SARS-CoV-2 と COVID-19 に関する備忘録 Vol.41

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SARS-CoV-2 と COVID-19 に関するメモ・備忘録

◆Structural brain changes in post-COVID condition and its relationship with cognitive impairment【OXFORD ACADEMIC BRAIN COMMUNICATION　2025年2月12日】

Abstract

It has been estimated that ∼4% of individuals infected with SARS-CoV-2 will be diagnosed with post-COVID condition. Previous studies have evidenced the presence of cognitive dysfunction and structural brain changes in infected individuals; however, the relationship between structural changes and cognitive alterations in post-COVID condition is still not clear. Consequently, the aim of this work is to study structural brain alterations in post-COVID condition patients after almost 2 years of infection and their likely relationship with patients’ cognitive impairment. Additionally, the association with blood biomarkers and clinical variables was also explored. One hundred and twenty-eight individuals with post-COVID condition and 37 non-infected healthy controls from the Nautilus Project (ClinicalTrials.gov IDs: NCT05307549 and NCT05307575) underwent structural brain magnetic resonance imaging and a comprehensive neuropsychological assessment. A subsample of 66 post-COVID participants also underwent blood extraction to obtain levels of blood biomarkers. Cortical thickness and subcortical volumes were obtained and analysed using FreeSurfer (v7.1). FMRIB Software Library software (v6.0.4) was used to perform grey matter voxel-based analysis and to study microstructural white matter integrity. Patients with post-COVID performed significantly worse in working and verbal memory, processing speed, verbal fluency and executive functions, compared to healthy controls. Moreover, patients with post-COVID showed increased cortical thickness in the right superior frontal and the right rostral middle frontal gyri that negatively correlated with working memory performance. Diffusion tensor imaging data showed lower fractional anisotropy in patients in the right superior longitudinal fasciculus, the splenium and genu of the corpus callosum, the right uncinate fasciculus and the forceps major, that negatively correlated with subjective memory failures. No differences in blood biomarkers were found. Once patients were classified according to their cognitive status, post-COVID clinically cognitively altered presented increased cortical thickness compared to those classified as non-cognitively altered. In conclusion, our study showed that grey and white matter brain changes are relevant in this condition after almost 2 years of infection and partly explain long-term cognitive sequelae. These findings underscore the critical importance of monitoring this at-risk population over time.

◆SARS-CoV-2 nonspike structural proteins hijack mucosa epithelial cell fate【Research Square　2025年2月25日】

Abstract

COVID-19 patients readily present with severe epithelial damage, such as tissue ulceration and erosion, along with disrupted tissue repair, in multiple organs. The mucous membranes of the lung alveoli 1,2, gastrointestinal tract 3,4, nasal 5and oral cavity 6,7 are the primary targets of the SARS-CoV-2 virus. The infected epithelium triggers a dysregulated immune response that further damages tissues and organs 8-10. Increasing evidence suggests that the SARS-CoV-2 virus can cause direct damage to epithelial cells and fibroblasts 11-13. Here, we report that the mucosa epithelia of COVID-19 patients can undergo cellular dedifferentiation before any pathological features are observed. SARS-CoV-2 nonspikestructural proteins, particularly the Envelope protein, can rapidly induce epithelial cell dedifferentiation, micronuclei formation, cell cycle arrest at the G1 phase and apoptosis. The protein can also severely affect the progenitor cell stratification program. Mechanistically, we identified a unique molecule, calponin 2 (CNN2), as a downstream effector of nonspike structural proteins. Moreover, CNN2 levels were elevated in the epithelia of COVID-19 patients. Downregulating CNN2 could inhibit epithelial cell apoptosis and promote cell differentiation. CNN2 expression is negatively regulated by GLIS2, a transcription factor associated with the disruption of ciliary dynamics in epithelial cells. Therefore, we propose that SARS-CoV-2 damages mucosal epithelium integrity via a novel “double hijack” mechanism and suggest new therapeutic targets for COVID-19 treatment.

