SARS-CoV-2 と COVID-19 に関する備忘録 Vol.10――BA.2.75xが遺伝子多様性の源泉？SARS-CoV-2とテング熱は混ぜるな危険！…etc.

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SARS-CoV-2 と COVID-19 に関するメモ・備忘録


◆Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study【LANCET　2023年9月22日】

Summary

Introduction

The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures.

Methods

In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ≥18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025.

Findings

Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5·0 months (IQR 4·2–6·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MRI were more frequent in patients than in controls (157 [61%] of 259 vs 14 [27%] of 52; p<0·0001) and independently associated with COVID-19 status (odds ratio [OR] 2·9 [95% CI 1·5–5·8]; padjusted=0·0023) after adjusting for relevant confounders. Compared with controls, patients were more likely to have MRI evidence of lung abnormalities (p=0·0001; parenchymal abnormalities), brain abnormalities (p<0·0001; more white matter hyperintensities and regional brain volume reduction), and kidney abnormalities (p=0·014; lower medullary T1 and loss of corticomedullary differentiation), whereas cardiac and liver MRI abnormalities were similar between patients and controls. Patients with multiorgan abnormalities were older (difference in mean age 7 years [95% CI 4–10]; mean age of 59·8 years [SD 11·7] with multiorgan abnormalities vs mean age of 52·8 years [11·9] without multiorgan abnormalities; p<0·0001), more likely to have three or more comorbidities (OR 2·47 [1·32–4·82]; padjusted=0·0059), and more likely to have a more severe acute infection (acute CRP >5mg/L, OR 3·55 [1·23–11·88]; padjusted=0·025) than those without multiorgan abnormalities. Presence of lung MRI abnormalities was associated with a two-fold higher risk of chest tightness, and multiorgan MRI abnormalities were associated with severe and very severe persistent physical and mental health impairment (PHOSP-COVID symptom clusters) after hospitalisation.

Interpretation

After hospitalisation for COVID-19, people are at risk of multiorgan abnormalities in the medium term. Our findings emphasise the need for proactive multidisciplinary care pathways, with the potential for imaging to guide surveillance frequency and therapeutic stratification.

 


◆SARS-CoV-2 antibodies cross-react and enhance dengue infection【bioRxiv　2023年10月9日】

Abstract

Dengue disease is highly prevalent in tropical and subtropical regions worldwide. However, its pathogenesis is still incompletely understood, particularly in comparison to other endemic viruses. Antibody-dependent enhancement (ADE) is a well-known phenomenon for dengue viruses. Given the recent surge in dengue cases and potential cross-reactivity with SARS-CoV-2 antibodies, this study explores the impact of anti-SARS-CoV-2 antibodies on DENV-2 infection.

The study assessed the cross-reactivity of SARS-CoV-2 antibodies with the DENV-2 Virus. Human convalescent plasma samples collected during different waves of COVID-19 and monoclonal and polyclonal antibodies raised against SARS-CoV-2 were examined for their potential to cause ADE of DENV-2 infection using cell-based assays. The study found that anti-SARS-CoV-2 antibodies acquired from natural infection in humans or through experimental immunization in animals were cross-reactive with DENV-2 and had the potential to enhance DENV-2 infection in K562 and U937 cells. In-silico and in-vitro studies indicated a strong interaction between SARS-CoV-2 antibodies and DENV-2 E-protein, providing a molecular basis for these findings. This study is the first to demonstrate that anti-SARS-CoV-2 antibodies can cross-react with DENV-2 and can enhance its infection through ADE. These findings have implications for SARS-CoV-2 vaccine development and deployment strategies in regions where dengue is endemic.

Summary Antibodies against SARS-CoV-2 (RBD and Spike) showed significant cross reactivity with DENV-2 (E protein). Also, anti-SARS-CoV-2-commercial antibodies, immunised animal sera and 46 human convalescent plasma samples (from different waves of pandemic) demonstrated antibody-dependent enhancement (ADE) of DENV-2 infection.

