SARS-CoV-2 と COVID-19 に関する備忘録 Vol.43

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SARS-CoV-2 と COVID-19 に関するメモ・備忘録

◆Cytosolic nucleic acid sensing as driver of critical illness: mechanisms and advances in therapy【nature : signal transduction and targeted therapy　2025年3月19日】

Abstract

Nucleic acids from both self- and non-self-sources act as vital danger signals that trigger immune responses. Critical illnesses such as acute respiratory distress syndrome, sepsis, trauma and ischemia lead to the aberrant cytosolic accumulation and massive release of nucleic acids that are detected by antiviral innate immune receptors in the endosome or cytosol. Activation of receptors for deoxyribonucleic acids and ribonucleic acids triggers inflammation, a major contributor to morbidity and mortality in critically ill patients. In the past decade, there has been growing recognition of the therapeutic potential of targeting nucleic acid sensing in critical care. This review summarizes current knowledge of nucleic acid sensing in acute respiratory distress syndrome, sepsis, trauma and ischemia. Given the extensive research on nucleic acid sensing in common pathological conditions like cancer, autoimmune disorders, metabolic disorders and aging, we provide a comprehensive summary of nucleic acid sensing beyond critical illness to offer insights that may inform its role in critical conditions. Additionally, we discuss potential therapeutic strategies that specifically target nucleic acid sensing. By examining nucleic acid sources, sensor activation and function, as well as the impact of regulating these pathways across various acute diseases, we highlight the driving role of nucleic acid sensing in critical illness.

◆COVID infections are causing drops in IQ and years of brain aging, studies suggest【CBC radio : Amanda Buckiewicz　2024年4月13日】

When COVID-19 first reared its head back in 2019, it brought with it a slew of strange symptoms beyond just respiratory problems. One of the most puzzling symptoms in those early days was something called “brain fog” — cognitive issues like confusion, forgetfulness, and trouble focusing.

And while other symptoms have changed as the virus mutated, brain fog is still a common complaint of COVID sufferers not only during the initial illness, but extending for months or even years afterwards. Several recent studies have been trying to understand exactly what this virus is doing to our brains — and how to stop it.

Dr. Ziyad Al-Aly, the chief of research and development at the VA St. Louis Health Care System, spoke with Quirks & Quarks host Bob McDonald about what he’s seeing in his research on COVID and the brain. Here is part of their conversation.

Take me through some of these effects that COVID has had on the brain. What have you seen?

One of the key manifestations that people experience after SARS-CoV-2 infection is what we call colloquially as brain fog. That’s the mental haziness, the inability to remember things, to connect the dots, to really think clearly.

In addition to brain fog, we see people coming back to the clinics with mini strokes. We see a lot of people with headache disorders, sleep disturbances, sleep problems. A lot of people come back to the clinic with tingling of the extremities, tingling in the legs or sometimes in the arms. In rare cases, seizure disorders. So really a variety of health problems in the brain.

Is COVID actually affecting the way the brain functions?

There are studies that have been done comparing people who had COVID-19, versus people who didn’t, and then gave them cognitive testing to measure their ability to cognitively process information and test their IQ. And there’s very clear differences in the IQ of people who had been infected with COVID-19 versus people who did not. Even mild COVID can give people about a three-point loss of IQ.

The key caveat to those studies is that most of these were done from the original phase of the pandemic when we didn’t have vaccination, when the virus was very different and we didn’t have antivirals. And we also don’t really know whether those cognitive losses that I just described, that three-point IQ loss, we don’t really know how permanent that is.

What about brain aging?

It’s very, very clear that in some individuals they do experience structural abnormalities and some other abnormalities of imaging that are commensurate with what normal people experience with about seven years of brain aging.

Now the hope is that those effects are not are not long lasting and then the brain with neuroplasticity and other other sort of mechanisms will be able to restore itself back to normal health. But I think that really remains to be characterized and seen in studies.

How is the virus that comes in through the lungs affecting the brain so much?

It induces inflammation of the brain. One of the clear signals from the studies that we’ve done and a lot of other people have done over the past several years is that clearly in some people it can provoke inflammatory reactions in the brain or neuroinflammation and that may explain some of the symptoms that are experienced by some individuals.

It can affect multiple substances on which the brain really depends to function normally. One of them is cortisol. So people have studied this out of Yale University and have shown that people with long COVID or people after SARS-CoV-2 infection can experience inappropriately low level of cortisol and that’s actually an important hormone for a lot of certain normal physiologic processes, including cognitive performance, and a lower cortisol level than where it should be can explain some of the cognitive dysfunction that is seen in some people after SARS-CoV-2 infection. There are some studies also done on showing low serotonin levels and that can also explain some of the symptoms.

But doesn’t the brain have a protective mechanism, the so-called blood brain barrier?

