SARS-CoV-2 と COVID-19 に関する備忘録 Vol.58

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SARS-CoV-2 と COVID-19 に関するメモ・備忘録

◆Chronic post-COVID neuropsychiatric symptoms persisting more than 1 year after infection during the ‘Omicron wave’【CAMBRIDGE UNIVERSUTY PRESS　2025年7月25日】

Abstract

Background

The heterogeneity of chronic post-COVID neuropsychiatric symptoms (PCNPS), especially after infection by the Omicron strain, has not been adequately explored.

Aims

To explore the clustering pattern of chronic PCNPS in a cohort of patients having their first COVID infection during the ‘Omicron wave’ and discover phenotypes of patients based on their symptoms’ patterns using a pre-registered protocol.

Method

We assessed 1205 eligible subjects in Hong Kong using app-based questionnaires and cognitive tasks.

Results

Partial network analysis of chronic PCNPS in this cohort produced two major symptom clusters (cognitive complaint–fatigue and anxiety–depression) and a minor headache–dizziness cluster, like our pre-Omicron cohort. Participants with high numbers of symptoms could be further grouped into two distinct phenotypes: a cognitive complaint–fatigue predominant phenotype and another with symptoms across multiple clusters. Multiple logistic regression showed that both phenotypes were predicted by the level of pre-infection deprivation (adjusted P-values of 0.025 and 0.0054, respectively). The severity of acute COVID (adjusted P = 0.023) and the number of pre-existing medical conditions predicted only the cognitive complaint–fatigue predominant phenotype (adjusted P = 0.003), and past suicidal ideas predicted only the symptoms across multiple clusters phenotype (adjusted P < 0.001). Pre-infection vaccination status did not predict either phenotype. Conclusions

Our findings suggest that we should pursue a phenotype-driven approach with holistic biopsychosocial perspectives in disentangling the heterogeneity under the umbrella of chronic PCNPS. Management of patients complaining of chronic PCNPS should be stratified according to their phenotypes. Clinicians should recognise that depression and anxiety cannot explain all chronic post-COVID cognitive symptoms.

◆Your Gut May Be the Key to Chronic Fatigue, Long COVID【Neuroscience: Cara McDonough　2025年7月27日】

Key Questions Answered

Q: What did the study uncover about ME/CFS?
A: The study revealed that ME/CFS disrupts key interactions between the gut microbiome, immune system, and metabolism, identifying biological markers that distinguish patients from healthy individuals with up to 90% accuracy.

Q: How does the AI platform, BioMapAI, help?
A: BioMapAI integrates thousands of data points—including microbiome profiles, blood tests, immune markers, and symptoms—to identify patterns and disruptions unique to ME/CFS, making precision medicine approaches more feasible.

Q: Why are these findings important for patients?
A: The research not only strengthens the biological legitimacy of ME/CFS but also offers personalized insight into symptom origins, potentially guiding future dietary, lifestyle, and therapeutic interventions—especially for long COVID and related conditions.

Summary: A groundbreaking study using AI has revealed how ME/CFS disrupts critical connections between the immune system, gut microbiome, and metabolism. The new platform, BioMapAI, achieved 90% accuracy in identifying ME/CFS patients based on stool, blood, and symptom data—offering long-overdue validation for millions living with this debilitating illness.

Researchers found that patients had distinct biological signatures, including lower levels of beneficial fatty acids, disrupted immune cell activity, and metabolic imbalances. These findings could guide personalized treatments and provide a scientific foundation for future therapies, especially for long COVID sufferers with overlapping symptoms.

Key Facts:

  • AI Breakthrough: BioMapAI distinguished ME/CFS patients with 90% accuracy using immune, microbiome, and metabolic data.
  • Biological Signatures: Patients showed disrupted tryptophan metabolism, inflammatory immune cells, and reduced butyrate levels.
  • Precision Medicine Potential: Findings may lead to targeted interventions for ME/CFS and long COVID.

