SARS-CoV-2 と COVID-19 に関する備忘録 Vol.15――感染したことのある人はできるだけ車の運転を控えた方がいい、一度に複数株に感染して感染中に別の変異株に感染して途中でさらに変異する＝変異株単位で注目するやり方では現実を追えない…etc.

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SARS-CoV-2 と COVID-19 に関するメモ・備忘録


◆Did “long COVID” increase road deaths in the U.S.?【medRxiv　2023年10月11日】

Abstract

Objective To examine data on COVID-19 disease associated with a 10 percent increase in U.S. road deaths from 2020 to 2021 that raises the question of the potential effect of pandemic stress and neurological damage from COVID-19 disease.

Methods Poisson regression was used to estimate the association of recent COVID-19 cases, accumulated cases, maximum temperatures, truck registrations, and gasoline prices with road deaths monthly among U.S. states in 2021. Using the regression coefficients, changes in each risk factor from 2020 to 2021 were used to calculate expected deaths in 2021 if each factor had remained the same as in 2020.

Results Corrected for the other risk factors, road deaths were associated with accumulated COVID-19 cases but not cases in the previous month. More than 20,700 road deaths were associated with the changes in accumulated COVID-19 cases but were substantially offset by about 19,100 less-than-expected deaths associated with increased gasoline prices.

Conclusions While more research is needed, the data are sufficient to warn people with “long COVID” to minimize road use.

What is already known about this topic Previous short-term fluctuations in road deaths are related to changes in temperature, fuel prices, and truck registrations.

What this study adds Corrected for other risk factors, the monthly changes in road deaths from 2020 to 2021 in U.S. states were associated with cumulative COVID-19 cases.

How this study might affect research, practice, or policy Studies are needed to distinguish the potential relative effects of neurological damage as well as the stress of coping with the pandemic on driving, walking, and bicyclist behavior. Warning people with “long covid” about road risk is warranted.

Introduction

While many countries experienced a reduction in road deaths during the first year of the COVID-19 pandemic, deaths increased 6.9 percent from 2019 to 2020 in the U.S. In 2021 road deaths in the U.S. increased 10.5 percent above those experienced in 2020. Analysis of the 2020 increase among U.S. states found most of it correlated to changes in temperatures, truck registrations, and fuel prices. The increase month by month was not significantly correlated with COVID-19 cases in the prior month among U.S. states, controlling statistically for the three mentioned risk factors. Fluctuations in monthly state road deaths have been related consistently to changes in temperatures, truck registrations, and fuel prices for decades. Fatal vehicle crashes occur disproportionately at night and on weekends when traffic is lighter. Temperature and gas prices are proxy variables for discretionary travel. Trucks are disproportionately involved in fatal crashes.

In 2021 The U.S. average maximum temperature averaged monthly among the states, changed little from the average in 2020. Truck registrations increased 4.4 percent but fuel prices rose 38 percent. The latter should have more than offset the effect of the increase in truck registrations on the road death rate per population. The possible role of COVID-19 as a risk factor for the increased road deaths in 2021 deserves a closer look.

The neurological changes in people with COVID-19 disease include the potential for an increase in road deaths. A wide variety of neurological symptoms occur in the aftermath of infection of many people and changes in the brains of those infected have been observed. Rather than an association of recent COVID-19 cases and road deaths, a “long covid” effect would be associated with accumulated cases. The purpose of this paper is to report a test of the hypothesis that differences in road deaths among U.S. states in 2021 are associated with accumulated COVID-19 cases, controlling statistically for the other mentioned risk factors.

 


◆Caveolin-1 mediates neuroinflammation and cognitive impairment in SARS-CoV-2 infection【bioRxiv　2023年10月18日】

Abstract

Leukocyte infiltration of the CNS can contribute to neuroinflammation and cognitive impairment. Brain endothelial cells regulate adhesion, activation, and diapedesis of T cells across the blood-brain barrier (BBB) in inflammatory diseases. The integral membrane protein Caveolin-1 (Cav-1) critically regulates BBB permeability, but its influence on T cell CNS infiltration in respiratory viral infections is unknown. In this study, we sought to determine the role of Cav-1 at the BBB in neuroinflammation in a COVID-19 mouse model. We used mice genetically deficient in Cav-1 to test the role of this protein in T cell infiltration and cognitive impairment. We found that SARS-CoV-2 infection upregulated brain endothelial Cav-1. Moreover, SARS-CoV-2 infection increased brain endothelial cell vascular cell adhesion molecule-1 (VCAM-1) and CD3+ T cell infiltration of the hippocampus, a region important for short term learning and memory. Concordantly, we observed learning and memory deficits. Importantly, genetic deficiency in Cav-1 attenuated brain endothelial VCAM-1 expression and T cell infiltration in the hippocampus of mice with SARS-CoV-2 infection. Moreover, Cav-1 KO mice were protected from the learning and memory deficits caused by SARS-CoV-2 infection. These results indicate the importance of BBB permeability in COVID-19 neuroinflammation and suggest potential therapeutic value of targeting Cav-1 to improve disease outcomes.

Introduction

COVID-19 is associated with leukocyte infiltration of the CNS. Some data suggests that T cells in the CNS contribute to neuroinflammatory processes in COVID-19; for example, high perivascular T cell density spatially correlates with microglial nodules enriched in disease-associated proinflammatory phenotypes. Immunopathologic contribution of T cell infiltration to microglial activation and neurodegeneration is commonly observed in CNS diseases. Hippocampal T cell infiltration particularly contributes to cognitive impairment, consistent with the important role of the hippocampus in cognition. Disorders of cognition are frequent in COVID-19. The contribution of hippocampal T cell infiltration to cognitive impairment in COVID-19 is incompletely understood.