By inducing that inflammation of the brain, that actually makes that barrier leaky, so it starts leaking things into the brain that shouldn’t be there. And things from the brain to outside the brain that also should not exit outside the brain. So a leaky blood brain barrier can also explain, you know, some of the manifestations that we see after COVID-19 infection.

How is this changing over time as the virus mutates?

We’re in a different phase of the pandemic now than what we all experienced in March 2020. We have a different virus. We have availability of vaccines now. We have antivirals. So all of these drivers have now sort of reduced overall the burden of long COVID.

That doesn’t mean that SARS-CoV-2 infection is benign, is inconsequential. We still see people in the hospital with SARS-CoV-2 infection, we still see people with strokes and heart attacks and, you know, brain fog and all other manifestations. But overall, I think the risk has sort of declined over the course of the pandemic.

How unique are these other effects on the body and the brain and the heart to COVID?

The big revelation or the big aha moment in this pandemic was the realization that SARS-CoV-2 infection can produce this really large basket of long-term adverse health effects. When we went back and started thinking about what happened to people after the Spanish flu, we found historical accounts that sort of resemble, to a large degree, what we described now after SARS-CoV-2 infection, people having increased risk of Parkinson’s disease, headaches, brain fog etcetera.

I think one of the major lessons that I learned from this pandemic is that there are long tails to pandemics. And yes, we can focus all we want on the acute phase, or the tip of the iceberg, but the reality is that there is a really much larger chunk of disability and disease beneath that tip of the iceberg.

◆Beyond long COVID — how reinfections could be causing silent long-term organ damage【CBC radio : Sonya Buyting　2025年3月21日】

COVID may no longer be considered an official global emergency, but mounting scientific evidence suggests every COVID infection a person gets increases their risk of developing long-term health issues.

“There is no such thing as a COVID infection without consequence,” says long COVID researcher, David Putrino, from the Icahn School of Medicine at Mount Sinai in New York.

The long-term effects can show up as long COVID, with symptoms such as shortness of breath, digestive problems, fast or irregular heartbeats, extreme fatigue and brain fog, or as silently accumulating cellular or organ damage.

Putrino has been studying the lingering effects of COVID since early in the pandemic five years ago. Here is part of his conversation with Quirks & Quarks host Bob McDonald.

What kind of cumulative, silent damage can a COVID infection cause, beyond long COVID?

There is more and more literature emerging to show that, beyond long COVID, there are also effects that SARS-CoV-2 infections are having on the bodies of the general public that manifest in a way that might be viewed as silent. So what I mean by that is no one’s going to their doctor and saying “I feel different” or “I feel as though my functional status has changed,” but what’s happening is, silently in the background, things are changing.

A good example of that is the effect that SARS-CoV-2 infections can have on cognition. There was a recent 2024 study that showed us that individuals who survive an acute COVID-19 infection — these are not individuals who are getting diagnosed with long COVID — on average will lose somewhere in the neighbourhood of two to six IQ points per infection.

Really, with each infection?

According to the most recent study, yes. So there is a cumulative effect that can be occurring with each infection.

Early in the pandemic, we actually published a paper where we showed that, even in animal models — when we infected mice with a very, very mild case of SARS-CoV-2 infection — which only caused lung inflammation, we still saw these inflammatory chemicals called chemokines emerging from the infected lungs and starting to attack central nervous system structures such as the spinal cord and the brain.

Wow. So in other words, COVID is doing more than just infecting the lungs; it’s going to other parts of the body.

Exactly. You know, this is a virus that, once it enters the body, is very capable of entering the bloodstream, creating immune responses that travel all over the body.

COVID is largely known as a respiratory disease. Can you walk me through the range of other body systems that might be vulnerable to long-term damage?

Well, in all of the peer-reviewed literature that has emerged on long COVID, we’ve seen that it is a very diffuse clinical syndrome where every single organ system can be affected. And at last count, over 200 symptoms have been catalogued as potential symptoms of long COVID.

When we actually dig into the science of why long COVID is causing the symptoms that it’s causing, we see that there are problems such as what we call “viral persistence.” Meaning the SARS-CoV-2 virus is not being effectively cleared by the body and it’s sticking around.

It’s hiding out in different areas of the body in what we typically call “immune privileged sites,” which mean that immune cells don’t actually go there and can’t sort of seek out and destroy the virus. So that can happen in a number of different locations in the body, which leads to a wide array of symptoms.

We also see that the virus can cause prolonged chronic inflammation that can be whole-body wide. So it can affect every single organ and so often, many of the symptoms that people are experiencing are more related to which organ is most susceptible to them given their past medical history.

So we see things that are quite insidious. People who were pre-diabetic are suddenly diabetic. People who were having a few issues with gallbladder, suddenly can’t digest fat anymore.


[COVID infections can lead to long-term health effects in nearly every organ system in the body. (Washington University School of Medicine in St. Louis)]

Well, what is it about the coronavirus that enables it to spread throughout the body like that?

