SARS-CoV-2 と COVID-19 に関する備忘録 Vol.31

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SARS-CoV-2 と COVID-19 に関するメモ・備忘録

◆Remodeling of intracellular architecture during SARS-CoV-2 infection of human endothelium【nature scientific reports　2024年11月30日】

Abstract

Clinical data indicate that COVID-19 causes cardiovascular complications, regardless of the severity of the disease. In this work, we have shown that SARS-CoV-2 infection causes vascular dysfunction due to the modification of endothelial cell elasticity. We used human pulmonary endothelial cells (HPAECs) expressing the ACE2 receptor as a model of the endothelium. This system mimics in vivo conditions, as it allows virus entry but not replication. As a reference, we used A549 epithelial cells, a well-described model that supports productive replication of SARS-CoV-2. We show that the infection of HPAECs results in loss of cell elasticity, which correlates with increased polymerization of actin filaments and induction of the inflammatory response. On the contrary, A549 epithelial cells supporting viral replication showed increased elasticity. We also showed that the endothelial cell elasticity were impaired after infection with Alpha, Beta and Delta variants. Consequently, we believe that nonproductive SARS-CoV-2 infection associated with loss of the endothelium elasticity may be clinically relevant and result in dysfunction and damage to this tissue.

◆Productive infection of the retinal pigment epithelium by SARS-CoV-2: Initial effects and consideration of long-term consequences【OXFORD ACADEMIC PNAS NEXUS　2024年12月3日】

Abstract

As the SARS-CoV-2 coronavirus continues to evolve and infect the global population, many individuals are likely to suffer from post-acute sequelae of SARS-CoV-2 infection (PASC). Manifestations of PASC include vision symptoms, but little is known about the ability of SARS-CoV-2 to infect and impact the retinal cells. Here, we demonstrate that SARS-CoV-2 can infect and perturb the retinal pigment epithelium (RPE) in vivo, after intranasal inoculation of a transgenic mouse model of SARS-CoV-2 infection, and in cell culture. Separate lentiviral studies showed that SARS-CoV-2 Spike protein mediates viral entry and replication in RPE cells, while the Envelope and ORF3a proteins induce morphological changes. Infection with major variants of SARS-CoV-2 compromised the RPE barrier function and phagocytic capacity. It also caused complement activation and production of cytokines and chemokines, resulting in an inflammatory response that spread across the RPE layer. This inflammatory signature has similarities to that associated with the onset of age-related macular degeneration (AMD), a major cause of human blindness, resulting from RPE pathology that eventually leads to photoreceptor cell loss. Thus, our findings suggest that post-acute sequelae of SARS-CoV-2 infection of the RPE may have long-term implications for vision, perhaps comparable to the increased occurrence of AMD found among individuals infected by HIV, but with greater public health consequences due to the much larger number of SARS-CoV-2 infections.

◆A 24-month National Cohort Study examining long-term effects of COVID-19 in children and young people【nature communications medicine　2024年12月4日】

Abstract

Background

Some children and young people (CYP) infected with SARS-COV-2 experience impairing symptoms post-infection, known as post-COVID-19 condition (PCC). Using data from the National Long COVID in Children and Young People (CloCk) study, we report symptoms and their impact up to 24-months post-infection.

Methods

CloCk is a cohort of CYP in England aged 11-to-17-years when they had a SARS-CoV-2 PCR-test (between September 2020 and March 2021). Of 31,012 eligible CYP 24-months post-PCR test, 12,632 participated (response = 40.7%). CYP were grouped by infection status: ‘initial test-negatives; no subsequent positive-test’ (NN); ‘initial test-negatives; subsequent positive-test’ (NP); ‘initial test-positives; no reported re-infection’ (PN); and ‘initial test-positives; reported re-infection’ (PP). The Delphi research definition of PCC in CYP was operationalised; symptom severity/impact and validated scales (e.g., Chalder Fatigue Scale) were recorded. We examine symptom profiles 24-month post-index-test by infection status.

