SARS-CoV-2 と COVID-19 に関する備忘録 Vol.53

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SARS-CoV-2 と COVID-19 に関するメモ・備忘録

◆The SARS-CoV-2 nucleocapsid protein induces microglia senescence- mediated cognitive impairment via glycolysis【Research Square　2025年6月20日】

Abstract

COVID-19-associated cognitive dysfunction has emerged as a significant public health challenge, creating substantial socioeconomic burdens for affected individuals, their families, and healthcare systems. Our study found that the SARS-CoV-2 nucleocapsid protein (SARS-CoV-2 N protein), the fundamental architectural element of viral particles, as a novel molecular driver of neurocognitive impairment. We observed that N protein caused microglial senescence both in vivo and in vitro. Mechanistically, N protein-induced metabolic shifting toward glycolysis initiates a cascade of microglial senescence that propagates cognitive impairment. We found that glycolysis inhibition inhibited N protein-triggered microglial senescence and attenuated cognitive impairment in mice. Disrupted mitochondrial dynamics impair oxidative phosphorylation capacity, forcing glycolytic reprogramming that ultimately triggers cellular senescence activation. We found that the N protein promotes excessive mitochondrial dysfunction in microglia, resulting in mitochondrial fragmentation. Inhibition of mitochondrial fission effectively rescued N protein-induced microglial senescence in microglia. In conclusion, our study suggests that the N protein induces senescence-mediated cognitive impairment by promoting glycolysis in microglia. Therapeutic targeting of glycolysis in N protein-triggered microglial senescence could be beneficial for treating or preventing cognitive impairment.

◆Pyrogallol-Type Catechins Inhibit SARS-CoV-2 by Disrupting Spike-ACE2 Binding【Research Square　2025年6月19日】

Abstract

Severe acute respiratory syndrome coronavirus 2 infects host cells through binding of the spike protein receptor-binding domain (RBD) to the human angiotensin-converting enzyme 2 receptor. In this study, the antiviral activity of 14 catechin derivatives was evaluated using a pseudovirus assay that emulates spike-mediated cell fusion. Among these, gallocatechin gallate, epigallocatechin gallate, epigallocatechin 3-(3”-O-methyl) gallate, and epigallocatechin notably exhibited strong inhibitory effects on infection. A structural comparison of the compounds revealed that catechins with a pyrogallol-type B-ring configuration exhibited greater inhibitory effects than their catechol-type counterparts. Docking simulations demonstrated that the hydroxyl group at the 5-position of the B-ring forms a hydrogen bond with Gln493 on the spike RBD, thereby facilitating additional stabilizing interactions with adjacent residues, such as Tyr453. Although catechin bioavailability is low, the results of this study suggest that regular consumption or gargling may offer localized antiviral activity at mucosal surfaces, such as those found in the oral or nasal cavity, because the catechin concentrations used in the cell assays are similar to those observed in green tea (100 µM). This study underscores the potential of pyrogallol-type catechins to act as antiviral agents.

◆Excess US Deaths Before, During, and After the COVID-19 Pandemic【JAMA Health Forum　2025年6月23日】

Introduction

Mortality rates decreased more slowly in the US than in other high-income countries (HICs) between 1980 and 2019,1 resulting in growing numbers of excess US deaths compared with other HICs. We assessed trends in excess US deaths before (1980-2019), during (2020-2022), and after (2023) the acute phase of the COVID-19 pandemic.

Methods

This cross-sectional study was deemed exempt from review and informed consent by the Boston University Institutional Review Board because no human participants were included. We followed the STROBE reporting guideline.

We obtained all-cause mortality data for the US and 21 other HICs from the Human Mortality Database from January 1980 to December 2023. For each year, we computed age-specific mortality rates for the US and the population-weighted average of other HICs. We then calculated the number of US deaths that would have been expected each year had the US population experienced the age-specific mortality rates of other HICs. We computed ratios of observed-to-expected US deaths. We then computed numbers of excess deaths attributable to the US mortality disadvantage by taking the difference between observed and expected US deaths. We stratified by age. Finally, we fit a linear regression model to assess whether the number of excess US deaths in 2023 differed from the 2014-2019 prepandemic trend. Analyses were conducted with Stata/MP, version 18.0 (StataCorp LLC), and R, version 4.42 (R Project for Statistical Computing).