In 2021, two colleagues of mine published a really wonderful paper that I think is very prescient and it spoke about why SARS-CoV-2 presents such an increased threat to cause persistent symptoms. The reality of that situation is that this virus has a lot of very unique qualities that specifically cause immune damage to the host.

So it’s not just about infecting you and causing respiratory illness and fever and all of the things that we usually get with the viral infection. This virus also specifically causes your immune system to become weaker.

It disrupts what we call “interferon signalling,” which is part of the immune system that helps you to fight off infections or latent infections, such as Epstein Barr virus.

Typically our immune system can keep these things suppressed, but when SARS-CoV-2 enters the picture, it starts to cause altered interferon signalling. It causes immune damage and dysregulation.

And suddenly, not only does your body have trouble clearing the SARS-CoV-2 virus itself, but it also starts to have trouble keeping some of these other viruses that have been latent from reactivating and causing problems.

In addition to SARS-CoV-2’s ability to dysregulate the immune system and suppress the immune system, the spike protein itself is very damaging to blood vessel structures as well as red blood cells and platelets themselves.

And so between those two features, the ability to dysregulate the immune system and the ability to cause systemic damage throughout the bloodstream, you have a very dangerous novel virus on your hands.


[A scanning electron micrograph of an cell heavily infected with SARS-CoV-2 virus. (US National Institute of Allergy and Infectious Disease)]

Well, if it has the ability to suppress the immune system, how does that affect our ability to fight off other external pathogens that we might be susceptible to?

It’s something that we worry about a lot. In 2023, we published a paper in Nature where we showed that individuals with long COVID were much more likely than a cohort of healthy controls to express signs of what we call “T-cell exhaustion.” Meaning that their T cells, which are parts of the immune system that are typically used to fight off infections, are starting to present as exhausted — that there has been a persistent stimulation of these T cells for long enough that their responses over time are starting to weaken.

As a result, in this study we saw immune dysregulation, we saw hormonal dysregulation, we saw reactivation of herpes viruses that were previously thought to be latent.

And as we have made leaps and bounds in our ability to understand the role of these persistent pathogens, these things that we used to think, “Everybody’s got Epstein-Barr virus, but don’t worry, it sort of just lays dormant in your body and it doesn’t cause any trouble.”

What we’re learning is that, well, it very much can cause trouble. If it’s mixed with another pathogen and that pathogen causes the reactivation, then people can get very, very sick.

For the longest time in the field of immunology, there was the sort of adage that your immune system needs to be tested every now and again to stay strong. That’s an old-fashioned idea.

The more new-fashioned and evidence-based idea is that, although your immune system can take on [a COVID] infection, you want to avoid testing it as much as possible because your body is sustaining damage with each infection that it survives.

◆Variant connective tissue as a risk factor for Long COVID: a case-control study【Research Square　2025年3月19日】

Abstract

Long COVID (LC) is a major medical challenge, with approximately 20 million sufferers in the US and UK alone. Determining the risk factors for LC is of utmost importance to aid in effective and preventative treatment. We assessed whether variant connective tissue, a known risk factor for several illnesses, is predictive of LC risk. We administered a survey to 1,816 respondents recruited from representative online panels in the US and UK assessing joint hypermobility and LC status. In separate well-controlled binomial logistic regressions, both generalized joint hypermobility (OR 1.29, 95% CI 1.00 to 1.65) and extreme hypermobility (OR 2.12, 95% CI 1.43 to 3.16) were predictive of LC. Our findings suggest that hypermobility influences the odds of developing LC by both increasing the likelihood of developing severe initial symptoms from COVID-19 and increasing the risk that individuals with no or moderate initial symptoms experience LC.

◆Wearable heart rate variability monitoring identifies autonomic dysfunction and thresholds for post-exertional malaise in Long COVID【medRxiv　2025年3月19日】

Abstract

Objectives Patients with Long COVID experience disabling fatigue, autonomic dysfunction, reduced exercise capacity, and post-exertional malaise (PEM). Heart rate variability (HRV) can evaluate autonomic function and monitor overexertion, potentially helping to mitigate PEM. This study aimed to use continuous multi-day HRV recordings to monitor overexertion and study autonomic function in Long COVID.

Method Heart rate and HRV were continuously measured in 127 patients with long COVID (43±11 years, 32% male) and 21 healthy controls (42±13 years, 48% male), and daily life activities tracked in a logbook. Participants underwent a (sub)maximal cardiopulmonary exercise test to determine heart rate at the first ventilatory threshold (VT1) to study HRV responses to exercise at different intensities.

Results HRV was lower in patients with long COVID compared to healthy controls during various daily activities and sleep (p<0.027). HRV remained lower for 24 hours after exercise below, at or above VT1 in patients, but not in healthy controls (p=0.010). Nighttime HRV decreased with intense exercise and longer durations in patients with long COVID (p=0.018), indicative of exercise-induced diurnal disturbances of the autonomic nervous system in long COVID. Conclusion Heart rate variability, assessed by wearables, confirms autonomic dysfunction in patients with long COVID. The delayed recovery of the sympathovagal balance after exercise close and above to VT1 suggests that VT1 can be practically interpreted as a PEM threshold.

