SARS-CoV-2 と COVID-19 に関する備忘録 Vol.47

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SARS-CoV-2 と COVID-19 に関するメモ・備忘録

◆Persistent neurocognitive deficits in long COVID: Evidence of structural changes and network abnormalities following mild infection【ScienceDirect　2025年5月2日】

Abstract

This study aimed to investigate the neurocognitive deficits, structural brain alterations, and network abnormalities in individuals who had a mild SARS-CoV-2 infection, with and without brain fog, as a symptom of long COVID. A cross-sectional study was conducted involving 75 participants, categorized into three groups: 24 healthy controls (HCs), 26 COVID-19 survivors without brain fog (woFOG), and 25 with brain fog (wFOG). Neuropsychological assessments included the Free and Cued Selective Reminding Test (FCSRT) and Addenbrooke’s Cognitive Examination–Revised (ACE-R). Structural and functional brain alterations were examined using voxel-based morphometry (VBM) and resting-state functional MRI (rs-fMRI). The wFOG group exhibited significant cognitive impairments, particularly in delayed free recall, attention, memory, and visuospatial skills, compared to both the woFOG and HC groups. Structural MRI analyses revealed reduced gray matter concentrations (GMC) in the left inferior temporal gyrus, left fusiform gyrus, and right orbital gyri in both COVID-19 groups relative to HCs. Additionally, the wFOG group exhibited further GMC reductions in the bilateral caudate nuclei, right putamen/pallidum, and amygdala compared to the woFOG group. rs-fMRI analyses demonstrated altered connectivity patterns in COVID-19 survivors, characterized by increased connectivity in the default mode network and visual networks, alongside decreased connectivity in the dorsal attention network. These findings indicate that even mild COVID-19 can result in persistent neurocognitive deficits, structural brain alterations, and functional network abnormalities, both in individuals with and without brain fog. The observed changes highlight the importance of long-term monitoring and targeted interventions to address potential cognitive and neurological consequences of long COVID.

◆Spike proteins of coronaviruses activate mast cells for degranulation via stimulating Src/PI3K/AKT/Ca2+ intracellular signaling cascade【ASM Journals : Journal of Virology　2025年4月30日】

Abstract

Mast cells (MCs) are strategically located at the interface between host and environment. The non-allergic functions of MCs in immunosurveillance against pathogens have been recently underscored. However, the activation of MCs by pathogens may beneficially or detrimentally regulate immune inflammation to combat or promote pathogen invasion. We and others have conclusively demonstrated that MCs serve as a crucial mediator in the induction of hyperinflammation initiated by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), leading to substantial tissue damage across multiple organs in murine and nonhuman primate models. Whereas the precise mechanism underlying virus-induced MC activation and degranulation remains largely elusive, our previous findings have indicated that the binding of the Spike proteins to cellular receptors is sufficient to elicit MC activation for rapid degranulation. This study aims to corroborate the ubiquity of coronavirus-induced MC degranulation and elucidate the intracellular signaling pathways that mediate the activation of MCs upon Spike protein binding to the cellular receptors. Our transcriptome analysis revealed MC activation upon the stimulations with a range of Spike/RBD proteins and viral particles of coronavirus. Notably, the interaction between these Spike/RBD proteins and cellular receptors triggered the activation of src kinase, a member of Src Family Kinases (SFKs). This activation, in turn, stimulated the PI3K/AKT signaling pathway, resulting in an accumulation of intracellular calcium ions. These calcium ions subsequently facilitated microtubule-dependent granule transport, ultimately promoting MC degranulation. In summary, this study elucidates the mechanism underlying virus-triggered activation of MCs and has the potential to aid in the development of MC-targeted antiviral therapeutic strategies.

◆Spike proteins of coronaviruses activate mast cells for degranulation via stimulating Src/PI3K/AKT/Ca2+ intracellular signaling cascade【ASM Journals : Journal of Virology　2025年4月30日】

Abstract

Objective

The aim of this study was to investigate the psychological distress associated with long-lasting COVID-19 olfactory dysfunction (OD).