Results

7.2% of CYP consistently fulfil the PCC definition at 3-, 6-, 12- and 24-months. These CYPs have a median of 5-to-6 symptoms at each time-point. Between 20% and 25% of all infection status groups report 3+ symptoms 24-months post-testing; 10–25% experience 5+ symptoms. The reinfected group has more symptoms than the other positive groups; the NN group has the lowest symptom burden (p < 0.001). PCC is more common in older CYPs and in the most deprived. Symptom severity/impact is higher in those fulfilling the PCC definition. Conclusions

The discrepancy in the proportion of CYP fulfilling the Delphi PCC definition at 24-months and those consistently fulfilling the definition across time, highlights the importance of longitudinal studies and the need to consider clinical impairment and range of symptoms.

◆Lethal COVID-19 associates with RAAS-induced inflammation for multiple organ damage including mediastinal lymph nodes【PNAS　2024年11月27日】

Significance

This work defines across multiple large, independent patient cohorts the downstream implications of cytokine storm in lethal COVID-19 as driven by upstream immune gene and mitochondrial signaling producing RAAS overactivation and subsequent organ damage. Furthermore, we delineate a lymphoid organ fibrosis phenotype occurring in severe COVID-19, which has potential implications in mediating the chronic B and T cell dysfunction prevalent in long COVID. Correlations between tissue findings and circulating markers suggest this last possibility.

Abstract

Lethal COVID-19 outcomes are attributed to classic cytokine storm. We revisit this using RNA sequencing of nasopharyngeal and 40 autopsy samples from patients dying of SARS-CoV-2. Subsets of the 100 top-upregulated genes in nasal swabs are upregulated in the heart, lung, kidney, and liver, but not mediastinal lymph nodes. Twenty-two of these are “noncanonical” immune genes, which we link to components of the renin-angiotensin-activation-system that manifest as increased fibrin deposition, leaky vessels, thrombotic tendency, PANoptosis, and mitochondrial dysfunction. Immunohistochemistry of mediastinal lymph nodes reveals altered architecture, excess collagen deposition, and pathogenic fibroblast infiltration. Many of the above findings are paralleled in animal models of SARS-CoV-2 infection and human peripheral blood mononuclear and whole blood samples from individuals with early and later SARS-CoV-2 variants. We then redefine cytokine storm in lethal COVID-19 as driven by upstream immune gene and mitochondrial signaling producing downstream RAAS (renin-angiotensin-aldosterone system) overactivation and organ damage, including compromised mediastinal lymph node function.

◆Younger, Middle-Aged Adults Face Higher Burden of Neurologic Long COVID Symptoms【Drug Topics　2024年11月27日】

Younger and middle-aged adult patients are impacted more by neurologic symptoms of long COVID compared to older adults, according to recent research data published in the journal Annals of Neurology. The authors of the study said the findings support enhanced prevention, detection and treatment of long COVID in patients who are disproportionately affected.

An estimated 17 million adults in the United States have long COVID, a number that has stayed relatively steady for the past year. According to a poll from KFF, 79% of adults with long COVID reported that it limits their activity either a lot or a little. And although 5% to 10% of adults in the country may continue to experience the condition at any point, research seeking to improve its diagnosis and treatment continues to lag.

“The symptoms attributed to [long COVID] are widespread and multi-systemic, involving constitutional, respiratory, cardiovascular, musculoskeletal, neurologic, psychiatric, and gastrointestinal systems,” the authors wrote. “The neurologic manifestations of [long COVID], also known as ‘Neuro-[Long COVID],’ may be particularly debilitating and contribute to a significant proportion of the morbidity and disability faced by [long COVID] patients.”

Investigators from Northwestern University Feinberg School of Medicine conducted a study to characterize the neurologic manifestations of long COVID across the adult lifespan. The cross-sectional study evaluated patients seen at the Neuro-COVID-19 clinic at Northwestern Memorial Hospital between May 2020 and March 2023. The study aimed to assess neurologic symptoms, neurologic exam findings, quality of life, and cognitive performance among the patients.

The study cohort included 1300 patients who tested positive for SARS-COV-2 and had persistent neurological symptoms lasting 6 weeks or longer from the onset of COVID-19. Of the patients, 200 were post-hospitalization Neuro-Long COVID and 1100 were non-hospitalized Neuro-Long COVID. Patients were accepted for evaluation if they had any neurologic symptoms associated with a SARS-CoV-2 infection. The patients were separated into 3 age groups: 18 to 44 years, 45 to 64 years, and 65 years or older.