Application These results confirm the applicability of wearables to assess autonomic function and manage overexertion in long COVID patients.

What is already known on this topic Patients with long COVID often experience fatigue, autonomic dysfunction, and post-exertional malaise (PEM). HRV can be used as a non-invasive tool to measure autonomic function and recovery. Anecdotal evidence suggests lower HRV in patients with long COVID, but measurements are usually very short.

What this study adds This study demonstrates that continuous HRV monitoring through wearables can effectively identify overexertion and autonomic dysfunction during daily activities in patients with long COVID. Patients with long COVID have a lower heart rate variability during sleep and HRV remained significantly lower for a longer period after moderate-to-heavy exercise, that is generally associated with the induction of post-exertional malaise.

How this study might affect research, practice, or policy This study supports the use of wearables for assessing autonomic function and overexertion in daily life, helping patients with long COVID in pacing daily activities to mitigate symptoms of post-exertional malaise. HRV tracking after exercise shows that VT1 is a potential threshold for PEM. Sports physicians and physiotherapists can incorporate HRV biofeedback measures into pacing advice to patients. Additional research is needed to further investigate the effect of such an intervention.

◆Whole-body visualization of SARS-CoV-2 biodistribution in vivo by immunoPET imaging in non-human primates【nature communications　2025年3月21日】

Abstract

The COVID-19 pandemic has caused at least 780 million cases globally. While available treatments and vaccines have reduced the mortality rate, spread and evolution of the virus are ongoing processes. Despite extensive research, the long-term impact of SARS-CoV-2 infection is still poorly understood and requires further investigation. Routine analysis provides limited access to the tissues of patients, necessitating alternative approaches to investigate viral dissemination in the organism. We address this issue by implementing a whole-body in vivo imaging strategy to longitudinally assess the biodistribution of SARS-CoV-2. We demonstrate in a COVID-19 non-human primate model that a single injection of radiolabeled [89Zr]COVA1-27-DFO human monoclonal antibody targeting a preserved epitope of the SARS-CoV-2 spike protein allows longitudinal tracking of the virus by positron emission tomography with computed tomography (PET/CT). Convalescent animals exhibit a persistent [89Zr]COVA1-27-DFO PET signal in the lungs, as well as in the brain, three months following infection. This imaging approach also allows viral detection in various organs, including the airways and kidneys, of exposed animals during the acute infection phase. Overall, the technology we developed offers a comprehensive assessment of SARS-CoV-2 distribution in vivo and provides a promising approach for the non-invasive study of long-COVID pathophysiology.

◆Asymmetrical glymphatic dysfunction in patients with long Covid associated neurocognitive impairment- correlation with BBB disruption【BMC Neurology　2025年3月19日】

Abstract

Background and purpose

The glymphatic system, a waste clearance pathway, has been implicated in several neurological conditions associated with neuroinflammation. COVID-19 associated neurocognitive impairment, part of the post-acute sequelae of SARS-CoV-2 infection (PASC), is strongly associated with neuroinflammation and disrupted blood-brain barrier (BBB). Several studies have implicated a synergistic interaction between the glymphatic system dysfunction and BBB disruption. In this proof-of-concept study, we investigated the role of the MRI metric diffusion along the perivascular spaces DTI (DTI-ALPS) in patients with PASC and correlated this with the BBB capillary permeability metric- K trans derived from Dynamic contrast enhanced (DCE) perfusion.

Materials and methods

14 subjects with PASC who had persisting symptoms of anosmia, ageusia, fatigue, and cognitive impairment (CI) and ten healthy age and sex matched controls were recruited. All PASC subjects underwent routine and advanced MR brain imaging at two time points, (3 months +/- 2 weeks) after initial infection – referred as Time Point 1 (TP-1) – and 10 repeated the MRI scan 12 months (+/- 2 weeks) later – referred as Time Point 2 (TP-2), while the controls had MR imaging done only at TP-1. All had mild neurocognitive impairment. In the final analysis we included those who had DTI study at both time points (n-10). MR imaging included DCE perfusion and DTI in addition to anatomical imaging.

Statistical analysis

Given the small size of the sample and nonnormality of data in the descriptive analyses, nonparametric analyses were used for group comparisons. A two-sample Wilcoxon rank sum test was used to show the differences in DTI-ALPS between the patients and controls in the predefined regions of interest. Spearman’s correlation coefficient (rho) was used to assess the correlation between DTI-ALPS index with K trans.

