The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force.

Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection.

DOCK2 is involved in the host genetics and biology of severe COVID-19.

Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge1-5. Here we conducted a genome-wide association study (GWAS) involving 2,393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3,289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target.

Quantitative evaluation of the inactivation effect of ozonated water on SARS-CoV-2 based on corrected CT values

There are many issues in the evaluation protocols based on CT (mg min/L) values, which have been used to assess the germicidal effect of highly oxidative and unstable ozonated water. The major problems include the carryover of culture medium components in virus inactivation assays and the reaction volume ratio between the virus suspension and ozonated water. Furthermore, it is essential to correct the CT value with the decay curve of dissolved ozone under the same conditions as the inactivation assay. In this study, these concerns were reexamined to obtain quantitative CT values. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) inactivation test using ozonated water prepared from pure water was assessed by determining the corrected concentration time (CCT) values. Moreover, a possible inactivation mechanism of SARS-CoV-2 was discussed with the aid of findings from this study and previous reports. The findings revealed that the CCT value required for 99.95% inactivation of SARS-CoV-2 with ozonated water was 0.97 mg·min/L. To quantitatively evaluate the SARS-CoV-2 inactivation test, the virus purification procedure during the pretreatment and the CT value correction using a dissolved ozone decay curve obtained under the same condition as the inactivation test were demonstrated to be essential.We proposed a possible mechanism of SARS-CoV-2 inactivation with ozonated water. Amino acids such as tyrosine, tryptophan, methionine, cysteine, and histidine in the SARS-CoV-2 spike protein are susceptible to oxidative attack by the ozone dissolved in water. This attack may induce structural destruction of the spike protein and inhibit its binding to the angiotensin converting enzyme 2 (ACE2) receptor, an essential host receptor for viral infection, resulting in viral inactivation and contributing to infection suppression. [ FROM AUTHOR] Copyright of Ozone: Science & Engineering is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)