Introduction

Dengue virus (DENV) is a positive-sense single-stranded RNA virus with a genome size of ∼11kb belonging to the Flaviviridae family and causes the most prevalent mosquito-borne disease called dengue. Dengue is endemic to more than 120 countries with Asia contributing 70% of the global burden. The COVID-19 pandemic has had a substantial impact on Dengue cases globally with many countries reporting significant a surge since 2020. In 2021, prevalence of dengue has increased over three times in India (44,585 versus 193,245 cases), 19 times in Bangladesh (1,405 versus 28,429 cases), 2 times in Singapore (5,000 versus 11,000), over 1.8 times in Malaysia (87,000 versus 120,000 cases), and more than seven times (6,016 vs. 52,894 instances) in Pakistan. Taiwan, Sri Lanka, Mexico, and the Philippines have also reported notable increase, while Brazil documented a surge in severe cases and fatalities predominantly impacting younger population under 20 years of age during the period of 2021-2022. DENV circulates as four serotypes (DENV 1-4) each containing multiple distinct genotypes. Infection with any serotype can lead to mild fever or severe forms like Dengue Haemorrhagic Fever (DHF) and Dengue Shock Syndrome (DSS). Primary infection provides lifelong immunity to homotypic secondary infection but gives partial immunity from heterotypic challenge. Such heterotypic secondary infections positively correlate with severe symptoms, as a consequence of higher viremia through Antibody-dependent Enhancement (ADE). ADE is caused by sub-neutralizing antibodies from previous infection binding to DENV virion and promoting FcR-mediated viral entry into the cells bearing Fc-receptor. ADE occurs when the number of bound antibodies support stable attachment to Fc receptors, without reaching the neutralization threshold.

Presently there are multiple reports showing modest serological cross-reactivity between SARS-CoV-2 and DENV-2, significantly impacting dengue diagnostics. However, it is yet unclear if this would have any clinical impact on dengue cases. A study reported IgG produced in rabbits upon immunization with purified SARS-CoV-2 S1-RBD, to cross-react with DENV proteins, particularly the Envelope (E), precursor-Membrane (PrM), and Non-structural protein 1 (NS1). However, these antibodies did not enhance DENV infection (ADE) in THP-1 cells which express FcR. Contrarily a study showed in-vitro inhibition of dengue infection by sera from convalescent COVID-19 patients sera.

In this pretext, our current study aimed to examine if SARS-CoV-2 antibodies have any impact on DENV-2 infection. To the best of our knowledge, this will be the first study to provide a blueprint as to how SARS-CoV-2 antibodies cross-reactive with DENV-2 (particularly E protein) may enhance dengue infection via ADE, using a combination of experimental and computational studies.

 


◆Mapping SARS-CoV-2 antigenic relationships and serological responses【Science　2023年10月6日】

Structured Abstract

We previously reported that treatment of mice with 6-gingerol, the most abundant phytochemical in ginger root, leads to phosphodiesterase inhibition that counteracts neutrophil hyperactivity in models of antiphospholipid syndrome (APS) and lupus. Here, we explored the extent to which oral intake of a whole-ginger extract would similarly impact neutrophils in both autoimmune mice and healthy humans. In vitro, a solubilized ginger extract was able to attenuate neutrophil extracellular trap formation (NETosis) by human neutrophils through a mechanism that was dependent upon the cyclic AMP–dependent kinase, protein kinase A. When mice with features of either APS or lupus were administered a ginger extract orally, they demonstrated reduced circulating NETs, as well as the tempering of other disease outcomes, such as large-vein thrombosis (APS) and autoantibody production (lupus). In a pilot clinical trial, which was validated in a second cohort, daily intake of a ginger supplement for 7 days by healthy volunteers boosted neutrophil cAMP, inhibited NETosis in response to disease-relevant stimuli, and reduced circulating plasma NET levels. In summary, this work demonstrates that ginger intake restrains neutrophil hyperactivity in autoimmune mouse models and that ginger consumption by healthy individuals makes their neutrophils more resistant to NETosis.

