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 a Malignant Lymphoma Patient Persistently Infected with SARS-CoV-2 for More than 6 Months

Coronavirus disease 2019 (COVID-19) is an emerging infectious disease caused by severe acute respiratory syndrome 2 (SARS-CoV-2). There are many unknowns regarding the handling of long-term SARS-CoV-2 infections in immunocompromised patients. Here, we describe the lethal disease course in a SARS-CoV-2-infected patient during Bruton’s tyrosine kinase inhibitor therapy. We performed whole-genome analysis using samples obtained during the course of the disease in a 63-year-old woman who was diagnosed with intraocular malignant lymphoma of the right eye in 2012. She had received treatment since the diagnosis. An autologous transplant was performed in 2020, but she experienced a worsening of the primary disease 26 days before she was diagnosed with a positive SARS-CoV-2 RT-PCR. Tirabrutinib was administered for the primary disease. A cluster of COVID-19 infections occurred in the hematological ward while the patient was hospitalized, and she became infected on day 0. During the course of the disease, she experienced repeated remission exacerbations of COVID-19 pneumonia and eventually died on day 204. SARS-CoV-2 whole-viral sequencing revealed that the patient shed the virus long-term. Viral infectivity studies confirmed infectious virus on day 189, suggesting that the patient might be still infectious. This case report describes the duration and viral genetic evaluation of a patient with malignant lymphoma who developed SARS-CoV-2 infection during Bruton’s tyrosine kinase inhibitor therapy and in whom the infection persisted for over 6 months

Invasive meningococcal disease due to a non-capsulated Neisseria meningitidis strain in a patient with IgG4-related disease

Abstract Background Invasive Meningococcal Disease (IMD) is a rare and critical disease in Japan. Most of these cases are caused by capsulated Neisseria meningitidis strains. Non-capsulated (non-typable) strains are considered relatively low-pathogenic and can colonize in the nasopharynx of healthy children and young adults. As far as could be ascertained, only twelve IMD cases due to non-capsulated strains have been reported in the literature. No clear risk factors could be identified in a literature review (unknown or immunocompetent, seven cases; C6 deficiency, three cases). Case presentation We report a Japanese male taxi driver with bacteremia and meningitis due to non-capsulated N. meningitidis. He had a fever and shaking chills. Ceftriaxone was administered, and the patient finally recovered. During the clinical course, relative adrenal insufficiency occurred and was treated with hydrocortisone. A hidden co-morbidity, immunoglobulin G4 (IgG4)-related disease, was revealed in the past surgical history (a resection of bilateral orbital tumors), which included symptoms (swelling lachrymal glands and lymph nodes), elevated IgG4, immunoglobulin E, and hypocomplementemia. He recovered finally and no recurrence was observed. Conclusions Our IMD case is the first reported in Japan, where IMD is not considered pandemic. The patient had a history of IgG4-related disease, although we could not establish a clear relationship between the patient’s IMD and co-morbidity. A collection of further clinical cases might establish the risk factors and characteristics of IMD that could be caused by this neglected pathogen, non-capsulated N. meningitidis

A Case of a Malignant Lymphoma Patient Persistently Infected with SARS-CoV-2 for More than 6 Months

Coronavirus disease 2019 (COVID-19) is an emerging infectious disease caused by severe acute respiratory syndrome 2 (SARS-CoV-2). There are many unknowns regarding the handling of long-term SARS-CoV-2 infections in immunocompromised patients. Here, we describe the lethal disease course in a SARS-CoV-2-infected patient during Bruton’s tyrosine kinase inhibitor therapy. We performed whole-genome analysis using samples obtained during the course of the disease in a 63-year-old woman who was diagnosed with intraocular malignant lymphoma of the right eye in 2012. She had received treatment since the diagnosis. An autologous transplant was performed in 2020, but she experienced a worsening of the primary disease 26 days before she was diagnosed with a positive SARS-CoV-2 RT-PCR. Tirabrutinib was administered for the primary disease. A cluster of COVID-19 infections occurred in the hematological ward while the patient was hospitalized, and she became infected on day 0. During the course of the disease, she experienced repeated remission exacerbations of COVID-19 pneumonia and eventually died on day 204. SARS-CoV-2 whole-viral sequencing revealed that the patient shed the virus long-term. Viral infectivity studies confirmed infectious virus on day 189, suggesting that the patient might be still infectious. This case report describes the duration and viral genetic evaluation of a patient with malignant lymphoma who developed SARS-CoV-2 infection during Bruton’s tyrosine kinase inhibitor therapy and in whom the infection persisted for over 6 months

Repetitive rebrightening of EG Cancri: evidence for viscosity decay in the quiescent disk?

SIGLEAvailable from: http://www.mpa-garching.mpg.de / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekDEGerman