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

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.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

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. 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

川崎医科大学におけるブース形式診療科別説明会の学内開催

川崎医科大学は,中核市の倉敷市内と政令指定都市の岡山市内に二つの附属病院を有している。両病院の卒後臨床研修プログラムは独立しているが,研修は両方の病院の診療科から選択することが可能である。平成27年7月,初めて川崎医科大学生を対象にした大学附属病院診療科の説明会をブース形式で学内開催した。研修プログラム説明会とは趣を異にし,各診療科の特徴や業務内容を広報することを目的とした。1年生から6年生までの学生が参加し,アンケート調査に回答した52名全員が将来の研修病院の選択に役に立ったと答え,うち27%は非常に役立ったと高い満足度を示した。また,研修医だけで計画した学生向けのミニシンポジウムも同時に開催し,来場した約70%の学生が参加し貴重な情報収集の場となった。次年度以降も改善を加えながら,学生が身近に附属病院スタッフや先輩研修医と交流できるイベントとして育てていきたい。Kawasaki Medical School has one hospital in Kurashiki City, a core city, and another in Okayama City, an ordinance-designated city. These hospitals have independent postgraduate clinical training programs. However, departments of both hospitals can be selected for training. In July 2015, a boothtype meeting regarding Kawasaki Medical School Hospital departments was held for Kawasaki Medical School students for the first time. The intent of the meeting differed from that of other training program meetings, and its goal was to provide information on the characteristics and tasks of each department. First- to sixth-year students participated in the meeting. All 52 students who responded to a questionnaire survey answered that the meeting was useful in helping them select a hospital for their future training, and 27% of them reported that the meeting was very useful and showed high levels of satisfaction. A mini symposium for students planned only by residents was also held at the same time. About 70% of visiting students participated in the symposium and were given a valuable opportunity to gather information. By making improvements, we will cultivate the meeting as an event in which students can have contact with hospital staff and junior residents from the next year

Commensal Bacteria-Dependent Indole Production Enhances Epithelial Barrier Function in the Colon

<div><p>Microbiota have been shown to have a great influence on functions of intestinal epithelial cells (ECs). The role of indole as a quorum-sensing (QS) molecule mediating intercellular signals in bacteria has been well appreciated. However, it remains unknown whether indole has beneficial effects on maintaining intestinal barriers <i>in vivo</i>. In this study, we analyzed the effect of indole on ECs using a germ free (GF) mouse model. GF mice showed decreased expression of junctional complex molecules in colonic ECs. The feces of specific pathogen-free (SPF) mice contained a high amount of indole; however the amount was significantly decreased in the feces of GF mice by 27-fold. Oral administration of indole-containing capsules resulted in increased expression of both tight junction (TJ)- and adherens junction (AJ)-associated molecules in colonic ECs in GF mice. In accordance with the increased expression of these junctional complex molecules, GF mice given indole-containing capsules showed higher resistance to dextran sodium sulfate (DSS)-induced colitis. A similar protective effect of indole on DSS-induced epithelial damage was also observed in mice bred in SPF conditions. These findings highlight the beneficial role of indole in establishing an epithelial barrier <i>in vivo</i>.</p></div

Indole-containing capsules show preventative effect on colitis development in SPF mice.

<p>SPF mice were treated with indole- (n = 7) or MCT- (n = 7) containing capsules for 1 week, and then challenged by 5% DSS for 6 days. Body weight changes relative to the value prior to colitis induction are shown. Data are representative of two independent experiments and mean ± S.E.M of 7 mice at each time point is shown. *P<0.05. MCT, Medium-Chain Triglycerides.</p