The study found that middle-aged patients made up most of the post-hospitalization group and younger patients made up most of the non-hospitalized group. In total, younger and middle-aged patients accounted for 71% of post-hospitalization patients and 90.5% of non-hospitalized patients. Patients had a median of 5 neurologic manifestations or symptoms attributed to long COVID. In the post-hospitalization group, younger adults had a higher number of symptoms with between 4 to 8, followed by middle-aged with 3 to 7 and older adults with 2 to 6. The number of symptoms between patients in the non-hospitalized group was not as significant.

Additionally, the higher burden of neurological symptoms among younger and middle-aged adults translated to worse subjective quality of life. Although older adults had the highest number of comorbidities and an increased frequency of abnormal neurologic exams, they had a lower burden of most neurologic and non-neurologic symptoms attributed to long COVID.

“While deaths from COVID-19 continue to decrease, people still get repetitive infections with the virus and may develop long COVID along the way,” Igor Koralnik, MD, a corresponding author on the study, said in a release. “Long COVID is causing an alteration in patients’ quality of life. Despite vaccinations and boosters, about 30% of COVID patients develop some long COVID symptoms. These findings have an immense public health impact, given that long COVID significantly contributes to the leading global burden of disability and disease caused by the neurological disorders.”

◆Mitochondrial dysfunction in acute and post-acute phases of COVID-19 and risk of non-communicable diseases【PNAS　2024年12月4日】

Abstract

The COVID-19 pandemic, caused by SARS-CoV-2, has resulted in widespread morbidity and mortality, with a significant portion of the affected population experiencing long-term health complications. This review explores the mechanisms of mitochondrial dysfunction in both the acute and post-acute phases of COVID-19, highlighting its impact on various organs and its potential role in the development of non-communicable diseases (NCDs). We discuss how SARS-CoV-2 directly affects mitochondrial function and the role of the virus-induced immune response in exacerbating mitochondrial impairment. This review highlights the critical role of mitochondria in COVID-19 pathogenesis and the importance of addressing mitochondrial health to mitigate acute and chronic effects of the disease.

◆The proteome content of blood clots observed under different conditions: successful role in predicting clot amyloid(ogenicity)【bioRxiv　2024年12月3日】

Abstract

A recent analysis compared the proteome of (i) blood clots seen in two diseases – sepsis and long COVID – when blood was known to have clotted into an amyloid microclot form (as judged by staining with the fluorogenic amyloid stain thioflavin T) with (ii) that of those non-amy-loid clots considered to have formed normally. Such fibrinaloid microclots are also relatively resistant to fibrinolysis. The proteins that the amyloid microclots contained differed markedly both from the soluble proteome of typical plasma and that of normal clots, and also between the disease studies (an acute syndrome in the form of sepsis in an ITU and a chronic disease represented by Long COVID). Many proteins in the amyloid microclots were low in concentration in plasma and were effectively accumulated into the fibres, whereas many other abundant plasma proteins were excluded. The proteins found in the microclots associated with the diseases also tended to be themselves amyloidogenic. We here ask effectively the inverse question. This is: can the clot proteome tell us whether the clots associated with a particular disease contained proteins that are observed uniquely (or are highly over-represented) in known amyloid clots relative to normal clots, and thus were in fact amyloid in nature? The answer is in the affirmative in a variety of major coagulopathies, viz. venous thromboembolism, pulmonary embolism, deep vein thrombosis, various cardiac issues, and ischaemic stroke. Galectin-3-binding protein and thrombospondin-1 seem to be especially widely associated with amyloid-type clots, and the latter has indeed been shown to be incorporated into growing fibrin fibres. These may consequently provide useful biomarkers with a mechanistic basis.

◆Long-term dysregulation of plasma peptidome in mild and multiple COVID-19 recovered patients revealed by a novel efficient peptidomics workflow【SPRINGER NATURE　2024年12月7日】