◆A truncated SARS-CoV-2 nucleocapsid protein enhances virus fitness by evading antiviral responses【bioRxiv　2025年2月26日】

Abstract

Viruses face a selective pressure to evade cellular antiviral responses to control the outcome of an infection. However, due to their limited genome size, viruses must adopt unique strategies to confront cellular sensors. Since emerging in humans, SARS-CoV-2 has accrued multiple mutations throughout its genome, some of which enhanced virus replication and led to the rise of viral variants. However, the biological consequences of many of these changes remain to be discovered. Here, we show that SARS-CoV-2 produces a truncated form of the nucleocapsid protein, called N*M210. Due to the acquisition of a viral transcription regulatory sequence (TRS) in the N gene, certain variants, such as Omicron, produce a new viral mRNA that markedly increases N*M210 expression. We show that N*M210 is a dsRNA binding protein, which inhibits multiple arms of the cellular antiviral response, including blocking interferon induction and inhibiting stress granule formation. We created a panel of recombinant SARS-CoV-2 viruses (rSARS-2) with mutations in the N gene that increased or decreased N*M210 production. We show that N*M210 production increases virus fitness, as viruses that produce more N*M210 outcompeted wild-type rSARS-2. We demonstrate that the fitness advantage provided by N*M210 is partly due to its ability to potently block stress granules. We propose a model where, to evade the cellular antiviral response, SARS-CoV-2 has evolved a mechanism to increase the production of a truncated form of the N protein, which broadly limits the activation of dsRNA-induced antiviral responses, tipping the balance in favour of the virus in the battle for control of the cell.

◆Long COVID – a critical disruption of cholinergic neurotransmission?【BMC Bioelectronic Medicine　2025年2月27日】

Abstract

Background

Following the COVID-19 pandemic, there are many chronically ill Long COVID (LC) patients with different symptoms of varying degrees of severity. The pathological pathways of LC remain unclear until recently and make identification of path mechanisms and exploration of therapeutic options an urgent challenge. There is an apparent relationship between LC symptoms and impaired cholinergic neurotransmission.

Methods

This paper reviews the current literature on the effects of blocked nicotinic acetylcholine receptors (nAChRs) on the main affected organ and cell systems and contrasts this with the unblocking effects of the alkaloid nicotine. In addition, mechanisms are presented that could explain the previously unexplained phenomenon of post-vaccination syndrome (PVS). The fact that not only SARS-CoV-2 but numerous other viruses can bind to nAChRs is discussed under the assumption that numerous other post-viral diseases and autoimmune diseases (ADs) may also be due to impaired cholinergic transmission. We also present a case report that demonstrates changes in cholinergic transmission, specifically, the availability of α4β2 nAChRs by using (-)-[18F]Flubatine whole-body positron emission tomography (PET) imaging of cholinergic dysfunction in a LC patient along with a significant neurological improvement before and after low-dose transcutaneous nicotine (LDTN) administration. Lastly, a descriptive analysis and evaluation were conducted on the results of a survey involving 231 users of LDTN.

Results

A substantial body of research has emerged that offers a compelling explanation for the phenomenon of LC, suggesting that it can be plausibly explained because of impaired nAChR function in the human body. Following a ten-day course of transcutaneous nicotine administration, no enduring neuropathological manifestations were observed in the patient. This observation was accompanied by a significant increase in the number of free ligand binding sites (LBS) of nAChRs, as determined by (-)-[18F]Flubatine PET imaging. The analysis of the survey shows that the majority of patients (73.5%) report a significant improvement in the symptoms of their LC/MEF/CFS disease as a result of LDTN.

Conclusions

In conclusion, based on current knowledge, LDTN appears to be a promising and safe procedure to relieve LC symptoms with no expected long-term harm.

◆Large population study identifies long-term health risks after COVID-19 hospitalization【Medical press　2025年2月28日】

A French nationwide study has revealed that survivors of COVID-19 hospitalization face an increased risk of death or organ-related disorders for up to two-and-a-half years after discharge.

Published today in Infectious Diseases, the study of nearly 64,000 French residents provides valuable insights into the long-term health effects of COVID-19 and emphasizes the need for continued health care and monitoring for people who have been hospitalized with SARS-CoV-2 infection.

“These findings are a stark reminder of the far-reaching impact of COVID-19, which extends far beyond the initial infection,” says lead author Dr. Sarah Tubiana, who specializes in infectious diseases, at the Clinical Investigation Center at Bichat Hospital (Paris).

“While much attention has been given to the immediate dangers of the virus, our research shows that hospitalized COVID-19 survivors remain at greater risk of severe health complications months and even years later. The long-term implications for public health are significant.”