Results

There was significant reduction in the DTI-ALPS index between the patients and controls in the left hemisphere (z = 2.04, p < 0.04). However, there was no significant change over time in the index. There was a strong inverse correlation between the central white matter K trans and DTI-ALPS index (rho = 0.66, p < 0.03). Conclusion

Our study indicates that disordered para vascular drainage, a marker for glymphatic system and BBB damage may contribute to neurocognitive impairment (NCI) among patients with PASC. The DTI-ALPS index, which does not require contrast injection, has the potential to serve as a non-invasive biomarker.

◆COVID-19 Brought About a Large Rise in POTS Cases【The University of Toredo : Tyrel Linkhorn　2025年3月24日】

The number of patients diagnosed with a chronic and oftentimes debilitating blood circulation disorder has risen sharply in the wake of COVID-19, according to new research from The University of Toledo.

Scientists and physicians have long believed postural orthostatic tachycardia syndrome, commonly known as POTS, could be brought on by viral infections. The Epstein-Barr virus in particular has been posited as a possible trigger for the syndrome, which is characterized by an inability to regulate blood pressure and heart rate.

The UToledo study, however, points to the COVID-19 pandemic causing an unprecedented acceleration in what was once thought to be a relatively rare condition.

It also suggests, the researchers say, that many patients suffering from what clinicians have broadly called long COVID may actually have POTS.

“We’ve suspected for several years now that there is an association between COVID and POTS. I’m seeing this in my own clinic. My waiting list is longer than it has ever been,” said Dr. Blair Grubb, a UToledo Health cardiologist who has treated and studied POTS for more than three decades. “Now we have the data to back that up. This study helps give validity and voice to these patients, and it gives us a treatable target.”

Grubb and his colleagues examined data combed from the electronic medical records of more than 65 million U.S. patients, comparing the incidence and prevalence of POTS before and after the emergence of COVID-19.

The differences were stark.

From January 2018 to March 1, 2020 — the date researchers used as the cutoff for the pre-COVID era — the study found an estimate of 4.21 new cases diagnosed per month. That rose to 22.66 new cases per month from March 2, 2020, to June 2024, representing a more than five-fold increase.

The study also found the incidence rate of POTS was 1.42 per 1 million person-years before COVID and 20.3 cases per 1 million person-years after COVID.

The research was recently published in the European Heart Journal – Quality of Care and Clinical Outcomes.

Though the mechanisms behind it are not fully understood, POTS is effectively a blood pooling disorder. When someone stands up, gravity pulls the blood in their body downward. For most of us, our body compensates by tightening the blood vessels in the lower half of the body.

In POTS patients, however, that constriction of blood vessels doesn’t happen. Instead, blood drains downward and reduces the brain’s supply of oxygen. The heart beats harder and faster as it tries to ship more oxygen to the brain, but with limited blood supply coming in, it can’t catch up with demand.

The resulting symptoms can include dizziness, fatigue, fainting and a whole host of other symptoms including pain, anxiety and brain fog.

Dharmindra Dulal, fourth-year medical student and the lead author of the study, said the paper adds clear scientific evidence to the strong relationship between COVID-19 infection and the development of POTS — a link that previously had been limited to anecdotal accounts.

But more importantly, UToledo’s research helps to add clarity to the experience of some individuals who have been left dealing with debilitating aftereffects of COVID infection.

“We talk about long COVID,” Dulal said. “That’s a big umbrella and there is a lot of disease underneath it. We can’t just say ‘this patient has long COVID.’ We need to diagnose each condition separately, and I think what’s most valuable about this paper is that we can confidently say POTS is one part of long COVID.”

Intriguingly, there appears to be a parallel in the recent spike in POTS from our not-so-distant history. Following the 1918 influenza pandemic, one prominent physician wrote about a confounding group of cardiovascular symptoms in British soldiers who had served in World War I.

“They had POTS,” Grubb said. “He didn’t call it that, but he’s describing it absolutely perfectly. This is not new. I think viral infections have triggered these events throughout time, it’s just that we put it all together recently. We have a good idea of what’s going on now, whereas in the past they didn’t. And we’re seeing that COVID is really good at causing POTS.”

While UToledo researchers say the syndrome still lacks broad recognition even today, awareness has been growing.

“I think people are starting to recognize POTS more as a disease entity itself, and papers like this only help to raise awareness,” said Dr. Ahmed Maraey, a cardiology fellow in the College of Medicine and Life Sciences and the study’s corresponding author.

That awareness, Maraey said, brings with it hope for more effective ways of treating POTS in the future.

“If we know there is a disease here, we can do more for it. We can do more clinical trials, we can look for new treatments, we can train more people to be able to manage the disease,” he said. “Once we’ve identified there is a problem, we can better deal with it.”