INTRODUCTION

Vaccination has greatly reduced the disease burden of SARS-CoV-2. However, since late 2020, variants have emerged that are able to escape immunity from vaccination and previous infections, including B.1.351 (Beta), P.1 (Gamma), B.1.617.2 (Delta), and B.1.1.529 (Omicron and its descendants). In combination with vaccination, infections with different variants form the basis of current population immunity against SARS-CoV-2.

RATIONALE

Understanding the antigenic relationships among SARS-CoV-2 variants, the substitutions that cause antigenic change, and how the immune response is shaped by previous infections, is crucial for understanding the evolution of the virus, determining whether new variants avoid neutralization from antibodies induced by current vaccines, and evaluating the need for vaccine updates.
To this end, we analyzed patterns of neutralization and cross-reactivity among a panel of 21 SARS-CoV-2 variants and 15 groups of human sera obtained from individuals after primary infection with one of 10 different variants or after D614G or B.1.351 vaccination. First, we sought to understand patterns of cross-reactivity and response breadth in postvaccination responses 4 weeks and >3 months after second or third vaccine doses. Then, we used antigenic cartography to visualize antigenic relationships between 21 SARS-CoV-2 variants and experimentally test point mutations to investigate the drivers of the antigenic changes observed in the antigenic map. Lastly, we investigated how serological reactivity postinfection relates to the primary-exposure variant.

RESULTS

Quantifying changes in cross-reactivity and response breadth after vaccination, our results show the largest increase between 4 weeks and >3 months after a second dose. In particular, we found that the main short-term effect of the third vaccination was to boost the magnitude of a response that had already become more cross-reactive rather than to generate significant additional breadth of cross-reactivity.
Using antigenic cartography, we inferred and subsequently experimentally tested our inference that antigenic differences among pre-Omicron variants are primarily caused by substitutions at spike-protein positions 417, 452, 484, and 501 (see figure, top). The experimental effect of these substitutions was largely consistent with those inferred from the map.
We also found that sensitivity to these substitutions varied greatly between individuals infected with different variants. These differences are consistent with substantial changes in immunodominance of different spike regions, depending on the variant an individual was first exposed to and the amino acid present at these positions in the eliciting variant (see figure, bottom). For example, whereas sera of individuals exposed to D614G, B.1.1.7, and B.1.617.2 variants are sensitive to changes at position 484, sera of individuals exposed to B.1.351 and P.1 are not.

CONCLUSION

Our results provide a comprehensive analysis of the antigenic variation between SARS-CoV-2 variants and the development of the immune response after infection or vaccination. The large antigenic effect of a small number of substitutions in the receptor-binding domain (RBD) of SARS-CoV-2 is similar to the pattern observed for seasonal influenza viruses, for which major antigenic changes are often associated with single or double substitutions. These substitutions in the SARS-CoV-2 RBD not only allow the virus to escape from preexisting immunity but also influence the regions of the spike protein that the immune response targets. Depending on their infection history, different individuals can thus be sensitive to substitutions in different regions of the spike protein. As individuals increasingly experience multiple infections, choosing vaccine immunogens on the basis of immunodominance considerations may be an important aspect in ensuring high vaccine efficacy across populations with different patterns of preexisting immunity.

 


◆Role of Microglia, Decreased Neurogenesis and Oligodendrocyte Depletion in Long COVID-Mediated Brain Impairments【Aging and Disease　2023年9月24日】