Abstract

After recovering from COVID-19, many patients experience “long COVID” symptoms. Existing research has predominantly focused on moderate to severe cases, with limited studies examining mild cases and recurrent infections. The circulating low-molecular-weight (LMW) peptidome, involving lipid metabolism, coagulation, and immune pathways, is crucial for understanding COVID-19’s long-term effects. We developed a peptidomics workflow utilizing solid-phase extraction with highly wrinkled GO-Fe3O4 composite materials (HWGO-F) and nanoLC-MS/MS detection. By altering the pH, HWGO-F enhances plasma peptide adsorption and purification. Compared to traditional methods, our workflow offers improved detection depth and reproducibility for over 70% of peptide signals with CV < 20%. We investigated plasma peptide profiles in mild COVID-19 patients post-recovery from single or second infections. The findings indicate persistent abnormalities in initial COVID-19 infections’ plasma peptide profiles, gradually diminishing over time. Secondary infections prolong recovery. Disrupted functions include lipid metabolism, coagulation and complement cascades, and infection-related pathways. Lipid metabolism may normalize within 3 months, while coagulation and immune abnormalities can last 3–6 months. After secondary infections, lipid metabolism irregularities may last at least 1 month, with extended coagulation and immune imbalances. These results provide a theoretical foundation for understanding the widespread occurrence of long COVID and guide recovery care for mild cases.

◆Equivocating and Deliberating on the Probability of COVID-19 Infection Serving as a Risk Factor for Lung Cancer and Common Molecular Pathways Serving as a Link【MDPI　2024年12月6日】

Abstract

The COVID-19 infection caused by SARS-CoV-2 in late 2019 posed unprecedented global health challenges of massive proportions. The persistent effects of COVID-19 have become a subject of significant concern amongst the medical and scientific community. This article aims to explore the probability of a link between the COVID-19 infection and the risk of lung cancer development. First, this article reports that SARS-CoV-2 induces severe inflammatory response and cellular stress, potentially leading to tumorigenesis through common pathways between SARS-CoV-2 infection and cancer. These pathways include the JAK/STAT3 pathway which is activated after the initiation of cytokine storm following SARS-CoV-2 infection. This pathway is involved in cellular proliferation, differentiation, and immune homeostasis. The JAK/STAT3 pathway is also hyperactivated in lung cancer which serves as a link thereof. It predisposes patients to lung cancer through myriad molecular mechanisms such as DNA damage, genomic instability, and cell cycle dysregulation. Another probable pathway to tumorigenesis is based on the possibility of an oncogenic nature of SARS-CoV-2 through hijacking the p53 protein, leading to cell oxidative stress and interfering with the DNA repair mechanisms. Finally, this article highlights the overexpression of the SLC22A18 gene in lung cancer. This gene can be overexpressed by the ZEB1 transcription factor, which was found to be highly expressed during COVID-19 infection.

◆Dysbiosis of gut microbiota in COVID-19 is associated with intestinal DNA phage dynamics of lysogenic and lytic infection【ASM Journals　2024年12月10日】

Abstract

This study compared intestinal DNA phage dynamics and gut microbiota changes observed at the onset of coronavirus disease 2019 (COVID-19). The study participants included 19 healthy individuals and 19 patients with severe acute respiratory syndrome coronavirus 2 infection. Significant differences were observed in the diversity of the intestinal DNA virome after the onset of COVID-19 compared with that in healthy individuals. Classification by their tail morphology resulted in the order Caudovirales, a double-stranded DNA phage, accounting for >95% of all participants. In classifying phages based on host bacteria, a decreased number of phages infecting mainly the Clostridia class was observed immediately after the onset of COVID-19 and recovered over time. After the onset of COVID-19, two distinct movement patterns of intestinal phages and their host bacteria were observed: phage- and bacteria-predominant. The abundance of obligate anaerobes, such as Clostridium_sense_strict_1, Fusicatenibacter, and Romboutsia, and the phages hosting these bacteria decreased immediately after the onset of COVID-19, and faster phage recovery was observed compared with bacterial recovery. In contrast, the genus Staphylococcus, a facultative anaerobic bacterium, increased immediately after the onset of COVID-19, whereas the phages infecting Staphylococcus decreased. Furthermore, immediately after the onset of COVID-19, the percentage of lytic phages increased, whereas that of temperate phages decreased. These observations suggest that the gut microbiota dysbiosis observed immediately after the onset of COVID-19 may be linked to phage dynamics that control gut microbiota and may also affect the recovery from dysbiosis.