Methods

Patients with an OD lasting for more than 6 months were consecutively recruited from the Dour Medical Center (Belgium) from August 2023 to January 2024. The olfaction was investigated with the Olfactory Disorder Questionnaires (ODQ) and the threshold, identification, and discrimination (TDI) testing. General Anxiety Disorder (GAD-7) and Patient Health Questionnaire (PHQ-9) were used to investigate the psychological distress of patients. The olfactory and psychological outcomes of patients were compared with a group of individuals without OD.

Results

A total of 220 patients and 102 asymptomatic individuals completed the evaluations. The mean duration of OD was 31.1 ± 25.1 months. The mean GAD-7 and PHQ-9 scores were significantly higher in OD patients than in asymptomatic individuals (P < 0.008). The OD patient prevalence of mild-to-severe depression (51.2% vs. 44.1%) and mild-to-severe anxiety (39.5% vs. 32.4%) disorders was significantly higher than asymptomatic individuals. Severe anxiety was associated with the presence of anosmia. GAD-7 and PHQ-9 scores were higher in females than in males. The severity of depression (PHQ-9) and anxiety (GAD-7) was significantly associated with the severity of OD (ODQ) and nasal symptoms (SNOT-22). Conclusion

The presence of a long-lasting OD in patients consulting in otolaryngology is associated with psychological distress. While the causality relationship remains unclear, depression and anxiety symptoms must be investigated in this subgroup of patients with long COVID-19.

◆Tetherin antagonism by SARS-CoV-2 ORF3a and spike protein enhances virus release【National Library of Medicine　2023年9月21日】

Abstract

The antiviral restriction factor, tetherin, blocks the release of several different families of enveloped viruses, including the Coronaviridae. Tetherin is an interferon‐induced protein that forms parallel homodimers between the host cell and viral particles, linking viruses to the surface of infected cells and inhibiting their release. We demonstrate that SARS‐CoV‐2 infection causes tetherin downregulation and that tetherin depletion from cells enhances SARS‐CoV‐2 viral titres. We investigate the potential viral proteins involved in abrogating tetherin function and find that SARS‐CoV‐2 ORF3a reduces tetherin localisation within biosynthetic organelles where Coronaviruses bud, and increases tetherin localisation to late endocytic organelles via reduced retrograde recycling. We also find that expression of Spike protein causes a reduction in cellular tetherin levels. Our results confirm that tetherin acts as a host restriction factor for SARS‐CoV‐2 and highlight the multiple distinct mechanisms by which SARS‐CoV‐2 subverts tetherin function.

◆Skeletal muscle properties in long COVID and ME/CFS differ from those induced by bed rest【medRxiv　2025年5月6日】

Abstract

Patients with long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) suffer from a reduced exercise capacity, skeletal muscle abnormalities and post-exertional malaise (PEM), where symptoms worsen with cognitive or physical exertion. PEM often results in avoidance of physical activity, resulting in a lower aerobic fitness, which may contribute to skeletal muscle abnormalities. Here, we compared whole-body exercise responses and skeletal muscle adaptations after strict 60-day bed rest in healthy people with those in patients with long COVID and ME/CFS, and healthy age- and sex-matched controls. Bed rest altered the respiratory and cardiovascular responses to (sub)maximal exercise, while patients exhibited respiratory alterations only at submaximal exercise. Bed rest caused muscle atrophy, and the reduced oxidative phosphorylation related to reductions in maximal oxygen uptake. Patients with long COVID and ME/CFS did not have muscle atrophy, but had less capillaries and a more glycolytic fibers, none of which were associated with maximal oxygen uptake. While the whole-body aerobic capacity is similar following bed rest compared to patients, the skeletal muscle characteristics differed, suggesting that physical inactivity alone does not explain the lower exercise capacity in long COVID and ME/CFS.

◆Long COVID May Cause Long-Term Changes in the Heart and Lungs and May Lead to Cardiac and Pulmonary Diseases【Newswise : Mount Sinai Health System　2025年5月6日】

Patients suffering from long COVID may exhibit persistent inflammation in the heart and lungs for up to a year following SARS-CoV-2 infection—even when standard medical tests return normal results—potentially placing them at elevated risk for future cardiac and pulmonary conditions. These findings come from a new study conducted by researchers at the Icahn School of Medicine at Mount Sinai and published April 30, in the Journal of Nuclear Medicine.

