European Centre For Disease Prevention and Control, Deutsche Forschungsgemeinschaft.