◆Disruption in the Host-Phage Dynamics and Altered Microbial Diversity in the Upper Respiratory Tract of SARS-CoV-2 Infected Individualss【medRxiv　2025年3月25日】

Abstract

The Upper Respiratory Tract (URT) is an important site for the predisposition and multiplication of the SARS-CoV-2 virus. Therefore, URT is a critical site to investigate the changes in the microbiome caused by the SARS-CoV-2 infection. In this study, we have used the whole genome shotgun metagenomic approach to investigate URT swab samples (n=96) collected from SARS-CoV-2-positive individuals (n=48) (non-hospitalised but symptomatic) and healthy controls (n=48) belonging to five districts of central India. This study aims to compare the phageome diversity and investigate the correlation of the phageome profiles with the sample type (SARS-CoV-2 or Control) to determine the nature of phage-host interactions and to assess the effect of SARS-CoV-2 viral load over host and phage abundance. The results showed that Detrevirus was a prominent bacteriophage in controls and Maxrubnervirus in SARS-CoV-2 samples. Higher Chao1 indices were observed in the SARS-CoV-2 group for bacteria (886.00 vs. 351.00, p < 0.0001) and phages (39.00 vs. 16.00, p = 0.0002). The Simpson index was lower for bacteria (0.88 vs. 0.93, p = 0.0024) and higher for phages (0.86 vs. 0.79, p = 0.0384). Ct-dependent variations in bacterial (H = 6.69, p = 0.035) and phage (H = 8.97, p = 0.011) abundances were also observed. Disrupted host-phage interactions were observed in SARS-CoV-2 samples, with a weaker model fit (logistic R2 = 0.7425) than controls (logistic R2 = 0.9265). These findings highlight the need to integrate virome and bacteriome analyses with potential diagnostic, prognostic, and therapeutic applications for infectious disease research.

◆Vitamin B12 as an epidrug for regulating peripheral blood biomarkers in long COVID-associated visuoconstructive deficit【nature : scientific reports　2025年3月19日】

Abstract

Approximately four months after recovering from a mild COVID-19 infection, around 25% of individuals developed visuoconstructive deficit (VCD), which was found to be correlated with an increase in peripheral immune markers and alterations in structural and metabolic brain imaging. Recently, it has been demonstrated that supplemental vitamin B12 regulates hyperinflammation during moderate and severe COVID-19 through methyl-dependent epigenetic mechanisms. Herein, whole peripheral blood cultures were produced using samples obtained from patients with confirmed persistent VCD, and controls without impairment, between 10 and 16 months after mild COVID-19. This experimental model was used to assess the leukocyte expression patterns of 11 biomarkers previously associated with VCD in long COVID and explore the potential of pharmacological B12 in regulating these genes. The results showed that patients with persistent VCD displayed continued upregulation of CCL11 and LIF compared to controls. It is worth noting that elevated serum levels of CCL11 have been previously linked to age-related neurodegenerative diseases. Notably, the addition of 1 nM of vitamin B12 to blood cultures from individuals with VCD normalized the mRNA levels of CCL11, upregulated the neuroprotective HGF, and, to a lesser extent, downregulated CSF2 and CXCL10. There was an inverse correlation observed between CCL11 mRNA levels and methylation levels of specific cytosines in its promoter region. These findings underscore the significance of systemic inflammation in persistent VCD associated with long COVID. Moreover, the study provides evidence suggesting that B12, acting as an epidrug, shows promise as a therapeutic approach for addressing this cognitive impairment.

◆Patients’ experiences of living with Long Covid and their beliefs about the role of psychology in their condition【Sage Journals　2025年3月17日】

Abstract

Some patients with chronic conditions are unreceptive to a psychological approach. This study aimed to explore the experience of Long Covid (LC) with an emphasis on patients’ beliefs about the role of psychology. UK participants (n = 14) with either self-reported or diagnosed LC took part in semi-structured interviews. Thematic analysis described three main themes: ‘Living in uncertainty’, ‘Why should I trust you if you don’t believe me?’ and ‘Once I know the cause people will believe me’. Transcending these themes was a tension between professional experts and experts by lived experience and a dichotomy between psychological and medical explanations. Overarching all themes was a sense that synthesising the biological and psychological components of LC could help to resolve this tension. In summary. living with LC is characterised by feeling disbelieved which can drive the rejection of psychology. Helping patients feel listened to may encourage a more positive approach to psychological support.

◆Five years after COVID, North Texans continue to navigate toll of the pandemic【KERA News : Kailey Broussard　2025年3月26日】

After losing her mother, Mary Castro, during the first months of the COVID-19 pandemic, Rosie Davis has found healing and community in honoring her and others.

Every March since 2021, Davis has collected thousands of photos and yellow hearts bearing the names of people from all over the world who have died from COVID. Her exhibit, Yellow Heart Memorial, is now on display in the lobby of the Irving Archives and Museum.

“This has been my way of … humanizing them and not letting them go into history as just a number because they’re grandmothers, grandfathers, their parents, friends, neighbors, aunts, uncles,” Davis said. “They meant the world to somebody, to a family.”

For Davis, who was unable to say goodbye to her mother or bury her as planned, the exhibit offers her a way to honor Castro and others who died during a pandemic that left friends and families without avenues to process their grief.

