The Src-ZNRF1 axis controls TLR3 trafficking and interferon responses to limit lung barrier damage.

Type I interferons are important antiviral cytokines, but prolonged interferon production is detrimental to the host. The TLR3-driven immune response is crucial for mammalian antiviral immunity, and its intracellular localization determines induction of type I interferons; however, the mechanism terminating TLR3 signaling remains obscure. Here, we show that the E3 ubiquitin ligase ZNRF1 controls TLR3 sorting into multivesicular bodies/lysosomes to terminate signaling and type I interferon production. Mechanistically, c-Src kinase activated by TLR3 engagement phosphorylates ZNRF1 at tyrosine 103, which mediates K63-linked ubiquitination of TLR3 at lysine 813 and promotes TLR3 lysosomal trafficking and degradation. ZNRF1-deficient mice and cells are resistant to infection by encephalomyocarditis virus and SARS-CoV-2 because of enhanced type I interferon production. However, Znrf1-/- mice have exacerbated lung barrier damage triggered by antiviral immunity, leading to enhanced susceptibility to respiratory bacterial superinfections. Our study highlights the c-Src-ZNRF1 axis as a negative feedback mechanism controlling TLR3 trafficking and the termination of TLR3 signaling.

Seroprevalence of anti-SARS-CoV-2 IgG antibodies in the staff of a public school system in the midwestern United States.

Since March 2020, the United States has lost over 580,000 lives to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes COVID-19. A growing body of literature describes population-level SARS-CoV-2 exposure, but studies of antibody seroprevalence within school systems are critically lacking, hampering evidence-based discussions on school reopenings. The Lake Central School Corporation (LCSC), a public school system in suburban Indiana, USA, assessed SARS-CoV-2 seroprevalence in its staff and identified correlations between seropositivity and subjective histories and demographics. This study is a cross-sectional, population-based analysis of the seroprevalence of SARS-CoV-2 in LCSC staff measured in July 2020. We tested for seroprevalence with the Abbott Alinity™ SARS-CoV-2 IgG antibody test. The primary outcome was the total seroprevalence of SARS-CoV-2, and secondary outcomes included trends of antibody presence in relation to baseline attributes. 753 participants representative of the staff at large were enrolled. 22 participants (2.9%, 95% CI: 1.8% - 4.4%) tested positive for SARS-CoV-2 antibodies. Correcting for test performance parameters, the seroprevalence is estimated at 1.7% (90% Credible Interval: 0.27% - 3.3%). Multivariable logistic regression including mask wearing, travel history, symptom history, and contact history revealed a 48-fold increase in the odds of seropositivity if an individual previously tested positive for COVID-19 (OR: 48, 95% CI: 4-600). Amongst individuals with no previous positive test, exposure to a person diagnosed with COVID-19 increased the odds of seropositivity by 7-fold (OR: 7.2, 95% CI: 2.6-19). Assuming the presence of antibodies is associated with immunity against SARS-CoV-2 infection, these results demonstrate a broad lack of herd immunity amongst the school corporation's staff irrespective of employment role or location. Protective measures like contact tracing, face coverings, and social distancing are therefore vital to maintaining the safety of both students and staff as the school year progresses.

Dysregulated transcriptional responses to SARS-CoV-2 in the periphery.

SARS-CoV-2 infection has been shown to trigger a wide spectrum of immune responses and clinical manifestations in human hosts. Here, we sought to elucidate novel aspects of the host response to SARS-CoV-2 infection through RNA sequencing of peripheral blood samples from 46 subjects with COVID-19 and directly comparing them to subjects with seasonal coronavirus, influenza, bacterial pneumonia, and healthy controls. Early SARS-CoV-2 infection triggers a powerful transcriptomic response in peripheral blood with conserved components that are heavily interferon-driven but also marked by indicators of early B-cell activation and antibody production. Interferon responses during SARS-CoV-2 infection demonstrate unique patterns of dysregulated expression compared to other infectious and healthy states. Heterogeneous activation of coagulation and fibrinolytic pathways are present in early COVID-19, as are IL1 and JAK/STAT signaling pathways, which persist into late disease. Classifiers based on differentially expressed genes accurately distinguished SARS-CoV-2 infection from other acute illnesses (auROC 0.95 [95% CI 0.92-0.98]). The transcriptome in peripheral blood reveals both diverse and conserved components of the immune response in COVID-19 and provides for potential biomarker-based approaches to diagnosis.