Blood brain barrier (BBB) endothelial cells regulate T cell infiltration of the CNS. One way to address how T cell interactions at the BBB influence cognitive outcomes in COVID-19 is to assess function of specific proteins. Here, we focused on Caveolin-1 (Cav-1). Cav-1 promotes BBB permeability by facilitating endocytosis and transcellular transcytosis. Adhesion molecules are essential for the adhesion between leukocytes and endothelial cells that ultimately leads to diapedesis into inflamed tissues. Cav-1 contributes to the scaffolding, membrane retention, and recycling of leukocyte adhesion molecules including vascular cell adhesion molecule (VCAM)-1 and Intracellular Adhesion Molecule (ICAM)-1. Cav-1 upregulation in disease contributes to BBB leakage and neuroinflammation. Indeed, we and others have shown that Cav1 promotes migration of proinflammatory T cells across the BBB, whereas loss of endothelial Cav-1 impairs T cells and neutrophil adhesion and transmigration. Moreover, suppressing Cav-1 reduces proinflammatory leukocyte infiltration, neuroinflammation, and neurodegeneration.

Cav-1 might contribute to neuroinflammation in COVID-19. Strikingly, Cav-1 is upregulated in forebrains of COVID-19 decedents. Transcellular BBB permeability is described in models of COVID-19. These data raise the possibility that cerebrovascular Cav-1 upregulation might contribute to COVID-19 neuropathogenesis. However, the extent to which Cav-1 contributes to neuroinflammation and cognitive impairment in COVID-19 has not been tested.

Thus, the goal of the present study was to evaluate the extent to which Cav-1 contributes to cognitive impairment by promoting BBB permeability to T cells in a COVID-19 mouse model. We found that mild respiratory SARS-CoV-2 infection increased expression of Cav-1 and VCAM-1 on brain endothelial cells. This was accompanied by T cell neuroinflammation in the hippocampus and learning/memory deficits in infected mice. Genetic deficiency in Cav-1 offered protection from SARS-CoV-2 induced neuroinflammation and memory deficits. These data indicate that Cav-1-mediated BBB permeability to T cells is increased during acute SARS-CoV-2 respiratory infection and may contribute to neuropathology and cognitive impairment in COVID-19.

 


◆Duration of SARS-CoV-2 Culturable Virus Shedding in Children【JAMA Network　2023年10月23日】

COVID-19 quarantine and self-isolation policies continue to interrupt education. These policies, while typically more stringent than for routine viral illnesses, are guided by few data; the duration of SARS-CoV-2 infectivity in children is largely unknown. One study found that nasopharyngeal samples from infected children, compared with adults, were half as likely to contain culturable virus.1 No study to date has examined viral shedding of the Omicron variant in children longitudinally. We evaluated duration of infectivity and its association with vaccination using live viral recovery over a 10-day window after a positive COVID-19 test result in children in Los Angeles County.

 


◆ORF3c is expressed in SARS-CoV-2-infected cells and inhibits innate sensing by targeting MAVS【EMBO reports　2023年10月23日】

Abstract

Most SARS-CoV-2 proteins are translated from subgenomic RNAs (sgRNAs). While the majority of these sgRNAs are monocistronic, some viral mRNAs encode more than one protein. One example is the ORF3a sgRNA that also encodes ORF3c, an enigmatic 41-amino-acid peptide. Here, we show that ORF3c is expressed in SARS-CoV-2-infected cells and suppresses RIG-I- and MDA5-mediated IFN-β induction. ORF3c interacts with the signaling adaptor MAVS, induces its C-terminal cleavage, and inhibits the interaction of RIG-I with MAVS. The immunosuppressive activity of ORF3c is conserved among members of the subgenus sarbecovirus, including SARS-CoV and coronaviruses isolated from bats. Notably, however, the SARS-CoV-2 delta and kappa variants harbor premature stop codons in ORF3c, demonstrating that this reading frame is not essential for efficient viral replication in vivo and is likely compensated by other viral proteins. In agreement with this, disruption of ORF3c does not significantly affect SARS-CoV-2 replication in CaCo-2, CaLu-3, or Rhinolophus alcyone cells. In summary, we here identify ORF3c as an immune evasion factor of SARS-CoV-2 that suppresses innate sensing in infected cells.

 


◆Virological characteristics of the SARS-CoV-2 Omicron EG.5.1 variant【bioRxiv　2023年10月19日】

Abstract

In middle-late 2023, a sublineage of SARS-CoV-2 Omicron XBB, EG.5.1 (a progeny of XBB.1.9.2), is spreading rapidly around the world. Here, we performed multiscale investigations to reveal virological features of newly emerging EG.5.1 variant. Our phylogenetic-epidemic dynamics modeling suggested that two hallmark substitutions of EG.5.1, S:F456L and ORF9b:I5T, are critical to the increased viral fitness. Experimental investigations addressing the growth kinetics, sensitivity to clinically available antivirals, fusogenicity and pathogenicity of EG.5.1 suggested that the virological features of EG.5.1 is comparable to that of XBB.1.5. However, the cryo-electron microscopy reveals the structural difference between the spike proteins of EG.5.1 and XBB.1.5. We further assessed the impact of ORF9b:I5T on viral features, but it was almost negligible at least in our experimental setup. Our multiscale investigations provide the knowledge for understanding of the evolution trait of newly emerging pathogenic viruses in the human population.