◆The comprehensive SARS-CoV-2 ‘hijackome’ knowledge base【nature Cell Discovery　2024年12月9日】

Abstract

The continuous evolution of SARS-CoV-2 has led to the emergence of several variants of concern (VOCs) that significantly affect global health. This study aims to investigate how these VOCs affect host cells at proteome level to better understand the mechanisms of disease. To achieve this, we first analyzed the (phospho)proteome changes of host cells infected with Alpha, Beta, Delta, and Omicron BA.1 and BA.5 variants over time frames extending from 1 to 36 h post infection. Our results revealed distinct temporal patterns of protein expression across the VOCs, with notable differences in the (phospho)proteome dynamics that suggest variant-specific adaptations. Specifically, we observed enhanced expression and activation of key components within crucial cellular pathways such as the RHO GTPase cycle, RNA splicing, and endoplasmic reticulum-associated degradation (ERAD)-related processes. We further utilized proximity biotinylation mass spectrometry (BioID-MS) to investigate how specific mutation of these VOCs influence viral–host protein interactions. Our comprehensive interactomics dataset uncovers distinct interaction profiles for each variant, illustrating how specific mutations can change viral protein functionality. Overall, our extensive analysis provides a detailed proteomic profile of host cells for each variant, offering valuable insights into how specific mutations may influence viral protein functionality and impact therapeutic target identification. These insights are crucial for the potential use and design of new antiviral substances, aiming to enhance the efficacy of treatments against evolving SARS-CoV-2 variants.

◆Is It Dangerous to Keep Getting COVID-19?【TIME　2024年1月10日】

Getting COVID-19 today is much less scary and more common than it was three years ago. By now, many people have had it not just once, but two, three, or even more times. Most of the time, repeat infections aren’t as severe as they were the first time, leading to a sense of complacency about getting COVID-19 over and over.

But reinfections aren’t harmless. As cases continue to rise and more variants arrive on the scene, infectious-disease experts are warning that repeat infections could have cumulative, lasting effects.

“There is some early evidence starting to show that if you had COVID-19, there can be all sorts of problems after getting infected” and reinfected, says Dr. Robert Murphy, professor of medicine and executive director of the Havey Institute for Global Health at Northwestern’s Feinberg School of Medicine. “We are just at the beginning of learning about them.”

A higher risk of Long COVID

Dr. Ziyad Al-Aly, clinical epidemiologist at Washington University in St. Louis, studies Long COVID: a condition marked by health effects that linger after infection. “Reinfection remains consequential,” he says.

In a paper published in Nature Medicine in 2022, he found that people who had gotten COVID-19 at least twice experienced higher rates of short- and long-term health effects, including heart, lung, and brain issues, compared to those who were only infected once.

But why? Dr. Davey Smith, a virologist and head of infectious diseases at University of California San Diego, says that certain characteristics—such as older age—may make people more vulnerable to complications after repeat bouts. “The older you get, the worse you do with viruses in general, but specifically with SARS-CoV-2,” he says. “Every time you get COVID-19 again and again, you increase the likelihood of having a worse infection just based on age.”

Underlying health conditions that people may not necessarily be aware of—like prediabetes or increased inflammation—could also put them at higher risk after each infection. “For somebody who is already on the edge of developing diabetes and then gets COVID-19, that could damage the pancreas and the endocrine system enough to change things,” Smith says. Similarly, having high rates of inflammation before COVID-19 could raise the risk of heart events such as stroke or a heart attack after an infection.

Regardless of a person’s health status, each COVID-19 infection can raise the risk of developing blood clots, which can travel to the brain or lungs. That’s why Smith believes anyone who is eligible for antiviral drugs such as Paxlovid should take them, since controlling the virus as quickly as possible can reduce any potential long-term or lingering effects an infection can have on the body.

COVID-19 may alter the immune response

At this point, many people view COVID-19 as relatively benign. But even if you’ve already recovered from a mild case, there’s no guarantee that next time will go as smoothly. “Just because you did okay with it last year doesn’t mean you’ll do okay with it this year,” Smith says.

“There is a mischaracterization in the public understanding that you can get an acute infection with fever, cough, malaise, and fatigue, get over it after a few days or a week or so, then bounce back, and it’s gone,” says Al-Aly. “The data are showing that [some] people still display increased risk of problems even two years after an infection.”

That’s what he found in his study. People who had multiple infections were three times more likely to be hospitalized for their infection up to six months later than those who only got COVID-19 once, and were also more likely to have problems with clotting, gastrointestinal disorders, kidney, and mental-health symptoms. The risks appeared to increase the more infections people experienced.