Results

Our analysis encompassed 107 586 398 deaths in the US and 230 208 265 deaths in other HICs from 1980 to 2023. We estimate that 14 735 913 excess deaths occurred in the US in this period compared with other HICs. US mortality rose rapidly in 2020 and 2021 during the pandemic, then declined in 2022 and 2023. The pandemic-era mortality surge was less pronounced in other HICs.

◆Comprehensive molecular characterization of post-COVID condition: Immunoglobulin suppression and persistent SARS-CoV-2 antigens as key pathophysiological drivers【ScienceDirect　2025年6月6日】

Abstract

Background

Post-COVID condition (PCC), or long COVID, affects a significant proportion of individuals following SARS-CoV-2 infection, yet its molecular framework remains poorly understood. This study aimed to define the molecular profile of PCC by integrating broad proteomic analysis using Sequential Window Acquisition of All Theoretical Mass Spectra (SWATH-MS) with targeted antigen quantification through targeted mass spectrometry (MRM/SRM).

Methods

Plasma and pellet fractions from 65 PCC patients, classified as symptomatic or asymptomatic, were analyzed using SWATH-MS with updated SARS-CoV-2 protein libraries (v2022 and v2024), enabling a comprehensive profiling of immune- and viral-related proteins. The presence of viral antigens, specifically spike and nucleocapsid proteins, was quantified using MRM/SRM. A protein-concentration-based severity metric using clustering analysis and dimensionality reduction methods was proposed to assess correlations between proteomic alterations and clinical symptoms.

Results

A key finding in PCC patients, particularly in symptomatic cases, was a pronounced downregulation of immunoglobulins, including kappa and lambda light chains. SWATH-MS analysis identified six proteins (corresponding to UniProt entries Q8N5F4, LV147, KV311, KVD20, A0A5C2G1U0, and KV315) that strongly correlated with disease severity (R² > 0.9), highlighting their potential as biomarkers. In pellet samples, the protein G1SG72 (ABCE1) emerged as a marker associated with severity, suggesting possible alterations in antiviral responses. The severity metric proposed showed a strong correlation with clinical symptoms, providing a quantifiable measure of PCC severity and enabling effective patient stratification. Additionally, MRM/SRM analysis detected the persistent presence of SARS-CoV-2 antigens, specifically the Spike and Nucleocapsid proteins, in symptomatic PCC patients.

Conclusions

This study defines a molecular profile of PCC, marked by immunoglobulin downregulation and the persistence of SARS-CoV-2 antigens, which may contribute to ongoing immune alterations in PCC. The severity metric derived from proteomic profiling provides a tool for categorizing PCC patients based on symptom severity and could support future studies aimed at targeted interventions.

◆Multimodal MRI Reveals Consistent Basal Ganglia and Limbic System Alterations in COVID-19 Survivors【medRxiv　2025年6月20日】

Abstract

The long-term impact of COVID-19 on the brain is multifaceted, encompassing structural and functional disruptions. A cohesive theory of the underlying mechanisms of the Post-COVID Syndrome (PCS) remains unknown, primarily due to high variability in findings across independent studies. Here, we present a multimodal, cross-sectional MRI analysis of brain morphology (T1-MRI), tissue microstructure (diffusion-MRI), functional connectivity (functional-MRI), and cerebral blood flow (Arterial Spin Labeling MRI) in COVID-Recovered Patients (CRPs, N=76) and Healthy Controls (HCs, N=51). Although the global brain volumes did not differ between the two groups, CRPs showed focal atrophy in the right basal ganglia and limbic structures, along with cortical thinning in paralimbic regions (prefrontal cortex, insula) (p<0.05). Diffusion MRI analysis revealed reduced fractional anisotropy and elevated radial diffusivity in the uncinate fasciculus and cingulum. No differences were observed in resting-state functional connectivity (RSFC) and cerebral blood flow between HCs and CRPs (p>0.05). We further investigated the effect of infection severity by stratifying the CRPs into hospitalized (HP; N = 21) and non-hospitalized (NHP; N = 46) groups. The microstructural damage was linked to infection severity, more pronounced in the HPs (p<0.05). In HPs, RSFC was diminished between components of the default mode network and the insula and caudate as compared to HCs and NHPs (p<0.05). Results suggest COVID-19 is associated with selective structural and functional alterations in basal ganglia–limbic–cortical circuits, with stronger effects in severe cases. Our findings are in line with common prevalent behavioral symptoms such as fatigue, memory impairment, attentional deficits, and insomnia. This study suggests that localized microstructural neuroinflammatory mechanisms contribute to post-COVID neurological symptoms and offers potential imaging biomarkers for targeted therapies and monitoring recovery.