Using data from the French national claims database, the study followed 63,990 adults admitted to hospital with COVID-19 between January and August 2020. These individuals—with an average age of 65 years, with 53.1% male—were matched with 319,891 people from the general population of similar age, sex and location who had not been hospitalized for COVID-19 during the same period.

The researchers tracked the study participants for up to 30 months, monitoring deaths and hospital admissions, both for any cause and for specific organ-related conditions. By comparing outcomes between the two groups, the researchers identified significant long-term health risks in hospitalized COVID-19 survivors than the general population.

COVID-19 patients experienced a higher rate of deaths from any cause (5,218 per 100,000 person-years) compared to the control group (4,013 per 100,000 person-years). They were also more likely to be hospitalized for any reason, with particularly high risks for neurological, psychiatric, cardiovascular and respiratory problems.

There was no difference between men and women in the risk of hospitalization except for psychiatric, for which the excess risk was mainly found in women.

The odds of re-hospitalization—following discharge of a COVID-19 hospitalization—was higher for all age groups.

However, as perhaps expected, the incidence of all-cause re-hospitalization and re-hospitalization for organ specific disorders were higher in patients older than 70.

While these excess risks decreased after the first six months for all outcomes, they remained elevated for up to 30 months for neurological and respiratory disorders, chronic kidney failure and diabetes.

“Even 30 months after hospitalization, COVID-19 patients remained at an increased risk of death or severe health complications, reflecting the long-lasting, wider consequences of the disease on people’s lives,” states co-author Dr. Charles Burdet, an Infectious Diseases specialist, at Université Paris Cité.

“These results highlight the need for further research to understand the mechanisms behind these long-term health risks and how to mitigate them.”

A key strength of this study is its use of a large, nationwide database covering the entire French population, making the findings broadly applicable to similar Western populations. Using longitudinal data and detailed electronic health records also allowed the researchers to distinguish new health issues arising after COVID-19 from pre-existing conditions.

However, the findings may not fully apply to later SARS-CoV-2 variants, as the study focused on patients infected in early 2020 before new variants emerged. Further research is needed to assess whether more recent variants have similar long-term health consequences.

◆The role of masks and respirators in preventing respiratory infections in healthcare and community settings【the bmj　2025年2月27日】

Abstract

The covid-19 pandemic saw frequent changes and conflicts in mask policies and politicization of masks. On reviewing the evidence, including studies published after the pandemic, the data suggest respirators are more effective than masks in healthcare, but must be continuously worn to be protective. Healthcare and aged care settings amplify outbreaks, so protection of patients and staff is paramount. Most guidelines assume risk is only present during close contact or aerosol generating procedures, but studies show intermittent use of respirators is not protective. New research in aerosol science confirms the risk of infection is widespread in health facilities. In community settings, any mask use is protective during epidemics, especially if used early, when combined with hand hygiene, and if wearers are compliant. Community use of N95 respirators is more protective than surgical masks, which are more protective than cloth masks, but even cloth masks provide some protection. Mask guidelines should be adaptable to the specific context and should account for rising epidemic activity, and whether a pathogen has asymptomatic transmission. The main rationale for universal masking during pandemics is asymptomatic transmission, which means risk of transmission cannot be self-identified. The precautionary principle should be applied during serious emerging infections or pandemics when transmission mode is not fully understood, or vaccines and drugs are not available. If respirators are not available, medical or cloth masks could be used as a last resort. Data exist to support extended use and reuse of masks and respirators during short supply. In summary, extensive evidence generated during the covid-19 pandemic confirms the superiority of respirators and supports the use of masks and respirators in the community during periods of high epidemic activity. Some gaps in research remain, including economic analyses, research in special population groups for whom masking is challenging, and research on countering disinformation.