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of a recent worldwide coronavirus disease-2019 (COVID-19) pandemic. SARS-CoV-2 primarily causes an acute respiratory infection but can progress into significant neurological complications in some. Moreover, patients with severe acute COVID-19 could develop debilitating long-term sequela. Long-COVID is characterized by chronic symptoms that persist months after the initial infection. Common complaints are fatigue, myalgias, depression, anxiety, and “brain fog,” or cognitive and memory impairments. A recent study demonstrated that a mild COVID-19 respiratory infection could generate elevated proinflammatory cytokines and chemokines in the cerebral spinal fluid. This commentary discusses findings from this study, demonstrating that even a mild respiratory SARS-CoV-2 infection can cause considerable neuroinflammation with microglial and macrophage reactivity. Such changes could also be gleaned by measuring chemokines and cytokines in the circulating blood. Moreover, neuroinflammation caused by mild SARS-CoV-2 infection can also impair hippocampal neurogenesis, deplete oligodendrocytes, and decrease myelinated axons. All these changes likely contribute to cognitive deficits in long-COVID syndrome. Therefore, strategies capable of restraining neuroinflammation, maintaining better hippocampal neurogenesis, and preserving oligodendrocyte lineage differentiation and maturation may prevent or reduce the incidence of long-COVID after SARS-CoV-2 respiratory infection.

 


◆Autoimmune and Autoinflammatory Connective Tissue Disorders Following COVID-19【JAMA Network　2023年10月6日】

Key Points

Question Is COVID-19 associated with an increased risk of autoimmune and autoinflammatory disorders?

Findings This cohort study including 354 527 individuals with COVID-19 and 6 134 940 controls identified a significant elevation in the risk of multiple incident autoimmune and autoinflammatory disorders subsequent to COVID-19. Notably, certain disease risks exhibited a positive association with the severity of COVID-19.

Meaning These findings suggest that autoimmune and autoinflammatory connective tissue disorders may manifest as post–COVID-19 sequelae, highlighting the potential long-term health ramifications associated with COVID-19; long-term management should include evaluating the development of such disorders in patients who had COVID-19.

Abstract

Importance Multiple cases of autoimmune and autoinflammatory diseases after COVID-19 have been reported. However, their incidences and risks have rarely been quantified.

Objective To investigate the incidences and risks of autoimmune and autoinflammatory connective tissue disorders after COVID-19.

Design, Setting, and Participants This was a retrospective population-based study conducted between October 8, 2020, and December 31, 2021, that used nationwide data from the Korea Disease Control and Prevention Agency COVID-19 National Health Insurance Service cohort and included individuals who received a diagnosis of COVID-19 via polymerase chain reaction testing and a control group with no evidence of COVID-19 identified from National Health Insurance Service of Korea cohort. Data analysis was conducted from September 2022 to August 2023.

Exposures Receipt of diagnosis of COVID-19.

Main Outcomes and Measures The primary outcomes were the incidence and risk of autoimmune and autoinflammatory connective tissue disorders following COVID-19. A total of 32 covariates, including demographics, socioeconomic statuses, lifestyle factors, and comorbidity profiles, were balanced through inverse probability weighting. The incidences and risks of autoimmune and autoinflammatory connective tissue disorders were compared between the groups using multivariable Cox proportional hazard analyses.

Results A total of 354 527 individuals with COVID-19 (mean [SD] age, 52.24 [15.55] years; 179 041 women [50.50%]) and 6 134 940 controls (mean [SD] age, 52.05 [15.63] years; 3 074 573 women [50.12%]) were included. The risks of alopecia areata (adjusted hazard ratio [aHR], 1.12; 95% CI, 1.05-1.19), alopecia totalis (aHR, 1.74; 95% CI, 1.39-2.17), antineutrophil cytoplasmic antibody–associated vasculitis (aHR, 2.76; 95% CI, 1.64-4.65), Crohn disease (aHR, 1.68; 95% CI, 1.31-2.15), and sarcoidosis (aHR, 1.59; 95% CI, 1.00-2.52) were higher in the COVID-19 group. The risks of alopecia totalis, psoriasis, vitiligo, vasculitis, Crohn disease, ulcerative colitis, rheumatoid arthritis, adult-onset Still disease, Sjögren syndrome, ankylosing spondylitis, and sarcoidosis were associated with the severity of COVID-19.

Conclusions and Relevance In this retrospective cohort study, COVID-19 was associated with a substantial risk for autoimmune and autoinflammatory connective tissue disorders, indicating that long-term management of patients with COVID-19 should include evaluation for such disorders.