◆Akkermansia Muciniphila Primes Lung-Resident Antiviral Immunity via the Gut–Lung Axis During SARS-CoV-2 Infection【SSRN　2025年6月23日】

Abstract

Background: The gut microbiota is essential for shaping systemic immunity and modulating the gut–lung axis, playing a crucial role during respiratory infections, including COVID-19. Although SARS-CoV-2 infection significantly disrupts gut microbiota composition, the functional consequences of these changes, especially the enrichment of Akkermansia muciniphila, remain poorly understood.

Methods: Using K18-hACE2 transgenic mice, we examined the effects of SARS-CoV-2 variants (WA and Omicron) on gut microbiota dynamics and host immune responses. We assessed microbial composition and functional profiles post-infection. To test therapeutic potential, A. muciniphila was administered prophylactically, and outcomes such as weight loss, lung pathology, immune cell phenotypes, and cytokine profiles were evaluated.

Findings: SARS-CoV-2 infection significantly reduced gut microbial diversity and selectively enriched A. muciniphila. Prophylactic administration of A. muciniphila conferred substantial protection, mitigating weight loss and improving lung histopathology. Treated mice displayed enhanced local antiviral immune responses, increased tissue-resident memory T cells, elevated Th2 and Th17 cytokines, and the formation of inducible bronchus-associated lymphoid tissue (iBALT), without excessive systemic inflammation.

Interpretation: Our findings reveal A. muciniphila as both a biomarker of COVID-19-associated dysbiosis and a promising live biotherapeutic candidate. Its capacity to bolster mucosal immunity via gut-lung axis modulation positions it as a potential prophylactic strategy against respiratory viral infections, including SARS-CoV-2.

◆Cardiac Arrhythmias and Autonomic Dysfunction Associated With COVID-19: A Scientific Statement From the American Heart Association【AHA ASA Journals　2024年10月14日】

Abstract

Cardiac arrhythmias are commonly noted in patients during infections with and recovery from COVID-19. Arrhythmic manifestations span the spectrum of innocuous and benign to life-threatening and deadly. Various pathophysiological mechanisms have been proposed. Debate continues on the impact of incident and exacerbated arrhythmias on the acute and chronic (recovery) phase of the illness. COVID-19 and COVID-19 vaccine–associated myocardial inflammation and autonomic disruption remain concerns. As the pandemic has transformed to an endemic, with discovery of new SARS-CoV-2 variants, updated vaccines, and potent antiviral drugs, vigilance for COVID-19–associated arrhythmic and dysautonomic manifestations remains. The objective of this American Heart Association scientific statement is to review the available evidence on the epidemiology, pathophysiology, clinical presentation, and management of cardiac arrhythmias and autonomic dysfunction in patients infected with and recovering from COVID-19 and to provide evidence-based guidance. The writing committee’s consensus on implications for clinical practice, gaps in knowledge, and directions for future research are highlighted.

◆SARS-CoV-2 Nsp14 binds Tollip and activates pro-inflammatory pathways while downregulating interferon-α and interferon-γ receptors【ASM Journals　2025年6月25日】

