Effect of inactivated Streptococcus pneumoniae as non-pathogenic particles on the severity of pneumonia caused by respiratory syncytial virus infection in mice

The severity of pneumonia in respiratory syncytial virus (RSV) infection is strongly related to hostimmune response and external factors such as bacteria and environmental chemicals. Weinvestigated the effect of inactivated Streptococcus pneumoniae (ISP) as non-pathogenic particleson the severity of pneumonia in RSV-infected mice. Mice were intranasally exposed to ISP beforeRSV infection. On day 5 post-infection, we examined the lung tissues, virus titer, and infiltratedcells in the lungs. The ISP did not cause significant histopathological effects on lungs of RSVinfectedmice and reduced virus titer in the lungs. It reduced the ratio of lymphocyte infiltrationinto the lungs and consequently the ratio of macrophage increased. In addition, we found that ISPincreased RANTES level in bronchoalveolar lavage fluid from RSV-infected mice on day 1 postinfection,but reduced type I interferon levels. Thus, ISP did not exacerbate pneumonia in RSVinfection; rather, it might mildly reduce the severity. We characterize and discuss the inherentactivity of ISP as non-pathogenic particles inducing the role of RANTES on the pneumonia in RSVinfection.九州保健福祉大学201

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

Enzymatic characteristics of d-mannose 2-epimerase, a new member of the acylglucosamine 2-epimerase superfamily

Carbohydrate epimerases and isomerases are essential for the metabolism and synthesis of carbohydrates. In this study, Runella slithyformis Runsl_4512 and Dyadobacter fermentans Dfer_5652 were characterized from a cluster of uncharacterized proteins of the acylglucosamine 2-epimerase (AGE) superfamily. These proteins catalyzed the intramolecular conversion of d-mannose to d-glucose, whereas they did not act on beta-(1 -> 4)-mannobiose, N-acetyl-d-glucosamine, and d-fructose, which are substrates of known AGE superfamily members. The k(cat)/K-m values of Runsl_4512 and Dfer_5652 for d-mannose epimerization were 3.89 and 3.51min(-1)mM(-1), respectively. Monitoring the Runsl_4512 reaction through H-1-NMR showed the formation of beta-d-glucose and beta-d-mannose from d-mannose and d-glucose, respectively. In the reaction with beta-d-glucose, beta-d-mannose was produced at the initial stage of the reaction, but not in the reaction with alpha-d-glucose. These results indicate that Runsl_4512 catalyzed the 2-epimerization of the beta-anomer substrate with a net retention of the anomeric configuration. Since H-2 was obviously detected at the 2-C position of d-mannose and d-glucose in the equilibrated reaction mixture produced by Runsl_4512 in (H2O)-H-2, this enzyme abstracts 2-H from the substrate and adds another proton to the intermediate. This mechanism is in accordance with the mechanism proposed for the reactions of other epimerases of the AGE superfamily, that is, AGE and cellobiose 2-epimerase. Upon reaction with 500g/L d-glucose at 50 degrees C and pH8.0, Runsl_4512 and Dfer_5652 produced d-mannose with a 24.4 and 22.8% yield, respectively. These d-mannose yields are higher than those of other enzyme systems, and ME acts as an efficient biocatalyst for producing d-mannose