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

A case of allergic bronchopulmonary mycosis: 3D‐CT Findings led to successful multidisciplinary treatment with dupilumab and cryoprobe

Abstract The present case involved a 78‐year‐old woman with repeated recurrences of allergic bronchopulmonary mycosis (ABPM) who presented to our outpatient clinic with a chief complaint of dyspnoea with respiratory failure. Computed tomography (CT) of the chest showed atelectasis of the lower lobes due to mucus plugs. Blood and biochemical tests showed a high peripheral blood eosinophil count (1330/μL) and elevated immunoglobulin E (15,041 IU/mL; normal, < 361 IU/mL). Recurrent ABPM was diagnosed. The patient also showed chronic lower respiratory tract infection associated with Mycobacterium avium complex and Pseudomonas aeruginosa. First, we removed the mucus plug with a cryoprobe to avoid administering corticosteroids. However, subsequent 3‐dimensional CT showed residual mucus plugs, so we administered dupilumab as an additional treatment. After initiating dupilumab, mucus plugs disappeared and respiratory failure resolved. We were able to implement multidisciplinary treatment that did not rely on corticosteroids

2D resistivity model around the rupture area of the 2011 Tohoku-oki earthquake (Mw 9.0)

Abstract The 2011 Tohoku-oki earthquake (Mw 9.0) was characterized by a huge fault slip on the shallowest part of the plate interface, where fault behavior had been believed to be aseismic. In this study, we modeled the two-dimensional resistivity distribution across the slip area based on ocean-bottom electromagnetic measurements to understand the physical properties around the plate interface controlling fault rupture processes. The optimal 2D resistivity model showed a conductive area around the shallowest plate interface where the huge coseismic slip was observed, whereas the deeper plate interface where the fault rupture was nucleated was relatively more resistive. The shallowest plate interface was interpreted to have a high pore seawater fraction, whereas the deeper interface was interpreted as a dry area. These findings are consistent with the hypothesis that aseismic frictional conditions changed to conditions enhancing fault rupture when the rupture propagated to the wet, clay-rich shallowest plate area. The optimal resistivity model also revealed a conductive area under the outer-rise area of the Pacific Plate. This finding supports the existence of a hydrated oceanic crust that supplied aqueous water to the subduction zone, including to the huge fault slip area. Graphical Abstrac

Continuous Professional Oral Health Care Intervention Improves Severe Aspiration Pneumonia

Professional oral health care (POHC) is known to prevent aspiration pneumonia in patients with dysphagia and/or those at the perioperative stage of surgery. However, the effect of POHC on patients suffering from aspiration pneumonia remains unknown. Here, we report a case where continual POHC intervention improved severe aspiration pneumonia. A 74-year-old male patient with a brain infarction suffered from severe aspiration pneumonia (PSI: IV, A-DROP: 3) complicated by vascular dementia and severe dysphagia. Because an antimicrobial approach following the treatment guidelines for pneumonia was not effective, we started a POHC intervention to improve his poor oral condition at the request of the attending doctor and the patient’s family. The severe pneumonia markedly improved after continual POHC by the dental team. This case suggests that continual POHC intervention by a dental hygienist may improve severe aspiration pneumonia

Epipharyngeal Abrasive Therapy (EAT) Has Potential as a Novel Method for Long COVID Treatment

COVID-19 often causes sequelae after initial recovery, referred to collectively as long COVID. Long COVID is considered to be caused by the persistence of chronic inflammation after acute COVID-19 infection. We found that all long COVID patients had residual inflammation in the epipharynx, an important site of coronavirus replication, and some long COVID symptoms are similar to those associated with chronic epipharyngitis. Epipharyngeal abrasive therapy (EAT) is a treatment for chronic epipharyngitis in Japan that involves applying zinc chloride as an anti-inflammatory agent to the epipharyngeal mucosa. In this study, we evaluated the efficacy of EAT for the treatment of long COVID. The subjects in this study were 58 patients with long COVID who were treated with EAT in the outpatient department once a week for one month (mean age = 38.4 ± 12.9 years). The intensities of fatigue, headache, and attention disorder, which are reported as frequent symptoms of long COVID, were assessed before and after EAT using the visual analog scale (VAS). EAT reduced inflammation in the epipharynx and significantly improved the intensity of fatigue, headache, and attention disorder, which may be related to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). These results suggest that EAT has potential as a novel method for long COVID treatment