The study, the largest of its kind using advanced PET/MRI imaging, discovered significant abnormalities in cardiovascular and pulmonary tissues, as well as altered levels of circulating immune-regulating proteins, in long COVID patients. These abnormalities could serve as early warning signs of diseases such as heart failure, valvular heart disease, and pulmonary hypertension.

“Long COVID has emerged as a major public health challenge, and the long-term sequelae remain largely undefined,” says corresponding author Maria G. Trivieri, MD, PhD, Associate Professor of Medicine (Cardiology), and Diagnostic, Molecular and Interventional Radiology at the Icahn School of Medicine. “This study brings us closer to understanding how SARS-CoV-2 affects the heart and lungs over time. We believe long COVID results in an inflammatory response that may predispose patients to premature coronary artery disease, pulmonary hypertension, and valvular damage such as stenosis or regurgitation.”

“Since 2020, we have been publishing work showing that even mild or asymptomatic COVID infections can have serious cardiovascular consequences, even in previously fit and healthy individuals,” says David Putrino, PhD, the Nash Family Director of Mount Sinai’s Cohen Center for Recovery from Complex Chronic Illness. “This paper provides more data to highlight that SARS-CoV-2 is a virus that profoundly affects vascular health and that every new infection can do damage. Infection prevention is crucial.”

Researchers studied 100 adult Mount Sinai patients who had a confirmed COVID-19 infection between December 2020 and July 2021 and were experiencing persistent cardiopulmonary symptoms. Most of these patients had no previous diagnosis of cardiovascular disease. About 300 days after their initial infection, 91 participants underwent hybrid 18F-fluorodeoxyglucose positron emission tomography combined with magnetic resonance imaging (PET/MRI), an advanced imaging method that simultaneously detects structural and metabolic abnormalities. Among those scanned, 52 patients—representing 57 percent—demonstrated evidence of inflammation affecting the heart muscle, pericardium (the thin sac that surrounds the heart), heart valves, particularly the mitral valve, and the aortic and pulmonary blood vessels. In several cases, more than one of these regions was affected.

The PET/MRI scans revealed myocardial (heart muscle) abnormalities in 22 participants, characterized by scarring and thickening of the tissue, similar to findings of myocarditis or cardiomyopathy. Pericardial involvement was seen in 20 patients, indicating either inflammation or effusion, a buildup of fluid. Inflammation near the mitral valve was identified in 10 participants, and vascular inflammation involving the aorta or pulmonary arteries was observed in 28 participants. All abnormalities were associated with persistent symptoms such as chest pain, fatigue, and shortness of breath.

In parallel, researchers performed plasma protein analysis, which showed abnormal patterns in key biomarkers that regulate inflammation and immune signaling. These findings correlated with the imaging abnormalities, providing molecular-level confirmation of persistent inflammation.

To further validate the results, a control group of nine individuals with confirmed prior COVID-19 infection but no lingering cardiopulmonary symptoms was studied between March and October 2023. These controls underwent the same imaging and blood testing and did not exhibit the inflammatory changes observed in the symptomatic long COVID cohort.

“We found a range of cardiopulmonary inflammatory patterns, backed by abnormal protein profiles,” Dr. Trivieri says. “These insights could have far-reaching implications for diagnosis and surveillance. If patients experience lingering symptoms such as shortness of breath, they should consult a physician for further evaluation. Our results should also raise awareness among clinicians to consider a patient’s COVID history and evaluate persistent symptoms more thoroughly.”

Zahi Fayad, PhD, senior author of the study and Director of the Biomedical Engineering and Imaging Institute at the Icahn School of Medicine at Mount Sinai, emphasized the broader impact of these findings. “This study highlights the unique power of hybrid PET/MRI imaging to uncover hidden disease processes in long COVID patients,” Dr. Fayad says. “These findings should change how we approach care and surveillance—not only recognizing SARS-CoV-2 as a potential long-term cardiovascular risk factor, but also integrating molecular imaging into post-COVID evaluation protocols. We now have objective evidence that can guide earlier detection and potentially prevent future cardiopulmonary events.”

The Mount Sinai team continues to follow this patient cohort to assess long-term outcomes and is exploring whether these imaging and biomarker patterns can help predict who is most at risk for developing chronic cardiovascular or pulmonary disease after COVID-19.

