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

Modification of Xyloglucan Metabolism during a Decrease in Cell Wall Extensibility in 1-Aminocyclopropane-1-Carboxylic Acid-Treated Azuki Bean Epicotyls

The exogenous application of ethylene or 1-aminocyclopropane-1-carboxylic acid (ACC), the biosynthetic precursor for ethylene, to plants decreases the capacity of the cell wall to extend, thereby inhibiting stem elongation. In this study, the mechanism by which the extensibility of cell walls decreases in ACC-treated azuki bean epicotyls was studied. ACC decreased the total extensibility of cell walls, and such a decrease was due to the decrease in irreversible extensibility. ACC increased the molecular mass of xyloglucans but decreased the activity of xyloglucan-degrading enzymes. The expression of VaXTHS4, which only exhibits hydrolase activity toward xyloglucans, was downregulated by ACC treatment, whereas that of VaXTH1 or VaXTH2, which exhibits only transglucosylase activity toward xyloglucans, was not affected by ACC treatment. The suppression of xyloglucan-degrading activity by downregulating VaXTHS4 expression may be responsible for the increase in the molecular mass of xyloglucan. Our results suggest that the modification of xyloglucan metabolism is necessary to decrease cell wall extensibility, thereby inhibiting the elongation growth of epicotyls in ACC-treated azuki bean seedlings

Modification of Xyloglucan Metabolism during a Decrease in Cell Wall Extensibility in 1-Aminocyclopropane-1-Carboxylic Acid-Treated Azuki Bean Epicotyls

Plants. 2023, 12 (2), P.36

Clinical characteristics and prognostic factors of pneumonia in patients with and without rheumatoid arthritis.

BACKGROUND:To elucidate the characteristics of pneumonia in rheumatoid arthritis (RA) patients and to assess whether pneumonia in RA patients differs from that in non-RA patients. METHODS:We retrospectively divided pneumonia patients into two groups, those with RA and those without RA, and compared the two groups. We evaluated the risk factors for mortality with univariate and multivariate logistic regression analysis. RESULTS:Among 1549 patients, 71 had RA. The RA patients with pneumonia were 71.0±8.9 years old, 54.9% were female, 40.9% had a smoking history, and 71.8% had underlying respiratory disease. Female sex, non-smoker, and respiratory comorbidities were statistically more frequent in the RA patients than non-RA patients. The most frequent causative microbial agents of pneumonia in the RA patients were Streptococcus pneumoniae, Pseudomonas aeruginosa, Haemophilus influenzae, Mycoplasma pneumoniae, and influenza virus, whereas those of pneumonia in non-RA patients were S. pneumoniae, influenza virus, M. pneumoniae, Legionella spp., P. aeruginosa, H. influenzae, and Moraxella catarrhalis. Polymicrobial infection were identified as etiologies more frequently in the RA patients than non-RA patients. Although the severity of pneumonia did not differ between the two groups, mortality was statistically higher in the RA patients than non-RA patients. Multivariate analysis showed RA to be an independent risk factor for mortality. CONCLUSIONS:P. aeruginosa, H. influenzae, M. catarrhalis, and polymicrobial infection were statistically more frequent etiologies of pneumonia in the RA patients than non-RA patients. RA itself was found to be an independent risk factor for mortality from pneumonia