◆Complement activity and autophagy are dysregulated in the lungs of patients with nonresolvable COVID-19 requiring lung transplantation【BMC Respiratory Research　2025年2月27日】

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced coronavirus disease 2019 (COVID-19) pandemic has challenged the current understanding of the complement cascade mechanisms of host immune responses during infection-induced nonresolvable lung disease. While the complement system is involved in opsonization and phagocytosis of the invading pathogens, uncontrolled complement activation also leads to aberrant autophagic response and tissue damage. Our recent study revealed unique pathologic and fibrotic signature genes associated with epithelial bronchiolization in the lung tissues of patients with nonresolvable COVID-19 (NR-COVID-19) requiring lung transplantation. However, there is a knowledge gap if complement components are modulated to contribute to tissue damage and the fibrotic phenotype during NR-COVID-19. We, therefore, aimed to study the role of the complement factors and their corresponding regulatory proteins in the pathogenesis of NR-COVID-19. We further examined the association of complement components with mediators of the host autophagic response. We observed significant upregulation of the expression of the classical pathway factor C1qrs and alternative complement factors C3 and C5a, as well as the anaphylatoxin receptor C5aR1, in NR-COVID-19 lung tissues. Of note, complement regulatory protein, decay accelerating factor (DAF; CD55) was significantly downregulated at both transcript and protein levels in the NR-COVID-19 lungs, indicating a dampened host protective response. Furthermore, we observed significantly decreased levels of the autophagy mediators PPARγ and LC3a/b, which was corroborated by decreased expression of factor P and the C3b receptor CR1, indicating impaired clearance of damaged cells that may contribute to the fibrotic phenotype in NR-COVID-19 patients. Thus, our study revealed previously unrecognized complement dysregulation associated with impaired cell death and clearance of damaged cells, which may promote NR-COVID-19 in patients, ultimately necessitating lung transplantation. The identified network of dysregulated complement cascade activity indicates the interplay of regulatory factors and the receptor-mediated modulation of host immune and autophagic responses as potential therapeutic targets for treating NR-COVID-19.

◆Mitochondrial dysfunction in acute and post-acute phases of COVID-19 and risk of non-communicable diseases【nature : npj metabolic health and disease　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.

◆Almost 500,000 long Covid sufferers is “tip of the iceberg”【Dutch News　2025年3月3日】

Some 450,000 people have been diagnosed with long Covid since the virus first appeared in the Netherlands, 12,000 of whom are unable to work full-time, according to new figures.

The number of patients entitled to an incapacity benefit known as WIA, paid out to those who are off work for at least two years, has quadrupled from 3,000 since 2023, the unemployment insurance agency UWV said.

But patients’ organisation PostCovidNL said the figures represented the tip of the iceberg. They estimate that 90,000 people are currently struggling with long Covid, but many are not entitled to claim benefits.

Long Covid is defined as a chronic condition arising from a Covid-19 infection that lasts for at least three months. It affects at least 10% of all cases but 50-70% of cases where the patient needs hospital treatment.

Young people who fell ill while still at school cannot claim WIA because they have never worked, while the Wajong work incapacity benefit is only paid to people who are deemed unable to work for the rest of their lives.

Others try to get by by reducing their working hours or retiring early, rather than quitting and claiming incapacity support.

Gradual return

Many patients with long Covid are able to return to work eventually, but doctors say it is a long and difficult process that does not match the expectations of the benefits system.

“These days we know that you have to build up very gradually and not exceed your limits,” Iris Homeijer, director of medical affairs at occupational health specialist Human Capital Care told NOS.

“But it’s proven to be different from other diseases, because we can’t give a prognosis. It’s very difficult to tell with long Covid how long someone will be ill for and whether they will suffer a relapse.”

The uncertainty means UWV doctors are reluctant to approve young long Covid patients for the Wajong benefit even if they are unable to work in the short term, which can leave them financially in dire straits.

The UWV acknowledged that the strict rules had led to some desperate situations, but it was doing its best to help young people who were turned down for Wajong navigate the system.

◆A systematic review of post COVID-19 condition in children and adolescents: Gap in evidence from low-and -middle-income countries and the impact of SARS-COV-2 variants【PLOS One　2025年3月3日】