◆One-year cognitive follow-up in patients hospitalized for COVID-19 in a cohort from Mexico【ScienceDirect　2025年5月1日】

Abstract

Cognitive symptoms have been identified as a prevalent sequela of Covid-19 disease, that it they persist beyond the acute phase of infection. This situation has consequences for the general and emotional functionality of patients. The aim of this work was to explore the prevalence of both global and specific impairments in various cognitive domains in a group of SARS-CoV-2 infection survivors with subjective memory-related complaints from the COVID-19 clinic of the National Institute of Respiratory Diseases. Study subjects underwent a neuropsychological assessment three months after hospital discharge (first assessment T1) and again twelve months later (second assessment T2). The results show that although in the second assessment there was a significant improvement (p < 0.05) in several domains: attention, gnosias, visual memory and language, however, we noted a high persistence of impairments in executive functions (20.8 % at T2). On the other hand, in the analysis of the complete assessment we observed deficits in at least three tests, 73.7 % at T1 and 60.4 % at T2. While in memory and semantic and phonological verbal fluency tasks, we observed improvement without being statistically significant. Our results show that although symptoms such as depression and anxiety decreased significantly, cognitive impairment may still be observed after one year, so we suggest that those patients with severe COVID-19 should receive cognitive follow-up through periodic cognitive assessments.

◆Partnership formed to confront rise in illness, premature death in young Americans【Insurance NewsNet : Doug Bailey　2025年5月6日】

Reacting to a troubling rise in chronic illnesses among younger Americans, two organizations—GoMo Health and Insurance Collaboration to Save Lives (ICSL)— have joined forces to form a new initiative, dubbed the ForwardLiving Partnership, to help insurers better support policyholders before they become critically ill.

The ForwardLiving Partnership is a proactive push to adapt the insurance industry to a stark new reality: more Americans in their 20s, 30s, and 40s are developing serious conditions such as diabetes, hypertension, and heart disease—conditions once associated with aging. Insurers are taking note, as these early-life diagnoses lead not only to higher claim volumes but also to increased disability and premature death across multiple lines of insurance.

“The health trajectory of increasingly younger adults has changed dramatically since COVID-19,” said Bob Gold, Chief Behavioral Technologist at GoMo Health, which offers personalized patient and consumer engagement solutions using behavioral and cognitive science to improve outcomes and reduce costs. “Our partnership with ICSL gives insurers a way to address this shift head-on—by supporting their members with programs designed to prevent illness, manage chronic disease, and ultimately extend healthy years of life.”

ForwardLiving Partnership blends science, data

The ForwardLiving Partnership program brings together GoMo Health’s behavioral science platform with ICSL’s research and actuarial insights. The result is a suite of customizable, digital care tools to manage chronic illness, reduce risk, and keep younger people healthier for longer. These tools are designed to be integrated into existing insurance plans and focus on remote monitoring, mental health, and personalized support to promote healthier daily decisions.

The data backing this effort is stark. According to the CDC, 60% of U.S. adults now live with a chronic condition, and 40% have more than one. Research published in the Journal of the American Medical Association adds that people who had COVID-19 may face heightened long-term risks for heart and lung diseases.

ICSL’s analysis of mortality trends highlights five key areas driving earlier deaths: cardiac and circulatory disorders, neurological conditions, metabolic and digestive diseases, cancers, and external causes such as accidents or violence.

Disability cases have surged

The impact of these conditions is being felt not just in doctors’ offices, but in the workplace. U.S. Bureau of Labor Statistics data shows the number of working-age adults with a disability has surged—from 6.5 million pre-pandemic to over 8.4 million by early 2024.

“This is a critical time for our industry,” said Mitch Bagley, an ICSL board member. “Because of GoMo Health’s behavioral focus on health promotion and targeted risk mitigation, this partnership gives insurers a powerful tool to engage with members and improve health outcomes.”

GoMo Health’s technology—built on its proprietary BehavioralRx® science—offers real-time digital engagement and “concierge care” that extends support into people’s everyday lives. The platform uses a mobile bot to triage home health data, conduct live conversations, and collect patient-reported outcomes—all designed to nudge users toward healthier behaviors and improve adherence to care plans.