Source: Jackson Laboratory

Millions suffering from myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a debilitating condition often overlooked due to the lack of diagnostic tools, may be closer to personalized care, according to new research that shows how the disease disrupts interactions between the microbiome, immune system, and metabolism.

The findings—potentially relevant to long COVID due to its similarity with ME/CFS—come from data on 249 individuals analyzed using a new artificial intelligence (AI) platform that identifies disease biomarkers from stool, blood, and other routine lab tests.

“Our study achieved 90% accuracy in distinguishing individuals with chronic fatigue syndrome, which is significant because doctors currently lack reliable biomarkers for diagnosis,” said study author Dr. Derya Unutmaz, Professor in immunology at The Jackson Laboratory (JAX).

“Some physicians doubt it as a real disease due to the absence of clear laboratory markers, sometimes attributing it to psychological factors.”

The research was led by Dr. Julia Oh, formerly at JAX and now a microbiologist and professor at Duke University, in collaboration with ME/CFS clinicians Lucinda Bateman and Suzanne Vernon of the Bateman Horne Center, and Unutmaz, who directs the JAX ME/CFS Collaborative Research Center. Details appear today in Nature Medicine.

Mapping the Invisible

Chronic fatigue syndrome is characterized by severe symptoms that significantly impair physical and mental activities, including persistent fatigue, sleep abnormalities, dizziness, and chronic pain.

Experts often compare ME/CFS to long COVID, as both conditions frequently follow viral infections, such as Epstein-Barr virus. In the United States, ME/CFS affects between 836,000 and 3.3 million individuals— many undiagnosed—and costs the economy $18 to $51 billion annually due to healthcare expenditures and lost productivity, according to the Centers for Disease Control and Prevention.

Prior studies have noted immune disruptions in ME/CFS, Unutmaz said. This new research builds upon those findings by investigating how the gut microbiome, its metabolites, and immune responses interact.

The team linked these connections to 12 classes of patient-reported symptoms, which were aggregated from hundreds of datapoints generated by patient health and lifestyle surveys.

These include sleep disturbances, headaches, fatigue, dizziness, and other symptoms the researchers mapped in their entirety from microbiome changes to metabolites, immune responses, and clinical symptoms.

“We integrated clinical symptoms with cutting-edge omics technologies to identify new biomarkers of ME/CFS,” Oh said. “Linking symptoms at this level is crucial, because ME/CFS is highly variable. Patients experience a wide range of symptoms that differ in severity and duration, and current methods can’t fully capture that complexity.”

To conduct the study, the researchers analyzed comprehensive data collected from the Bateman Horne Center, a leading ME/CFS, Long-Covid, and fibromyalgia research center in Salt Lake City, Utah.

Dr. Ruoyun Xiong, also a lead author on the study, developed a deep neural network model called BioMapAI. The tool integrates gut metagenomics, plasma metabolomics, immune cell profiles, blood test data, and clinical symptoms from 153 patients and 96 healthy individuals over four years.

Immune cell analysis proved most accurate in predicting symptom severity, while microbiome data best predicted gastrointestinal, emotional, and sleep disturbances. The model connected thousands of patient data points, reconstructing symptoms such as pain and gastrointestinal issues, among several others.

It also revealed that patients who were ill for less than four years had fewer disrupted networks than those who were ill for more than ten years.

“Our data indicate these biological disruptions become more entrenched over time,” Unutmaz said. “That doesn’t mean longer-duration ME/CFS can’t be reversed, but it may be more challenging.”

The study included 96 age- and gender-matched healthy controls, showing balanced microbiome-metabolite-immune interactions, in contrast to significant disruptions in ME/CFS patients linked to fatigue, pain, emotional regulation issues, and sleep disorders.

ME/CFS patients also had lower levels of butyrate, a beneficial fatty acid produced in the gut, along with other nutrients essential for metabolism, inflammation control, and energy.

Patients with elevated levels of tryptophan, benzoate, and other markers indicated a microbial imbalance. Heightened inflammatory responses, particularly involving MAIT cells sensitive to gut microbial health, were also observed.

