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

Driving Behavior during Takeover Request of Autonomous Vehicle: Effect of Driver Postures

We investigated the effect of driver posture on driving control following a takeover request (TOR) from autonomous to manual driving in level 3 autonomous vehicles. When providing a TOR, driving behaviors need to be investigated to develop driver monitoring systems, and it is important to clarify the effect of driver postures. Experiments were conducted using driver postures that are likely to be adopted in autonomous driving. Driver postures were set based on combinations of two types of upper-body posture and three types of foot posture. The driver’s upper body and head were set to either a forward or sideways orientation. For each of these there were three types of foot posture: both feet on the floor, crossed legs, and cross-legged sitting. Following a TOR, we compared the braking and steering maneuvers of subjects driving normally and examined the effects of posture on driver reaction time. The results show that both the upper-body and foot postures of the driver affect the steering and braking reaction time. The driver monitoring system should be able to detect posture and activate a TOR warning, and detection times up to 2 and 1.3 times faster than those for normal postures should be considered for different upper-body and foot postures, respectively

Implications for Social Support on Prolonged Sleep Difficulties among a Disaster-Affected Population: Second Report from a Cross-Sectional Survey in Ishinomaki, Japan.

This study aimed to investigate the role of social factors, especially social support for sleep, among victims living at home around 1-2 years after the Great East Japan Earthquake and tsunami.A cross-sectional household survey was conducted between May and December 2012 (14-21 months after the disaster) in the Ishinomaki area, Japan. Univariate and multivariate logistic regression models were used to examine the association between social factors, including social support, and prolonged sleep difficulties (persisting over 1 month). Social support was divided into three functions: emotional, informational, and instrumental support.Data were obtained on 2,593 individuals who were living at home after the disaster.The prevalence of prolonged sleep difficulties was 6.9% (5.8% male, 7.7% female). This study showed that lack of social support has a stronger association with prolonged sleep difficulties than non-modifiable or hardly modifiable consequences caused directly by the disaster, i.e., severity of home damage, change in family structure and income. Among the three dimensions of social support, lack of emotional support showed the strongest association with prolonged sleep difficulties.Social support, especially emotional support, may positively affect sleep among victims living at home around 1-2 years after a disaster

Role of Interleukin-6 in the Antigen-Specific Mucosal Immunoglobulin A Responses Induced by CpG Oligodeoxynucleotide-Loaded Cationic Liposomes

An advantage of mucosal vaccines over conventional parenteral vaccines is that they can induce protective immune responses not only at mucosal surfaces but also in systemic compartments. Despite this advantage, few live attenuated or inactivated mucosal vaccines have been developed and applied clinically. We recently showed that the intranasal immunization of ovalbumin (OVA) with class B synthetic oligodeoxynucleotides (ODNs) containing immunostimulatory CpG motif (CpG ODN)-loaded cationic liposomes synergistically exerted both antigen-specific mucosal immunoglobulin A (IgA) and systemic immunoglobulin G (IgG) responses in mice. However, the mechanism underlying the mucosal adjuvant activity of CpG ODN-loaded liposomes remains unknown. In the present study, we showed that the intranasal administration of CpG ODN-loaded cationic liposomes elicited interleukin (IL)-6 release in nasal tissues. Additionally, pre-treatment with an anti-IL-6 receptor (IL-6R) antibody attenuated antigen-specific nasal IgA production but not serum IgG responses. Furthermore, the intranasal administration of OVA and CpG ODN-loaded cationic liposomes increased the number of IgA+/CD138+ plasma cells and IgA+/B220+ B cells in the nasal passages. This increase was markedly suppressed by pre-treatment with anti-IL-6R blocking antibody. In conclusion, IL-6 released by CpG ODN-loaded cationic liposomes at the site of administration may play a role in the induction of antigen-specific IgA responses by promoting differentiation into IgA+ plasma cells for IgA secretion from B cells

Characterization of tick-borne encephalitis virus isolated from a tick in central Hokkaido in 2017

Tick-borne encephalitis virus (TBEV) is a zoonotic virus in the genus Flavivirus, family Flaviviridae. TBEV is widely distributed in northern regions of the Eurasian continent, including Japan, and causes severe encephalitis in humans. Tick-borne encephalitis (TBE) was recently reported in central Hokkaido, and wild animals with anti-TBEV antibodies were detected over a wide area of Hokkaido, although TBEV was only isolated in southern Hokkaido. In this study, we conducted a survey of ticks to isolate TBEV in central Hokkaido. One strain, designated Sapporo-17-Io1, was isolated from ticks (Ixodes ovatus) collected in Sapporo city. Sequence analysis revealed that the isolated strain belonged to the Far Eastern subtype of TBEV and was classified in a different subcluster from Oshima 5-10, which had previously been isolated in southern Hokkaido. Sapporo-17-Io1 showed similar growth properties to those of Oshima 5-10 in cultured cells and mouse brains. The mortality rate of mice infected intracerebrally with each virus was similar, but the survival time of mice inoculated with Sapporo-17-Io1 was significantly longer than that of mice inoculated with Oshima 5-10. These results indicate that the neurovirulence of Sapporo-17-Io1 was lower than that of Oshima 5-10. Using an infectious cDNA clone, the replacement of genes encoding non-structural genes from Oshima 5-10 with those from Sapporo-17-Io1 attenuated the neuropathogenicity of the cloned viruses. This result indicated that the non-structural proteins determine the neurovirulence of these two strains. Our results provide important insights for evaluating epidemiological risk in TBE-endemic areas of Hokkaido

Flow diagram of study participants in the analyses.

<p>Flow diagram of study participants in the analyses.</p

Logistic regression results: odds ratios of prolonged sleep difficulties and 95% confidence intervals.

<p>95%CI, 95% confidence interval; OR, odds ratio</p><p>^a Model 1, univariate model</p><p>^b Model 2, multivariate model in which social support was rated dichotomously (having any social support or not)</p><p>^c Model 3, multivariate model in which social support was categorized into three dimensions</p><p>^d The odds ratio reflects the change in the odds of sleep difficulties per 10-year increase in age.</p><p>^e “Other” includes public livelihood assistance, unemployment allowance, and no regular income</p><p>Logistic regression results: odds ratios of prolonged sleep difficulties and 95% confidence intervals.</p