More than 1.2 million people in the U.S. have died from COVID-19 since 2020 – a number that researchers say may not full capture the virus’ toll. Similarly hard to measure, around 18 million adults, or 6% of the population, live with long COVID. Despite burgeoning research, there is still not a cure.

Five years after the pandemic started in the U.S., the effects remain, from a strain on hospital systems to distrust in public health experts and vaccinations.

Davis said that’s made it hard for people to access resources or move on.

“What are we supposed to do with our grief? How are we supposed to handle this?” she said. “I don’t feel like we’ve moved forward from the pandemic.”

Misinformation, disinformation, cut funding

Josh and Amanda Smith’s jobs in the entertainment industry meant their livelihoods depended on returning to work – and doing so vaccinated.

During the beginning of the pandemic, the couple created the Facebook group DFW Corona Connection to connect friends and family to each other and COVID-19. Soon after, membership boomed – and so did the volume of posts. Both saw a shift when the vaccine became available.

“It really did divide into two factions, and we’re […] still living in that space today as we speak,” Amanda Smith said.

Vaccine hesitancy rose during the pandemic and in the years that followed, along with overall distrust in public health institutions. In 2023 Texas banned private businesses from enforcing COVID-19 vaccine mandates, and a slate of bills now before state lawmakers would further weaken vaccine mandates as a measles outbreak in West Texas, Oklahoma and New Mexico has sickened more than 300 people – most of them unvaccinated.

“All of these things, there’s misinformation surrounding it has led us to where we are here now,” Amanda Smith said. “Why are we having conversations about measles? Why am I having a conversation about polio?”

The National Institutes of Health under President Donald Trump canceled more than 40 grants related to vaccine hesitancy, according to NPR. Officials with the NIH also urged scientists to remove references in grant applications to the mRNA vaccine technology used to develop COVID-19 vaccinations, according to the health policy nonprofit KFF.

Dr. Erin Carlson, director of graduate public health programs at the University of Texas at Arlington, said the pandemic highlighted the importance of widely available testing, as well as consistently funded research in immune systems and vaccine development.

She described the federal research cuts as “a gut punch” to science for both the U.S. and abroad.

“We will be less able to protect our families, will be less able to protect our country, will be less able to have the innovations that will help protect the world,” she said. “And a lot of it goes back to misinformation and disinformation.”

Carlson said patients are more likely to trust their family physicians over others, making education and relationship building important, as well as building relationships within different communities.

“We as public health practitioners have got to ask people, what about this vaccine scares you and listen because we have to know how to address the concerns and the fears of a particular prevention or treatment method if we are really going to be able to communicate it effectively,” Carlson said.

“Science always wins,” she said, but unnecessary public funding cuts, misinformation and disinformation will lead to unnecessary hospitalizations and deaths.

“This is going to be a very difficult time,” she said. “This is not going to get under control easily, but it will eventually get under control.”

Community, rebuilding trust take priority

Carlson said for future pandemics, communities will have to come together as they did in the early days of COVID-19 cases, when people pooled resources and supported neighbors through uncertain times.

“If we are going to fight another highly transmissible, highly virulent pandemic, we will have to get back together,” she said.

Steve Love of the Dallas-Fort Worth Hospital Council said the pandemic led to greater collaborations among local hospital officials.

“When some parts of the country were experiencing COVID two and three weeks ahead of us, it was amazing to me how some of the clinical people, especially physicians, contacted their colleagues in other parts of the country to kind of get a head start on some of the things we might see and what we might experience,” he said.

That collaboration has continued: Agencies have reorganized to address an IV fluids shortage caused by flooding at a North Carolina manufacturing plant. Hospitals are also coordinating in case measles cases associated with the West Texas outbreak appear in North Texas.

Carrie Kroll, senior vice president of advocacy and public policy at the Texas Hospital Association, said her organization has focused on addressing violence towards public health employees and educating the public about preventative efforts.

“I want the public to remember that while we may not be the health care heroes that everybody saw during the pandemic, we remain very committed to the communities we’re in and that we continue to be mindful of our goal to serve patients,” she said.

Meanwhile, Rosie Davis, whose Yellow Hearts Memorial is on display through the end of March, wants to see a national monument for people who have died of COVID-19. Permanent monuments are in the works or complete in Texas; Missouri; and California.

“It gives us as families the reassurance that our loved ones are forever going to be honored,” she said, “and they’re never going to be forgotten.”

◆Neurocognitive and emotional long-term effects of COVID-19 infections in children and adolescents: results from a clinical survey in Bavaria, Germany【BMC Infectious Diseases　2025年3月26日】

Abstract

Background

While children and adolescents typically experience mild symptoms during the acute phase of the COVID-19 infection, some may develop severe post-infectious symptoms. In our study Post-COVID Kids Bavaria we integrated somatic and psychiatric aspects of the post-COVID syndrome to provide a holistic description of symptoms, provide early treatment, and detect possible risk factors associated with post-infectious neurocognitive and emotional impairments.