“MAIT cells bridge gut health to broader immune functions, and their disruption alongside butyrate and tryptophan pathways, normally anti-inflammatory, suggests a profound imbalance,” said Unutmaz.

An Actionable Dataset

Even though the findings require further validation, they significantly advance scientists’ understanding of ME/CFS and provide clearer hypotheses for future research, the authors said.

Since animal models can’t fully reflect the complex neurological, physiological, immune, and other system disruptions seen in ME/CFS, Oh said it will be crucial to study humans directly to identify modifiable factors and develop targeted treatments.

“The microbiome and metabolome are dynamic,” Oh said. “That means we may be able to intervene—through diet, lifestyle, or targeted therapies—in ways that genomic data alone can’t offer.”

BioMapAI also achieved roughly 80% accuracy in external data sets, confirming key biomarkers identified in the original group. This consistency across diverse data was striking, the authors said.

“Despite diverse data collection methods, common disease signatures emerged in fatty acids, immune markers, and metabolites,” Oh said. “That tells us this is not random. This is real biological dysregulation.”

The researchers intend to share their dataset broadly with BioMapAI, which supports analyses across diverse symptoms and diseases, effectively integrating multi-omics data that are difficult to replicate in animal models.

“Our goal is to build a detailed map of how the immune system interacts with gut bacteria and the chemicals they produce,” Oh said.

“By connecting these dots we can start to understand what’s driving the disease and pave the way for genuinely precise medicine that has long been out of reach.” 

Additional authors include Elizabeth Aiken, Ryan Caldwell, Lina Kozhaya, and Courtney Gunter (The Jackson Laboratory), and Suzanne D. Vernon and Lucinda Bateman (Bateman Horne Center).

 

◆T Cell Dynamics in COVID-19, Long COVID and Successful Recovery【MDPI　2025年7月27日】

Abstract

Despite targeting mainly the respiratory tract, SARS-CoV-2 disrupts T cell homeostasis in ways that may explain both acute lethality and long-term immunological consequences. In this study, we aimed to evaluate the T-cell-mediated chain of immunity and formation of TCR via TREC assessment in COVID-19 and long COVID (LC). For this study, we collected 231 blood samples taken from patients with acute COVID-19 (n = 71), convalescents (n = 51), people diagnosed with LC (n = 63), and healthy volunteers (n = 46). With flow cytometry, we assessed levels of CD4+ and CD8+ minor T cell subpopulations (i.e., naïve, central and effector memory cells (CM and EM), Th1, Th2, Th17, Tfh, Tc1, Tc2, Tc17, Tc17.1, and subpopulations of effector cells (pE1, pE2, effector cells)). Additionally, we measured TREC levels. We found distinct changes in immune cell distribution—whilst distribution of major subpopulations of T cells was similar between cohorts, we noted that COVID-19 was associated with a decrease in naïve Th and CTLs, an increase in Th2/Tc2 lymphocyte polarization, an increase in CM cells, and a decrease in effector memory cells 1,3, and TEMRA cells. LC was associated with naïve CTL increase, polarization towards Th2 population, and a decrease in Tc1, Tc2, Em2, 3, 4 cells. We also noted TREC correlating with naïve cells subpopulations. Our findings suggest ongoing immune dysregulation, possibly driven by persistent antigen exposure or tissue migration of effector cells. The positive correlation between TREC levels and naïve T cells in LC patients points to residual thymic activity. The observed Th2/Th17 bias supports the hypothesis that LC involves autoimmune mechanisms, potentially driven by molecular mimicry or loss of immune tolerance.