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) non-structural protein 14 (Nsp14) possesses an N-terminal exonuclease (ExoN) domain that provides a proofreading function for the viral RNA-dependent RNA polymerase and a C-terminal N7-methyltransferase (N7-MTase) domain that methylates viral mRNA caps. Nsp14 also modulates host functions. This includes the activation of NF-κB and downregulation of interferon alpha/beta receptor 1 (IFNAR1). Here, we demonstrate that Nsp14 exerts broader effects, activating not only NF-κB responses but also extracellular-signal-regulated kinase (ERK), p38, and Jun amino-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) signaling, promoting cytokine production. Furthermore, Nsp14 downregulates not only IFNAR1 but also IFN-γ receptor 1 (IFNGR1), impairing cellular responses to both IFNα and IFNγ. IFNAR1 and IFNGR1 downregulation is via a lysosomal pathway and occurs in SARS-CoV-2-infected cells. Analysis of a panel of Nsp14 mutants reveals a consistent pattern. Mutants that disable ExoN function remain largely active, whereas N7-MTase mutations impair both pro-inflammatory pathway activation and IFN receptor downregulation. Innate immune modulating functions also require the presence of both the ExoN and N7-MTase domains, likely reflecting that the ExoN domain must be present to enable N7-MTase activity. We further identify multi-functional host protein Tollip as an Nsp14 interactor. Interaction requires the phosphoinositide-binding C2 domain of Tollip and sequences C-terminal to the C2 domain. Full-length Tollip or regions encompassing the Nsp14 interaction domain are sufficient to counteract both Nsp14-mediated and Nsp14-independent activation of NF-κB. Knockdown of Tollip partially reverses IFNAR1 and IFNGR1 downregulation in SARS-CoV-2-infected cells, suggesting the relevance of Nsp14-Tollip interaction for Nsp14 innate immune evasion functions.

◆SARS-CoV-2 Nsp14 binds Tollip and activates pro-inflammatory pathways while downregulating interferon-α and interferon-γ receptors【The Guardian : Caitlin Cassidy　2025年6月26日】

A new report has urged the federal government to collect national data on chronic absenteeism and embed layers of support in schools to tackle Australia’s growing student attendance crisis.

The report, provided exclusively to Guardian Australia by Independent Schools Australia (ISA), drew from interviews with academics, mental health clinicians and teachers. It called on the government to implement a multi-tiered system of support (MTSS) to better support children struggling to stay in school.

The approach would allow schools to begin systematically categorising and collecting national data on the reasons for non-attendance.

More than 40% of students in years 1 to 10 were missing at least one out of 10 school days, the latest Australian Curriculum Assessment And Reporting Authority data showed.

That rate had steadily worsened over the past five years. In 2019, 73.1% of students were attending at least 90% of school days. In 2024, the figure was just 59.8%, down from 61.6% in 2023.

Attendance also declined by socio-educational advantage and were lower for remote students and Aboriginal and Torres Strait Islander students. Just 35.2% of First Nations students had attendance levels at or above 90% in 2024, compared with about 49% before the pandemic.

The chief executive of ISA, Graham Catt, said there was no national consistency in how non-attendance was defined, recorded or addressed.

“Our new report highlights the need to differentiate types of absenteeism … and calls on the Australian government to lead a cross-sector pilot to test it,” he said.

The report found the term “school refusal” was “misleading” as it suggested a choice, pointing to complex barriers like anxiety, trauma and illness that prevented attendance.

It suggested school refusal often peaked at ages five to six and 10 to 11, during transitions like starting primary or high school or moving schools.

Mainstream schooling may also not be working for young people with additional needs. The report found there had been a 276% increase in enrolments at independent special assistance schools since 2016.

“Absentee recording systems can capture the level of non-attendance but are not nuanced enough to understand the reasons for it,” the report read.

“Schools need to differentiate school refusal from other forms of absenteeism … without a nationally consistent definition … accurate data cannot be collected, and it is difficult for schools to determine when intervention strategies may be required.”

The report said a MTSS model could be implemented to monitor attendance – from occasional absences to chronic disengagement —and help schools respond accordingly. The idea has also been backed by the Australian Education Research Organisation (Aero) after being commissioned by the government to investigate the issue.

Tiered interventions would range from initial whole-school strategies to address wellbeing and belonging, like peer support and anti-bullying programs, to early support interventions for students showing signs of distress and intensive wraparound support for students with complex needs.

For instance, students at a Tier 2 could be offered hybrid attendance or have safe spaces at the school for when they were feeling overwhelmed, while students at Tier 3 may be offered a specialised school support team and external health services.

A Senate inquiry into the issue, initiated by the Greens, released a report in 2023 that recommended a string of measures, including improved access to mental health care and more funding to parent support groups to address the “alarming rate” of absenteeism.