Dr. Kate Hendricks, a former CDC medical officer and ICSL’s medical advisor, put it bluntly: “Here in America, our health has been declining for the last several years. This partnership provides insurers with a wellness solution to help reverse this trend.”

The ForwardLiving Partnership is being rolled out to life, health, and supplemental insurance carriers that are rethinking their strategies for long-term risk and member engagement. The hope is to help insurers move beyond claims processing and into proactive, preventive care—particularly for younger people who now find themselves facing chronic illness earlier than any previous generation.

◆Cognitive impairment and associated neurobehavioral dysfunction in post-COVID syndrome【ScienceDirect　2025年5月3日】

Abstract

There is a high prevalence of neuropsychiatric sequelae in post-COVID syndrome, most commonly chronic fatigue, the mechanisms of which remain poorly understood. As altered function of the reward system has been suggested as a causal factor, we aimed to distinguish whether reward processing or task-unspecific cognitive operations are impaired in post-COVID syndrome. Our cohort study included 24 patients diagnosed with post-COVID syndrome and 24 demographically matched healthy controls. Questionnaire assessment of neuropsychiatric symptoms and socio-demographic variables, the Monetary Incentive Delay Task during an fMRI scan, and pupillary measurements were performed.
In addition to clinical neuropsychiatric symptoms, participants in the post-COVID group demonstrated significantly slower task performance compared to healthy controls, although the function of behavioral reward circuits appeared unimpaired. However, the influence of rewarding cues on post-COVID patients increased significantly over time during task performance, correlating with temporally delayed activation of the left frontal gyrus and increased activity in task-unspecific brain regions in post-COVID patients. Furthermore, slower reaction times on the task were associated with a lower pupil diameter and a higher pupillary unrest index.
This study proposes that post-COVID syndrome is a process that may not affect reward processing, but leads to neural hypoarousal and temporally altered brain activity in frontal and task-unspecific brain regions.

◆Genome-wide association study of post COVID-19 syndrome in a population-based cohort in Germany【nature : scientific reports　2025年5月6日】

Abstract

If health impairments due to coronavirus disease 2019 (COVID-19) persist for 12 weeks or longer, patients are diagnosed with Post-COVID Syndrome (PCS), or Long-COVID. Although the COVID-19 pandemic has largely subsided in 2024, PCS is still a major health burden worldwide, and identifying potential genetic modifiers of PCS remains of great clinical and scientific interest. We therefore performed a case-control type genome-wide association study (GWAS) of three recently developed PCS (severity) scores in 2,247 participants of COVIDOM, a prospective, multi-centre, population-based cohort study of SARS-CoV-2-infected individuals in Germany. Each PCS score originally represented the weighted sum of the binary indicators of all, or a subset, of 12 PCS symptom complexes, assessed six months or later after the PCR test-confirmed SARS-CoV-2 infection of a participant. For various methodical reasons, however, the PCS scores were dichotomized along their respective median values in the present study, prior to the GWAS. Of the 6,383,167 single nucleotide polymorphisms included, various variants were found to be associated with at least one of the PCS scores, although not at the stringent genome-wide statistical significance level of 5 × 10− 8. With p = 6.6 × 10− 8, however, the genotype-phenotype association of SNP rs9792535 at position chr9:127,166,653 narrowly missed this threshold. The SNP is located in a region including the NEK6, PSMB7 and ADGRD2 genes which, however, does not immediately suggest an etiological connection to PCS. As regards functional plausibility, variants of a possible effect mapped to the olfactory receptor gene region (lead SNP rs10893121 at position chr11:123,854,744; p = 2.5 × 10− 6). Impairment of smell and taste is a pathognomonic feature of both, acute COVID-19 and PCS, and our results suggest that this connection may have a genetic basis. Three other genotype-phenotype associations pointed towards a possible etiological role in PCS of cellular virus repression (CHD6 gene region), activation of macrophages (SLC7A2) and the release of virus particles from infected cells (ARHGAP44). All other gene regions highlighted by our GWAS did not relate to pathophysiological processes currently discussed for PCS. Therefore, and because the genotype-phenotype associations observed in our GWAS were generally not very strong, the complexity of the genetic background of PCS appears to be as high as that of most other multifactorial traits in humans.