Understanding why SARS-CoV-2 has a uniquely lasting effect on the body remains a challenge. Historically, when the immune system meets a new pathogen like a virus, it generates novel defenses and remembers the intruder, so it has a head start if the virus returns. That’s certainly the case with SARS-CoV-2—which is why vaccines work, and why getting reinfected generally leads to milder symptoms.

But there is also growing evidence that in some people, getting COVID-19 the first time may compromise the immune response in a way that makes the body less likely to respond effectively the next time it sees the virus. That could leave certain organs and body systems, such as the brain, weaker for months after infection—and subsequent ones. “It’s the balance of these two opposing forces—the immune system learning from the past and knowing how to deal with a virus and do a better job the second and third time around, and the idea that a first encounter with a virus might alter the immune system in some way that it becomes less efficient—that could explain why some people get Long COVID,” says Al-Aly.

Data also continue to show that even vaccinated people can get Long COVID—although the risk may be lower—since the protection provided by vaccines wanes over time, just as it does from infections. Vaccines are therefore a strong but not absolute barrier to the virus.

Preventing reinfections

“Each time you get hit, it does impact your body, so let’s try not to get it too many times,” says Smith. That’s easier said than done, since after three years, people are tired of taking precautions such as wearing masks and avoiding crowded public spaces. “We’ve lost the public-health battle; there is no appetite for public masking or stringent public health measures,” says Al-Aly.

That means other strategies need to become available, including universal vaccines that can protect against multiple variants and nasal spray vaccines that stand guard at the nose, which is where SARS-CoV-2 generally enters. Researchers are currently testing these next generation shots, so while “the good news is that these technologies do exist, they need to be accelerated and brought to market as soon as possible to protect the public,” says Al-Aly.

In the meantime, Smith says it’s important for people to understand that they still need to do everything they can to avoid getting COVID-19. That means staying up to date with vaccinations and taking some basic precautions, such as wearing high-quality masks indoors when cases are high, especially in crowded places and on public transportation.

“I wish we lived in a world where getting repeat infections doesn’t matter,” says Al-Aly, “but the reality is that‘s not the case.”

◆UK doctors and nurses with long COVID to sue for compensation【Context　2024年12月10日】

LONDON – Nearly 300 British doctors, nurses and other health workers with long COVID are suing the health service for compensation, saying they were not given proper protection during the pandemic.

They say their lives have been devastated by a host of severe health complications. Most cannot return to work and many are housebound.

“This is life changing. People are really suffering financially. Some are living in poverty,” said nurse Rachel Hext, one of the claimants.

“We’re suing because this is the only way of providing for our futures.”

Health staff with long COVID told Context they felt betrayed by the government after risking their lives to work on the frontline during the pandemic.

They contrasted the weekly public displays of appreciation for National Health Service (NHS) workers at the height of the crisis with the lack of support they had received since becoming ill.

“It’s been like hero to zero,” said Hext. “We were clapped on doorsteps one moment, and abandoned the next.”

The claimants include consultants, doctors, nurses and hospital porters. Many are in debt or using up savings to survive.

They say they were not given adequate personal protective equipment (PPE), including high grade masks, and often had to rely on flimsy surgical masks.

“I think we’ve got a very good chance of winning,” said solicitor Kevin Digby, who is representing many of them.

More than 200 symptoms have been linked to long COVID, including cognitive impairment or “brain fog”, extreme fatigue, shortness of breath and chronic pain.

The lawsuit is unlikely to be heard by the High Court before 2026 at the earliest because of Britain’s ongoing public inquiry into the handling of the COVID crisis in which more than 230,000 people died.

The defendants, who include NHS bodies covering most of England and Wales, have denied negligence and breach of duty.

Lost income

Hext, 37, said she caught COVID in 2020 while working 13-hour shifts at a hospital in southwest England. She was only given a plastic apron and basic mask which gaped at the sides.

She is now deaf, has blurred vision, joint and mobility problems, severe allergies and a condition which causes her heart to race and leaves her feeling ill.

A mother of two young boys, Hext used to enjoy beach trips and swimming with her sons, but a simple outing can now knock her out for days.

“I’ve lost my health, my career, very much my identity – and that’s before you even start on the financial implications,” she said.

An official study in April estimated 2 million people had long COVID in England and Scotland, with nearly 20% of participants reporting it seriously impacted daily life.

Experts believe thousands of health workers are affected.