The Senate report noted efforts to tackle school refusal had been hindered by the absence of a nationally consistent and coordinated approach, including a lack of agreed methodology for collecting and reporting on data on chronic absenteeism.

The federal government agreed or supported in principle just two of its 14 proposals, including tasking the Australian Education Research Organisation (Aero) with analysing school refusal and working with governments to embed school refusal training in teaching courses.

Last year, the federal government came under fire from the Greens, peak bodies and experts for refusing to implement the recommendations from the Senate reportto front a national action plan or offer peer support funding to reverse the national trend of school refusal.

A founding board member of School Can’t Australia, Tiffany Westphal, said MTSS was “not the solution in and of itself” and may yield “too little support, too late”.

“Instead of focusing on absence we need to tune into signs of distress which are frequently apparent prior to impacts on attendance,” she said.

But Catt said as it stood schools were being asked to solve the issue “without consistent tools or definitions”.

“We need to rise above politics and blame to do better for students, families, and schools across Australia,” he said.

◆Erstmals Daten zu typischen Symptomen von Long-COVID bei Kleinkindern – viel häufiger als bislang angenommen?【Medscape　2025年6月26日】

Bei Kleinkindern äußern sich Langzeitfolgen einer SARS-CoV-2-Infektion offenbar in einem anderen Beschwerdebild als bei älteren Kindern oder Erwachsenen. Eine aktuelle Studie in JAMA Pediatrics hat nun erstmals systematisch untersucht, welche Symptome sie haben und wie häufig Long-COVID bei unter 5-Jährigen auftritt.

Demnach zeigten 14% der Säuglinge und Kleinkinder sowie 15% der Vorschulkinder in der untersuchten Kohorte Beschwerden, die mit Long-COVID vereinbar waren. PD Dr. Roland Elling, Leiter der Sektion für pädiatrische Infektionsforschung und Infektionsepidemiologie am Universitätsklinikum Freiburg, äußert sich gegenüber Medscape überrascht über die Höhe dieser Zahlen.

Häufigkeit deckt sich nicht mit der klinischen Erfahrung

„Das würde bedeuten, dass 1 von 6 Kindern in diesen Altersgruppen nach einer SARS-CoV-2-Infektion Long-COVID entwickelt. Das deckt sich nicht mit der klinischen Realität, wie wir sie in unseren Spezialambulanzen erleben“, so Elling. Er koordiniert ein Modellprojekt zur Versorgung von Kindern und Jugendlichen mit Long-COVID an den Universitätskinderkliniken in Freiburg, Heidelberg, Tübingen und Ulm.

„In unserer Wahrnehmung ist Long-COVID eine Erkrankung der zweiten Lebensdekade, nicht der ersten 10 Jahre. Wir sehen verschwindend geringe bis gar keine Fälle bei Kleinkindern – und das gilt für alle Unikliniken in Baden-Württemberg, nicht nur für Freiburg“, sagt Elling.

Die nun von Dr. Rachel S. Gross von der NYU Grossman School of Medicine in New York, USA, und ihren Kollegen publizierte Analyse stammt aus der US-amerikanischen RECOVER-Initiative, einer multizentrischen Kohortenstudie mit retrospektiven und prospektiven Elementen. Ziel war es, Symptome zu identifizieren, die bei ehemals SARS-CoV-2-infizierten Kindern signifikant häufiger auftreten als bei Nichtinfizierten, und daraus einen Altersgruppen-spezifischen Long-COVID-Index zu entwickeln.

Erfasst wurden 472 Kinder im Alter von 0 bis 2 Jahren sowie 539 Kinder im Alter von 3 bis 5 Jahren. Zum Erhebungszeitpunkt (März 2022 bis Juli 2024) hatten laut elterlicher Angabe 278 (59%) der jüngeren und 399 (74%) der älteren Kinder eine SARS-CoV-2-Infektion durchgemacht.

Für Elling sind diese Angaben nicht schlüssig. „Seroprävalenzstudien zeigen, dass sich bis 2023 über 90% aller Kinder mit SARS-CoV-2 infiziert haben. Je jünger die Kinder, desto asymptomatischer verläuft die Infektion – viele Fälle dürften der Studie entgangen sein.“ Eine serologische Bestätigung erfolgte nicht; die Anamnese beruhte ausschließlich auf elterlichen Angaben.

