Interindividual clinical variability in the course of SARS-CoV-2 infection is immense. We report that at least 101 of 987 patients with life-threatening COVID-19 pneumonia had neutralizing IgG auto-Abs against IFN-ω (13 patients), the 13 types of IFN-α (36), or both (52), at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1,227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 were men. A B cell auto-immune phenocopy of inborn errors of type I IFN immunity underlies life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men.

Abstract. Integrin receptors play important roles in or-ganizing the actin-containing cytoskeleton and in signal transduction from the extracellular matrix. The initial steps in integrin function can be analyzed experimentally using beads coated with ligands or anti-integrin antibodies to trigger rapid focal transmembrane responses. A hierarchy of transmembrane actions was identified in this study. Simple integrin aggregation triggered localized transmembrane accumulation of 20 signal transduction molecules, including RhoA, Racl, Ras, Raf, MEK, ERK, and JNK. In contrast, out of eight cytoskeletal molecules tested, only tensin coaccumulated. Integrin aggregation alone was also sufficient to induce rapid activation of the JNK pathway, with kinetics of activation different from those of ERK. The tyrosine kinase inhibitors herbimycin A or genistein blocked both the accumulation of 19 out of 20 signal transduction molecules and JNK-and ERK-mediated signaling. Cytochalasin D had identical effects, whereas three other tyrosine kinase inhibitors did not. The sole exception among signaling molecules was the kinase pp125 FAK which continued to coaggregate with a5131 integrins even in the presence of these inhibitors. Tyrosine kinase inhibition also failed to block the ability of ligand occupancy plus integrin aggregation to trigger transmembrane accumulation of the three cytoskeletal molecules talin, et-actinin, and vinculin; these molecules accumulated even in the presence of cytochalasin D. However, it was necessary to fulfill all four conditions, i.e., integrin aggregation, integrin occupancy, tyrosine kinase activity, and actin cytoskeletal integrity, to achieve integrin-mediated focal accumulation of other cytoskeletal molecules including F-actin and paxillin. Integrins therefore mediate a transmembrane hierarchy of molecular responses.I NTEGRIN receptors for extracellular matrix molecules play central and complex roles in cell interactions. They mediate cell adhesion, migration, and invasion, but they also have a multitude of intracellular effects on the organization of the actin-containing cytoskeleton as well as roles in a variety of signaling processes (for reviews see Hynes, 1992;Sastry and Horwitz, 1993;Juliano and Haskill, 1993;Gumbiner, 1993;Pavalko and Otey, 1994;Schaller and Parsons, 1994;Shattil et al., 1994a;Clark and Brugge, 1995). A complex series of steps leads from initial integrin interactions with an extracellular ligand to transmembrane effects on the localization of cytoskeletal molecules or signaling molecules, to the activation of signaling pathways, and to eventual regulation of gene expression. Identifying distinct mechanisms of integrin responses to extracellular stimuli and patterns in the classes of responding molecules will be crucial for understanding how integrins function.

ARS-CoV-2 is the causal agent for COVID-19, and the World Health Organization classifies this virus as an airborne pathogen transmitted by asymptomatic, pre-symptomatic and symptomatic individuals through close contact via exposure to infected droplets and aerosols 1,2 . Although SARS-CoV-2 transmission can occur by activities involving the oral cavity, such as speaking, breathing, coughing, sneezing and even singing [3][4][5] , most attention has focused on the nasal-lung axis of infection 6 . Oral manifestations, such as taste loss, dry mouth and oral lesions, are evident in about half of COVID-19 cases [7][8][9] , although it remains unknown whether SARS-CoV-2 can directly infect and replicate in oral tissues, such as the salivary glands (SGs) or mucosa. This is critical because, if these are sites of early infection, they could play an important role in transmitting the virus to the lungs or the gastrointestinal tract via saliva, as has been suggested for other microbial-associated diseases, such as pneumonia 10 and inflammatory bowel diseases 11,12 (Extended Data Fig. 1a).SARS-CoV-2 uses host entry factors, such as ACE2 and TMPRSS family members (TMPRSS2 and TMPRSS4) 13,14 , and understanding the cell types that harbor these receptors is important for determining infection susceptibilities throughout the body [15][16][17] . ACE2 and TMPRSS2 expression has been reported in oral tissues 18,19 ; however, there are no comprehensive descriptions of viral entry factor expression nor direct confirmation of SARS-CoV-2 infection in oral tissues. We hypothesized that SGs and barrier epithelia of the oral cavity and oropharynx can be infected by SARS-CoV-2 and contribute to the transmission of SARS-CoV-2. To test this, we generated two human oral single-cell RNA sequencing (scRNA-seq) atlases to predict cell-specific susceptibilities to SARS-CoV-2 infection. We confirmed ACE2 and TMPRSS expression in SGs and oral mucosa epithelia. SARS-CoV-2 infection was confirmed using autopsy and outpatient samples. Saliva from asymptomatic individuals with COVID-19 demonstrated the potential for viral transmission. In a prospective clinical cohort, we found a positive correlation between salivary viral load and taste loss; we also demonstrated persistent salivary antibody responses to SARS-CoV-2 nucleocapsid and spike proteins. ResultsOral tissue atlases reveal resident immune cells and niche-specific epithelial diversity. The SGs and the barrier mucosa of the oral cavity and oropharynx are likely gateways for viral infection, replication SARS-CoV-2 infection of the oral cavity and saliva