A 2023 survey of about 600 doctors with long COVID showed nearly one in five were no longer working, and less than a third were working full-time.

About half had lost income because of long COVID, according to the study published by the British Medical Association (BMA) doctors’ union. Only a minority had had access to high-grade masks.

‘Bitter and betrayed’

Doctors and nurses are separately calling for the government to recognise long COVID as an occupational disease for health and social care workers, opening the door to compensation.

One hospital porter, who joined the NHS following a military career, said he felt better protected serving in Iraq than working during the pandemic.

He said the availability of PPE was very variable and that porters and cleaners working on COVID wards often struggled to access the same protection as doctors and nurses.

Health workers with long COVID – some of whom requested anonymity to talk more freely – spoke of grieving for their past lives, their deep social isolation, and their sadness at seeing their children forced to become their carers.

One general practitioner (GP), who can no longer work, estimated long COVID would cost her 2.5 million pounds ($3.18 million) in lost earnings over her lifetime. Her pension has also been decimated.

A nurse said she was left homeless after severe COVID-related complications forced her to quit work. She has moved house 16 times while ill, compromising her recovery.

Some young doctors with hefty student loans have had to move back to their parents after long COVID derailed their careers.

Amy Small, 44, a GP who lost her job six months after becoming sick in April 2020, has spearheaded calls for long COVID to be recognised as an occupational illness.

“I feel very bitter and absolutely betrayed. We said very early on that COVID was airborne and no one would listen to us,” she said.

The mother-of-two feared at one point they would lose their family home after her husband also got long COVID.

“We went to work on the frontline, got sick and have had zero backup,” she added. “The NHS chews you up and spits you out the other side.”

Small said another pandemic was possible, but feared the country was no better prepared than it was before COVID.

“It’s terrifying. Doctors still don’t have access to adequate PPE,” she said.

Two years ago, the government’s advisory body on industrial injuries recommended certain long COVID conditions be recognised as an occupational disease for health and social care workers. It recently made a similar recommendation for some transport workers.

Formal recognition would provide access to industrial injuries benefits, ranging from 44.30 to 221.50 pounds a week, depending on the disability level.

But the government has yet to respond.

The BMA and the Royal College of Nursing, a nurses’ union, wrote to Secretary of State for Work and Pensions Liz Kendall in November, criticising the long delay and urging action.

They said more than 50 other countries had recognised COVID as an occupational disease.

A spokesperson for the government’s Department for Work and Pensions said it was still assessing the recommendations.

Raymond Agius, a COVID lead with the BMA, said the delays were inexcusable.

“It’s not much money for someone who has lost their livelihood as a result of COVID contracted from work,” he said.

“The government had a moral duty to look after people who put their lives at risk for us all, and I think time may prove it had a legal duty as well.”

◆Case Report of a 47-Year-Old Long COVID Patient Diagnosed With Alzheimer’s Disease【Research Square　2024年12月11日】

Abstract

A 47-year-old female patient was diagnosed with Alzheimer disease (AD) based on positive Amyloid-PET and Tau-PET imaging results, coupled with increased levels of plasma biomarkers (Aβ42/Aβ40, pTau181, and pTau217). In this report, we characterized this unusual AD case by integrating data from various diagnostic methods, including PET, MRI imaging, genetic testing, plasma biomarker testing, etc, to contribute to future research and guide clinical practice. Given that this case emerged after the peak of the COVID-19 pandemic, we suggest that the AD cases analogous to this one be categorized under a distinct subset within the long COVID syndromes, termed AD-like COVID syndromes.

◆Profiling of SARS-CoV-2 Subgenomic RNAs in Clinical Specimens【ASM Journals　2022年3月21日】