Erhebung mehr als 1 Jahr nach der Infektion

Die Befragung der Eltern erfolgte bei den jüngeren Kindern median 318 Tage nach Infektion, bei den Vorschulkindern nach 520 Tagen. Das ermöglicht zwar die Abgrenzung zu kurzfristigen postinfektiösen Beschwerden, aber eine retrospektive Erhebung über einen derart langen Zeitraum hält Elling methodisch für sehr problematisch. „Ich kann Eltern nicht verlässlich fragen, ob ihr Kind vor über einem Jahr für mindestens 4 Wochen bestimmte Symptome hatte.“

Die standardisierten Fragebögen fragten bei den 0- bis 2-Jährigen 41 Symptome, bei den Vorschulkindern 75 Symptome aus 8 klinischen Domänen ab – darunter Allgemeinbefinden, HNO, Herz/Lunge, Gastrointestinaltrakt, Haut, Bewegungsapparat, neurologische und psychische Auffälligkeiten.

Anhand des im RECOVER-Projekt entwickelten Long-COVID-Symptomindex galten 14% der Säuglinge und Kleinkinder sowie 15% der Vorschulkinder als „wahrscheinlich betroffen“.

Daten deuten auf altersspezifische Symptome hin

Bei Säuglingen und Kleinkindern dominierten Schlafstörungen, Reizbarkeit, Appetitverlust, verstopfte Nase und produktiver Husten. Vorschulkinder litten laut Elternangabe häufiger unter trockenem Husten, Tagesmüdigkeit und Energiemangel. Kinder mit ausgeprägteren Symptomen wiesen laut elterlicher Einschätzung eine schlechtere Lebensqualität, ein reduziertes Allgemeinbefinden und teils Entwicklungsverzögerungen auf.

Elling hält dem entgegen: „Bei älteren Kindern und Jugendlichen sind es neurokognitive Symptome wie postexertionelle Malaise oder Brain Fog, die die Teilhabe massiv einschränken – nicht Husten oder andere Atemwegssymptome.“ Solche komplexen Symptome seien aber bei Kleinkindern naturgemäß schwer zu erfassen.

Zudem entwickelten laut Studienlage unter 1% der Jugendlichen Long-COVID – bei kleineren Kindern sei das Risiko vermutlich noch geringer. Das zeigten auch Ergebnisse aus Haushaltsstudien. „Kleine Kinder stecken COVID-19 besser weg als Jugendliche und Erwachsene“, so Elling.

Der zentralen Schlussfolgerung der Autorengruppe kann Elling dennoch zustimmen. Diese schreiben, Long-COVID äußere sich bei sehr jungen Kindern anders als bei älteren – und müsse altersdifferenziert definiert und untersucht werden. „Ich würde sogar noch weiter gehen“, so der Kinderinfektiologe. „Wenn wir in dem pathogenetischen Verständnis der Erkrankung weiterkommen wollen, müssen wir weg von dem generischen Begriff Long-COVID.“

Sammelbegriff Long-COVID hemmt die Forschung

Elling betont, wie wichtig es sei, Long-COVID nicht nur nach Alter, sondern auch nach Organsystem zu differenzieren: „Dass man alles, was über 12 Wochen andauert – egal ob Kopfschmerz, Riechstörung oder Luftnot – unter dem singulären Begriff Long-COVID zusammenfasst, ist wissenschaftlich schwierig. Das macht man bei keiner anderen Erkrankung.“

Es sei sehr wahrscheinlich, dass diesen Beschwerden unterschiedliche Mechanismen zugrunde liegen können – eine Riechstörung nach COVID-19 sei eine andere Erkrankung als persistierende Kopfschmerzen oder eine Atemstörung.

Aber trotz der methodischen Einschränkungen lobt Elling die Forschungsrichtung der US-Autoren: „Das Engagement, Long-COVID im frühen Kindesalter systematisch zu erfassen, ist richtig – aber die Ableitungen für die Versorgung müssen realistisch bleiben. Wenn die Daten suggerieren, dass in jeder Schulklasse 4 Kinder nach einer Infektion mit SARS-CoV-2 Long-COVID entwickeln, hätte das gravierende Public-Health-Implikationen. Doch das ist aus meiner Sicht nicht der Fall.“