◆Antibody repertoire associated with clinically diverse presentations of pediatric SARS-CoV-2 infection【medRxiv　2025年7月23日】

Abstract

Pediatric SARS-CoV-2 infection results in clinical presentations ranging from asymptomatic/mild infection to severe pulmonary COVID-19, to Multisystem Inflammatory Syndrome in Children (MIS-C), characterized by hyperinflammation and multi-organ involvement. While various aspects of antibody responses to pediatric SARS-CoV-2 infection manifestations have been reported, parallel studies of antibody responses to viral and self-antigens are understudied. We tested whether clinical presentations of increasing severity corresponded to different antiviral antibody and autoantibody signatures. Using custom arrays, we found that, relative to uninfected subjects, all SARS-CoV-2 infection manifestations were associated with increased autoantibody production, suggesting pediatric SARS-CoV-2 infection as a risk factor for autoimmune complications. Subtle differences were seen in autoantibody patterns among infection groups, with some autoantibodies more associated with mild manifestations and others with severe ones. When we compared MIS-C and severe COVID-19 subjects, we found differences in IgG (mostly IgG1) abundance but not in Fc-mediated effector functions. Thus, MIS-C may be associated with abnormal antibody function, suggesting that this syndrome, and perhaps other post-acute sequelae of SARS-CoV-2 infection, may be associated with antibody dysfunction. Our study shows that the antibody repertoire varies with clinical presentation of SARS-CoV-2 in children and its analysis may help understand long COVID pathogenesis.

◆Relative efficacy of masks and respirators as source control for viral aerosol shedding from people infected with SARS-CoV-2: a controlled human exhaled breath aerosol experimental study【THE LANCET : eBioMedicine　2024年5月29日】

Summary

Background

Tight-fitting masks and respirators, in manikin studies, improved aerosol source control compared to loose-fitting masks. Whether this translates to humans is not known.

Methods

We compared efficacy of masks (cloth and surgical) and respirators (KN95 and N95) as source control for SARS-CoV-2 viral load in exhaled breath of volunteers with COVID-19 using a controlled human experimental study. Volunteers (N = 44, 43% female) provided paired unmasked and masked breath samples allowing computation of source-control factors.

Findings

All masks and respirators significantly reduced exhaled viral load, without fit tests or training. A duckbill N95 reduced exhaled viral load by 98% (95% CI: 97%–99%), and significantly outperformed a KN95 (p < 0.001) as well as cloth and surgical masks. Cloth masks outperformed a surgical mask (p = 0.027) and the tested KN95 (p = 0.014). Interpretation

These results suggest that N95 respirators could be the standard of care in nursing homes and healthcare settings when respiratory viral infections are prevalent in the community and healthcare-associated transmission risk is elevated.

◆Causes of symptoms and symptom persistence in long COVID and myalgic encephalomyelitis/chronic fatigue syndrome【Cell reports Medicine　2025年7月30日】

Summary

Debilitating symptoms for many years can follow acute COVID-19 (“long COVID”), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and various post-acute infection syndromes (PAISs). Together, long COVID and ME/CFS affect 60–400 million individuals, globally. Many similar underlying biological abnormalities have been identified in both conditions including autoantibodies against neural targets, endothelial dysfunction, acquired mitochondrial dysfunction, and a pro-inflammatory gut microbiome. Each of these abnormalities may directly cause some of the symptoms. In addition, the symptoms also may be caused by ancient, evolutionarily conserved symptomatic and metabolic responses to vital threats—sickness behavior and torpor—responses mediated by specific, recently discovered neural circuits. These neural circuits constitute a symptom-generating pathway, activated by neuroinflammation, which may be targeted by therapeutics to quell neuroinflammation. Many factors cause the symptoms to become chronic, including persistent infectious agents (and/or their nucleic acids and antigens) and the fact that many of the underlying biological abnormalities reinforce each other, creating ongoing physiological vicious cycles.

◆Unmasking the ‘Zombie’ Cells: The shocking link between ME/CFS and Long Covid【IOL : Tracy-Lynn Ruiters　2025年7月30日】

Despite testing negative and being told they’re fine, millions of people recovering from infections like Covid-19, influenza and glandular fever are left battling crippling fatigue, brain fog, joint pain, gut issues and a strange crash after any physical effort — a pattern that’s becoming too common to ignore.

These symptoms are medically known as myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS).

Both the World Health Organization and the US Centers for Disease Control and Prevention officially classify ME/CFS as a brain disorder and post-viral fatigue syndrome.

