Dengue virus (DENV) is a pathogen with a high impact on human health. It replicates in a wide range of cells involved in the immune response. To efficiently infect humans, DENV must evade or inhibit fundamental elements of the innate immune system, namely the type I interferon response. DENV circumvents the host immune response by expressing proteins that antagonize the cellular innate immunity. We have recently documented the inhibition of type I IFN production by the proteolytic activity of DENV NS2B3 protease complex in human monocyte derived dendritic cells (MDDCs). In the present report we identify the human adaptor molecule STING as a target of the NS2B3 protease complex. We characterize the mechanism of inhibition of type I IFN production in primary human MDDCs by this viral factor. Using different human and mouse primary cells lacking STING, we show enhanced DENV replication. Conversely, mutated versions of STING that cannot be cleaved by the DENV NS2B3 protease induced higher levels of type I IFN after infection with DENV. Additionally, we show that DENV NS2B3 is not able to degrade the mouse version of STING, a phenomenon that severely restricts the replication of DENV in mouse cells, suggesting that STING plays a key role in the inhibition of DENV infection and spread in mice.

The distribution of upper respiratory viral loads (VL) in asymptomatic children infected with SARS-CoV-2 is unknown. We assessed PCR cycle threshold (Ct) values and estimated VL in infected asymptomatic children diagnosed in nine pediatric hospital testing programs. Records for asymptomatic and symptomatic patients with positive clinical SARS-CoV-2 tests were reviewed. Ct values were adjusted by centering each value around the institutional median Ct value from symptomatic children tested with that assay, and converted to estimated VL (copies/mL) using internal or manufacturer data. Adjusted Ct values and estimated VL for asymptomatic versus symptomatic children (118 vs. 197 ages 0-4; 79 vs 97 ages 5-9; 69 vs 75 ages 10-13; 73 vs 109 ages 14-17) were compared. The median adjusted Ct value in asymptomatic children was 10.3 cycles higher than for symptomatic children (p< 0.0001), and VL 3-4 logs lower (p<0.0001); differences were consistent (p<0.0001) across all four age brackets. These differences were consistent across all institutions and by sex, ethnicity, and race. Asymptomatic children with diabetes (OR 6.5, p = 0.01), recent contact (OR 2.3, p = 0.02), and testing for surveillance (OR 2.7, p = 0.005) had higher estimated risk of having a Ct value in the lowest quartile than children without, while immunocompromise had no effect. Children with asymptomatic SARS-CoV-2 infection had lower levels of virus in the nasopharynx/oropharynx than symptomatic children, but timing of infection relative to diagnosis likely impacted levels in asymptomatic children. Caution is recommended when choosing diagnostic tests for screening of asymptomatic children.

Context: There are sparse patient-level data available for children with novel coronavirus disease (COVID-19). Therefore, there is an urgent need for an updated systematic literature review that analyzes individual children rather than aggregated data in broad age groups. Methods: Six databases (MEDLINE, Scopus, Web of Science, CINAHL, Google Scholar, medRxiv) were searched for studies indexed from January 1 to May 15, 2020 with MeSH terms: children, pediatrics, COVID-19, SARS-CoV-2. 1241 records were identified, of which only unique papers in English with individual patient information and documented COVID-19 testing were included. This review of 22 eligible studies followed Preferred Reporting Items for Systematic Review and Meta-Analyses of individual participant data guidelines. Results: 123 patients from five countries were identified. 46% were females. Median age was five years (IQR=8). At presentation, 62% had fever, 32% had cough, 58% had a single symptom and 21% were asymptomatic. Abnormal chest imaging was seen in 62% (65/105) of imaged and 76.9% (20/26) of asymptomatic children. A minority of children had elevated platelets, CRP, lactate dehydrogenase, and d-dimer. Conclusion: Data from this independent participant data systematic review revealed that the majority of children with COVID-19 presented with either no symptoms or a single, nonrespiratory symptom.