Abstract

SARS-CoV-2 transcribes a set of subgenomic RNAs (sgRNAs) essential for the translation of structural and accessory proteins to sustain its life cycle. We applied RNA-seq on 375 respiratory samples from individual COVID-19 patients and revealed that the majority of the sgRNAs were canonical transcripts with N being the most abundant (36.2%), followed by S (11.6%), open reading frame 7a (ORF7a; 10.3%), M (8.4%), ORF3a (7.9%), ORF8 (6.0%), E (4.6%), ORF6 (2.5%), and ORF7b (0.3%); but ORF10 was not detected. The profile of most sgRNAs, except N, showed an independent association with viral load, time of specimen collection after onset, age of the patient, and S-614D/G variant with ORF7b and then ORF6 being the most sensitive to changes in these characteristics. Monitoring of 124 serial samples from 10 patients using sgRNA-specific real-time RT-PCR revealed a potential of adopting sgRNA as a marker of viral activity. Respiratory samples harboring a full set of canonical sgRNAs were mainly collected early within 1 to 2 weeks from onset, and most of the stool samples (90%) were negative for sgRNAs despite testing positive by diagnostic PCR targeting genomic RNA. ORF7b was the first to become undetectable and again being the most sensitive surrogate marker for a full set of canonical sgRNAs in clinical samples. The potential of using sgRNA to monitor viral activity and progression of SARS-CoV-2 infection, and hence as one of the objective indicators to triage patients for isolation and treatment should be considered.

IMPORTANCE Attempts to use subgenomic RNAs (sgRNAs) of SARS-CoV-2 to identify active infection of COVID-19 have produced diverse results. In this work, we applied next-generation sequencing and RT-PCR to profile the full spectrum of SARS-CoV-2 sgRNAs in a large cohort of respiratory and stool samples collected throughout infection. Numerous known and novel discontinuous transcription events potentially encoding full-length, deleted and frameshift proteins were observed. In particular, the expression profile of canonical sgRNAs was associated with genomic RNA level and clinical characteristics. Our study found sgRNAs as potential biomarkers for monitoring infectivity and progression of SARS-CoV-2 infection, which provides an alternative target for the management and treatment of COVID-19 patients.

◆Crystal structure of SARS-CoV-2 nsp10 bound to nsp14-ExoN domain reveals an exoribonuclease with both structural and functional integrity【OXFORD ACADEMIC　2021年5月21日】

Abstract

The emergence of SARS-CoV-2 infection has posed unprecedented threat to global public health. The virus-encoded non-structural protein 14 (nsp14) is a bi-functional enzyme consisting of an exoribonuclease (ExoN) domain and a methyltransferase (MTase) domain and plays a pivotal role in viral replication. Here, we report the structure of SARS-CoV-2 nsp14-ExoN domain bound to its co-factor nsp10 and show that, compared to the SARS-CoV nsp10/nsp14-full-length complex, SARS-CoV-2 nsp14-ExoN retains an integral exoribonuclease fold and preserves an active configuration in the catalytic center. Analysis of the nsp10/nsp14-ExoN interface reveals a footprint in nsp10 extensively overlapping with that observed in the nsp10/nsp16 structure. A marked difference in the co-factor when engaging nsp14 and nsp16 lies in helix-α1′, which is further experimentally ascertained to be involved in nsp14-binding but not in nsp16-engagement. Finally, we also show that nsp10/nsp14-ExoN is enzymatically active despite the absence of nsp14-MTase domain. These data demonstrate that SARS-CoV-2 nsp10/nsp14-ExoN functions as an exoribonuclease with both structural and functional integrity.

◆Evolution of enhanced innate immune evasion by SARS-CoV-2.【Europe PMC　2021年12月23日】

Abstract

The emergence of SARS-CoV-2 variants of concern suggests viral adaptation to enhance human-to-human transmission. Although much effort has focused on the characterization of changes in the spike protein in variants of concern, mutations outside of spike are likely to contribute to adaptation. Here, using unbiased abundance proteomics, phosphoproteomics, RNA sequencing and viral replication assays, we show that isolates of the Alpha (B.1.1.7) variant suppress innate immune responses in airway epithelial cells more effectively than first-wave isolates. We found that the Alpha variant has markedly increased subgenomic RNA and protein levels of the nucleocapsid protein (N), Orf9b and Orf6-all known innate immune antagonists. Expression of Orf9b alone suppressed the innate immune response through interaction with TOM70, a mitochondrial protein that is required for activation of the RNA-sensing adaptor MAVS. Moreover, the activity of Orf9b and its association with TOM70 was regulated by phosphorylation. We propose that more effective innate immune suppression, through enhanced expression of specific viral antagonist proteins, increases the likelihood of successful transmission of the Alpha variant, and may increase in vivo replication and duration of infection. The importance of mutations outside the spike coding region in the adaptation of SARS-CoV-2 to humans is underscored by the observation that similar mutations exist in the N and Orf9b regulatory regions of the Delta and Omicron variants.