Seroprevalence of anti-SARS-CoV-2 IgG Antibodies in the Staff of a Public School System in the Midwestern United States.

BACKGROUND: Since March 2020, the United States has lost over 200,000 lives to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes COVID-19. A growing body of literature describes population-level SARS-CoV-2 exposure, but studies of antibody seroprevalence within school systems are critically lacking, hampering evidence-based discussions on school reopenings. The Lake Central School Corporation (LCSC), a public school system in suburban Indiana, USA, assessed SARS-CoV-2 seroprevalence in its staff and identified correlations between seropositivity and subjective histories and demographics. METHODS: This study is a cross-sectional, population-based analysis of the seroprevalence of SARS-CoV-2 in LCSC staff measured in July 2020. We tested for seroprevalence with the Abbott Alinity™ SARS-CoV-2 IgG antibody test. The primary outcome was the total seroprevalence of SARS-CoV-2, and secondary outcomes included trends of antibody presence in relation to baseline attributes. FINDINGS: 753 participants representative of the staff at large were enrolled. 22 participants (2·9%, 95% CI: 1·8% - 4·4%) tested positive for SARS-CoV-2 antibodies. Correcting for test performance parameters, the seroprevalence is estimated at 1·7% (90% Credible Interval: 0·27% - 3·3%). Multivariable logistic regression including mask wearing, travel history, symptom history, and contact history revealed a 48-fold increase in the odds of seropositivity if an individual previously tested positive for COVID-19 (OR: 48.2, 95% CI: 4 - 600). Amongst individuals with no previous positive test, exposure to a person diagnosed with COVID-19 increased the odds of seropositivity by 7-fold (OR: 6.5, 95% CI: 2.06 - 18.9). INTERPRETATION: Assuming the presence of antibodies is associated with immunity against SARS-CoV-2 infection, these results demonstrate a broad lack of herd immunity amongst the school corporation's staff irrespective of employment role or location. Protective measures like contact tracing face coverings, and social distancing are therefore vital to maintaining the safety of both students and staff as the school year progresses. FUNDING: Lake Central School Corporation. RESEARCH IN CONTEXT: Evidence before this study: We searched PubMed, SSRN, Research Square, and Gale Power Search for peer-reviewed articles, preprints, and research reports on the seroprevalence of anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) IgG antibodies, published in English, using the search terms "COVID-19 in schools," "COVID-19 seroprevalence," "COVID antibodies," and similar terms up to August 30, 2020. We identified several articles pertaining to the spread of COVID-19 within schools and among children. Current evidence on the pediatric transmission of COVID-19 is mixed, but early data on secondary school transmission are sobering. Shared among this literature was an acknowledgement of the paucity of data regarding how the pandemic may progress in the students and staff of primary and secondary education systems. To our knowledge, there is no study that specifically interrogates the seroprevalence of COVID-19 among US public school staff.Added value of this study: As of September 2020, the United States has had more COVID-19 cases than any other country. With many US schools opening for in-person classes for the 2020-2021 school year, a granular understanding of the transmission dynamics within public school systems is vital to effectively and appropriately defending against COVID-19. Most seroprevalence studies have been based on city or hospital-level populations; this study establishes a baseline seroprevalence of SARS-CoV-2 antibodies in a Midwest public school district prior to the initiation of the school year.Implications of all available evidence: The results of this study reveal that the majority (98·3%) of LCSC staff have not been exposed to COVID-19 prior to the start of the school year. Staff are therefore vulnerable to a large outbreak after the school opens, underscoring the importance of maintaining rigorous sanitary practices within the schools. It is vital that all members of LCSC and similar school districts across the country continue social distancing and mask wearing throughout the school day to limit exposure to COVID-19. Contact tracing in combination with rapid testing for individuals exposed to an individual with COVID-19 should also be employed.