Methods

We conducted an observational study involving 85 pediatric patients aged 12–17 years (M = 12.48, 61.2% female) who had confirmed COVID-19 infections and were experiencing persistent symptoms for at least 4 weeks. Our neuropsychological assessment comprised infection-specific patient interviews, psychopathological examinations, emotional well-being and behavioral difficulty questionnaires, and (computerized) tests assessing concentration, attention, and memory skills. Additionally, patients underwent neurologic, pneumologic, gastrointestinal, and cardiologic assessments.

Results

Overall, the majority of patients reported experiencing elevated levels of fatigue (82.4%), loss of motivation (72.9%), concentration and attention deficits (71.8%), a worsened mood (53%), and a higher level of anxiety (31.8%). The most common diagnosis was the post-COVID adjustment disorder (ICD-10 F43.2, U09.9!; 38.8%) followed by the post-COVID attention deficit disorder (ICD-10 F98.80, U09.9!; 23.5%). Neuropsychiatric evaluation primarily identified deficits in sustained attention. There was a significant association between somatic and psychiatric post-COVID diagnoses. Patients with allergies exhibited a higher risk of developing a post-COVID adjustment disorder. For the post-COVID attention deficit disorder, age, sex, obesity, pre-existing psychiatric diagnosis, and the virus variant were relevant factors.

Conclusions

Our findings indicate a diverse array of neuropsychiatric symptoms associated with the post-COVID syndrome, emphasizing the interconnectedness between somatic and neuropsychiatric diagnoses. To optimize treatment, comprehensive strategies involving both somatic and psychiatric professionals are crucial for addressing the syndrome’s complexity and managing symptoms effectively.

Study registration

The study Post-COVID Kids Bavaria was registered with the German Clinical Trials Register (DRKS), funded by the Bavarian State Ministry of Health, Care and Prevention and approved by the Ethics Committee of the University of Regensburg on the 29th of November, 2021 (Reference: 21-2691-101).

◆Neurocognitive and emotional long-term effects of COVID-19 infections in children and adolescents: results from a clinical survey in Bavaria, Germany【IMMUNO INFOMATICS　2025年3月12日】

Abstract

Molecular mimicry is one mechanism by which an infectious agent may trigger an autoimmune disease in a human subject and occurs when foreign- and self-peptides contain similar epitopes that activate an autoimmune response in a susceptible individual. Here, we employ a scalable in-silico approach, to identify 861 pairs of known SARS-CoV-2 and autoimmune disease epitopes, out of more than one billion possible pairs. These SARS-CoV-2 epitopes show 1) sequence homology to human autoimmune disorder epitopes, 2) empirical binding data that predict that they bind the same major histocompatibility complex (MHC) molecule and 3) exhibit high empirical immunogenicity. Analysis of these epitope pairs reveals an association between autoimmune disorders, such as type 1 diabetes, autoimmune uveitis, ankylosing spondylitis, and SARS-CoV-2 infection. These associations are consistent with those reported in the literature from the analysis of clinical records.

◆Long-Term Intra-Host Evolution of SARS-CoV-2 in an Immunocompromised Patient: Recombination and Within-Host Mutations Driving Viral Adaptation【bioRxiv　2025年3月26日】

Abstract

An immuno-compromised patient with lymphoma experienced a prolonged SARS-CoV-2 infection lasting 14 months, initially infected with B.1.160, followed by B.1.1.7. This study focused on intra-host single nucleotide variants (iSNVs) and single nucleotide polymorphisms (SNPs), distinguishing their origin as either within-host mutations or parental. The whole genome analysis revealed accelerated evolution, with positive selection detected in key genes such as Spike, N, ORF9b, and nsp13, all involved in viral replication and immune evasion. Of the two evolutionary mechanisms involved, host-driven mutation has played a dominant role in this evolutionary story. C>T transitions emerged as the most widespread mutational signature, consistent with host-driven RNA editing mechanisms. Two host-internal mutations, A28271T in the translation initiation region of the N Kozak gene and C26858T in the M gene, were highly shared among the deposited SARS-CoV-2 sequences. Recombination with parental lineages played a major role particularly in Spike, ORF3a and M genes. In Spike, the B.1.1.7 sequence was selected, wild-type ORF3a and M were restored, suggesting a selective advantage in returning to an ancestral sequence. In addition, the temporary emergence of intra-host convergent mutations in Spike, notably L5F, D796H and T572I, underlines the strong selective pressures exerted on this gene. A 126-nucleotide deletion in ORF8 resulted in a truncated protein, reinforcing its uselessness for viral replication, as observed in circulating variants such as B.1.1.7. The present case highlights the complex interplay between viral recombination and mutations within the host in chronic infections and further underscores the remarkable evolutionary plasticity of SARS-CoV-2 and its potential to generate highly adapted viral strains.