Now, researchers from Stellenbosch University believe they may have found a common underlying factor linking ME/CFS and Long Covid: zombie-like cells hiding in our blood vessels.

Dr. Massimo Nunes, a Postdoctoral Research Fellow at Stellenbosch University, explained:“Uncovering how ME/CFS and Long Covid originate and evolve over time is essential to move beyond symptom management toward disease-modifying therapies.”

The Stellenbosch team’s latest hypothesis is based on a growing body of research into what happens to blood vessels after viral infections. It proposes that viruses like SARS-CoV-2 (which causes Covid-19), Epstein–Barr virus, and influenza A can infect the inner lining of blood vessels, known as endothelial cells.

Once infected, these cells enter a “senescent” state — they stop functioning normally but stay alive, releasing molecules that trigger inflammation and clotting, while resisting destruction by the immune system.

Prof. Resia Pretorius, Distinguished Professor in Physiological Sciences at Stellenbosch University, said: “The long-term economic and health burden of Long Covid is immense, and we’re seeing striking parallels with ME/CFS, a condition that has been historically neglected. Many Long Covid patients meet ME/CFS diagnostic criteria, highlighting the urgent need to recognize these overlapping diseases as serious physiological illnesses with real-world consequences.”

The phenomenon of cellular senescence isn’t new, but Stellenbosch’s research adds a new dimension by placing these “zombie” blood-vessel cells at the centre of disease progression in both ME/CFS and Long Covid.

These dysfunctional cells contribute to thickened blood, lower oxygen delivery to tissues and immune dysfunction — a combination that aligns with what many patients experience physically and cognitively.

Prof. Burtram Fielding, Dean of the Faculty of Sciences and Professor in the Department of Microbiology, Stellenbosch University, explained: “Long Covid refers to a range of symptoms and conditions that persist for weeks, months or even years after a Covid-19 infection. It is not a single illness, but rather a collection of new, returning or ongoing symptoms that vary from person to person.”

Dr. Nunes highlighted several studies showing the overlap between Long Covid and ME/CFS diagnostic criteria: “A systematic review and meta-analysis inferred that 51% of Long COVID patients meet the diagnostic criteria for ME/CFS, based on data from 1,973 individuals across 13 studies.

“Another review with 127,117 participants found 45% met chronic fatigue criteria. A smaller study of 465 patients found 58% met ME/CFS criteria. Even in a 42-patient sample, 42% matched the diagnosis,” Nunes said.

The research team believes that when blood-vessel cells become senescent, they disrupt circulation and immune responses in ways that echo what many patients report fatigue, cognitive dysfunction, gut issues and post-exertional crashes.

“We propose that when blood-vessel cells turn into ‘zombies’, they pump out substances that make blood thicker and prone to forming tiny clots. These clots slow down circulation, so less oxygen reaches muscles and organs. This is one reason people feel drained,” Dr. Nunes said.

During physical exertion, the problem worsens. Instead of relaxing, blood vessels tighten, leading to a drop in oxygen supply. In the brain, this may contribute to dizziness and brain fog. In the gut, weakened blood-vessel walls could allow bacteria and toxins to leak into the bloodstream, fuelling further inflammation.

Adding to this is immune system exhaustion. Senescent cells are typically cleared by healthy immune responses, but in Long Covid and ME/CFS patients, natural killer cells and macrophages appear sluggish or dysfunctional. The zombie cells send out signals that help them evade immune attack, creating a cycle that allows them to persist and perpetuate illness.

As part of the next phase of their research, the Stellenbosch team is now testing blood samples from patients to see if they trigger senescence in lab-grown endothelial cells. They’re also piloting non-invasive imaging techniques to detect these ageing blood-vessel cells in real time.

“Our aim is simple: find these ageing endothelial cells in real patients. Pinpointing them will inform the next round of clinical trials and open the door to therapies that target senescent cells directly, offering a route to healthier blood vessels and, ultimately, lighter disease loads,” Dr. Nunes said.