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

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

The first discovery of the genus Narycia (Lepidoptera, Psychidae) from Japan, with description of a new species

A new species of the family Psychidae Narycia emikoae Niitsu, Jinbo & Nasu, sp. n. is described from Japan with illustrations of adults and genitalia, biological information, and DNA barcode data. The larvae feed on lichens on rocks. The discovery of the new species might help us to understand the Palaearctic biogeography of psychid moths

Morphology and Ontogeny of Wing Bud Development During Metamorphosis in Females of the Wingless Bagworm Moth Epichnopterix Plumella (Denis & Schiffermueller, 1775) (Psychidae)

Volume: 34Start Page: 103End Page: 11

Ecdysteroid-induced programmed cell death is essential for sex-specific wing degeneration of the wingless-female winter moth.

The winter moth, Nyssiodes lefuarius, has a unique life history in that adults appear during early spring after a long pupal diapause from summer to winter. The moth exhibits striking sexual dimorphism in wing form; males have functional wings of normal size, whereas females lack wings. We previously found that cell death of the pupal epithelium of females appears to display condensed chromatin within phagocytes. To provide additional detailed data for interpreting the role of cell death, we performed light microscopy, transmission electron microscopy, and TUNEL assay. We consequently detected two modes of cell death, i.e., dying cells showed both DNA fragmentation derived from epithelial nuclei and autophagic vacuole formation. To elucidate the switching mechanism of sex-specific wing degeneration in females of N. lefuarius, we tested the effects of the steroid hormone 20-hydroxyecdysone (20E) on pupal diapause termination and wing morphogenesis in both sexes. When 20E (5.4 µg) was injected into both sexes within 2 days of pupation, wing degeneration started 4 days after 20E injection in females, whereas wing morphogenesis and scale formation started 6 days after 20E injection in males. We discuss two important findings: (1) degeneration of the pupal wing epithelium of females was not only due to apoptosis and phagocytotic activation but also to autophagy and epithelial cell shrinkage; and (2) 20E terminated the summer diapause of pupae, and triggered selective programmed cell death only of the female-pupal wing epithelium in the wingless female winter moth

Developmental profiles of pupal wings in <i>Nyssiodes lefuarius</i>.

<p>Pupal wings of females (A–D) and males (E–H). (A–D) modified from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0089435#pone.0089435-Niitsu1" target="_blank">[12]</a>. In non-differentiation, the pattern of the pupal wing trachea in the female (A) is the same as that of the male (E) during the non-differentiation period. After differentiation, the pupal wing of females is degenerated. Note the significant pupal-wing degeneration on Day 3 (B), Day 4 (C) and Day 7 (D) after the beginning of pupal-adult development. By contrast, the pupal wing of males is formed normally on Day 10 (F) and Day 20 (G) after the beginning of pupal-adult development. (H) is just before adult eclosion. The arrow (A–D) points to the distal end of the degenerating wing of female. White arrowheads (F, G) indicate the position of the bordering lacuna (BL). Scale bar  = 1 mm.</p

TUNEL and DAPI staining of cross sections in pupal wings.

<p>TUNEL assays (green: A, C, E, G) and DAPI staining (cyan: B, D, F, H) of cross sections of female and male pupal wings. (A) Cross section of female pupal wing on Day 4 after the beginning of pupal-adult development. (C) Cross section of female pupal wing on Day 6 after injection of 5.4 µg 20E. (E) Cross section of male pupal wing on Day 7 after beginning of pupal-adult development. (G) Cross section of male pupal wing on Day 8 after injection of 5.4 µg 20E. Note that TUNEL signals (light green) indicated by white arrows were visible in areas of the female wing epithelium. Scale bar  = 50 µm.</p

Cross sections of the pupal wing epithelium induced by injection of 20E.

<p>The pupal-wing epithelium of females (A–D) and males (E–H). Pupal wing epithelium of females (A) and males (E) on Day 6 after injection of 6 µl ethanol. Pupal-wing epithelium of females on Day 6 (B), Day 8 (C) and Day 11 (D) after injection of 5.4 µg 20E. Phagocytes (white arrows) and apoptotic-body-like structures (black arrows) are visible (D). Pupal-wing epithelium of males on Day 6 (F), Day 8 (G) and Day 11 (H) after injection of 5.4 µg 20E. Scale is visible in the pupal epithelium (F, G, H). BL, basal lamina; P, phagocyte; S, scale; T, trachea; t, tracheole. Scale bar  = 20 µm.</p