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

Nutritional intake of Aplanochytrium (Labyrinthulea, Stramenopiles) from living diatoms revealed by culture experiments suggesting the new prey-predator interactions in the grazing food web of the marine ecosystem.

Labyrinthuleans (Labyrinthulea, Stramenopiles) are recognized as decomposers in marine ecosystems but their nutrient sources are not fully understood. We conducted two-membered culture experiments with labyrinthuleans and diatoms to discover where labyrinthuleans obtain their nutrients from. The results showed that Aplanochytrium strains obtained nutrients by consuming living diatoms. Aplanochytrium cells did not release digestive enzymes into the medium, but adhered to diatom cells via the tip of their characteristic ectoplasmic net system to obtain nutrients from them. The chloroplast and cell contents of the diatoms shrank and were absorbed, and then the number of Aplanochytrium cells rapidly increased as multiple aplanospores were released. To estimate the effect of labyrinthulean organisms including Aplanochytrium on marine ecosystem, we explored the dataset generated by the Tara Oceans Project from a wide range of oceanic regions. The average proportion of all labyrinthulean sequences to diatom sequences at each station was about 10%, and labyrinthulids, oblongichytrids, and aplanochytrids were the major constituent genera, accounting for more than 80% of labyrinthuleans. Therefore, these groups are suggested to greatly affect the marine ecosystem. There were positive correlations between aplanochytrids and phototrophs, green algae, and diatoms. At many stations, relatively large proportions of aplanochytrid sequences were detected in the size fraction larger than their cell size. This implied that Aplanochytrium cells increased their particle size by adhering to each other and forming aggregates with diatoms that are captured by larger zooplankton in the environment, thereby bypassing the food web pathway via aplanochytrids to higher predators. The intake of nutrients from diatoms by aplanochytrids represents a newly recognized pathway in the grazing food chain in the marine ecosystem

海洋環境におけるラビリンチュラ類の生態学的役割とその影響に関する研究

　原生生物ラビリンチュラ類は，分解酵素を分泌すること，陸源有機物が豊富な河口域に多く生息することなどから，分解者として認識されてきた。また，沿岸域から外洋，熱帯から極域，表層から深海まで，あらゆる海洋環境中に分布していることが知られているが，具体的な栄養源や生態学的な影響力については，明らかになっていなかった。そこで本研究では，まず，海洋の一次生産者である植物プランクトンのうち，特に大きなバイオマスをもつ珪藻類を栄養摂取の対象としている可能性について検討した。系統的に多様なラビリンチュラ類と珪藻の二員培養を行った結果，Aplanochytrium類は外質ネットで生きている珪藻に付着し，積極的に栄養摂取する様子が観察され，未認識の生食連鎖が存在することが明らかとなった。また，栄養摂取の過程でAplanochytrium類は珪藻と集合体を形成し，動物プランクトンが捕食できる大きさとなり得るため，食物網の中で効率よくエネルギー転送をしていることが予想された。次に，定量PCR法によって大阪湾に生息するAplano¬chytrium類の細胞密度を，季節ごとに測定した結果，1年間の平均は湾奥で13,000 cells/L，湾央で2,100 cells/Lであった。さらに，これらの値から炭素に換算した単位面積あたりの年間生産量を試算し，瀬戸内海で示されている炭素循環に適用することで，Aplano¬chytrium類を介する経路の影響力を評価した。その結果，真核生物に消費される植物プランクトンのうち，湾奥では19.0%，湾央では6.1%をAplano¬chytrium類が消費していること，また動物プランクトンが消費する炭素のうち，湾奥では12.6%，湾央では3.6%をAplanochytrium類が供給していると推定され，その生態学的な影響力は１属の生物として大きいことが示された。さらに，環境DNAに対する18S rDNAの網羅的解読によるラビリンチュラ類の群集構造解析では，ラビリンチュラ類全体に対するAplanochytrium類と同定された配列の割合は，大阪湾では約70%を占め，全球的な環境DNAのデータベースでも，20%を超えており，環境中の主要な系統群であることが示された。以上の結果から，これまで分解者としてひとまとめに認識されてきたラビリンチュラ類には，消費者としての役割をもつものが存在し，海洋生態系に大きな影響を与えていることが示唆された。甲南大学平成30年度(2018年度