Abstract

The long-term health consequences following COVID-19 have largely been reported in adult populations living in high-income countries. We therefore did a systematic review of post COVID-19 condition symptoms reported in children and adolescents (<18 years), aiming to identify and include publications from low- or middle-income countries (LMICs). From EMBASE, Medline, and Pubmed until the 30th of October 2023, we searched all studies reporting original and complete data of long-term outcomes of at least 20 children or adolescents under 18 years of age with a history of confirmed acute COVID-19 infection. We excluded non-English publications, pre-prints, unreviewed articles, grey literature, studies with inaccessible full text, and those limited to a specific population. Risk of Bias was assessed using STROBE guidelines for observational studies. We used descriptive narrative analysis to summarize the findings. Forty studies reporting 825,849 children and adolescents; the median age of those with persistent symptoms was consistently in the adolescent age range but not all studies included young children (<5 years). Only one study, with 58 participants aged 6-17 years, population was from a LMIC. Studies relied on symptom reporting rather than objective measures of organ dysfunction. The definition of post COVID-19 condition varied; most studies used persistent symptom duration of two or three months or more. However, since the symptom onset was not specified, it was difficult to identify which study is truly consistent with WHO’s definition of post COVID-19 condition. Prevalence of post COVID-19 condition ranged from 1.8% to 70% but with marked heterogeneity between study populations and reporting criteria including the severity of acute COVID presentation. Most studies were undertaken when the Alpha variant was the predominant strain. The prevalence of post COVID-19 condition ranged from 6.7% to 70% in the Alpha variant-, 23% to 61.9% in the Delta-, 17% to 34.6% in the Omicron-, and 3.7% to 34% in the Other-variant predominated studies. The most reported symptoms were fatigue (70%), headache (37.5%) and respiratory symptoms (35%); fatigue was most reported in all variant subgroups. Only half of the studies included a control group. The variations in study population, reporting methods, reliance on symptom reporting alone and lack of control groups make it challenging to determine the impact of COVID-19 on post COVID health in children and adolescents. The lack of data from LMIC populations especially infants and young children is a major gap.

◆An Allele of the MTHFR one-carbon metabolism gene predicts severity of COVID-19【medRxiv　2025年3月3日】

Abstract

While the public health burden of SARS-CoV-2 infection has lessened due to natural and vaccine-acquired immunity, the emergence of less virulent variants, and antiviral medications, COVID-19 continues to take a significant toll. There are > 10,000 new hospitalizations per week in the U.S., many of whom develop post-acute sequelae of SARS-CoV-2 (PASC), or “long COVID”, with long-term health issues and compromised quality of life. Early identification of individuals at high risk of severe COVID-19 is key for monitoring and supporting respiratory status and improving outcomes. Therefore, precision tools for early detection of patients at high risk of severe disease can reduce morbidity and mortality. Here we report an untargeted and longitudinal metabolomic study of plasma derived from adult patients with COVID-19. One-carbon metabolism, a pathway previously shown as critical for viral propagation and disease progression, and a potential target for COVID-19 treatment, scored strongly as differentially abundant in patients with severe COVID-19. A follow-up targeted metabolite profiling revealed that one arm of the one-carbon metabolism pathway, the methionine cycle, is a major driver of the metabolic profile associated with disease severity. The methionine cycle produces S-adenosylmethionine (SAM), the methyl group donor important for methylation of DNA, RNA, and proteins, and its high abundance was reported to correlate with disease severity. Further, genomic data from the profiled patients revealed a genetic contributor to methionine metabolism and identified the C677T allele of the MTHFR gene as a pre-existing predictor of disease trajectory – patients homozygous for the MTHFR C677T have higher incidence of experiencing severe disease. Our results raise the possibility that screening for the common genetic MTHFR variant may be an actionable approach to stratify risk of COVID severity and may inform novel precision COVID-19 treatment strategies.

◆Longitudinal multi-omics analysis of convalescent individuals with respiratory sequelae 6–36 months after COVID-19【BMC Medicine　2025年3月5日】

Abstract

Background

Approximately 10–30% of individuals continue to experience symptoms classified as post-acute sequelae of coronavirus disease 2019 (COVID-19 (PASC)). PASC is a multisystem condition primarily characterized by respiratory symptoms, such as reduced diffusing capacity for carbon monoxide (DLco). Although many studies have investigated the pathogenesis of acute COVID-19, the long-term molecular changes in COVID-19 convalescents with PASC remain poorly understood.

Methods

We prospectively recruited 70 individuals who had been diagnosed with COVID-19 from 7 January 2020 to 29 May 2020 (i.e., COVID-19 convalescents); we performed follow-up visits at 6 months, 1 year, 2 years, and 3 years after hospital discharge. Thirty-five healthy controls (CONs), recruited from a physical examination center before the COVID-19 pandemic, served as a comparison group. We explored the proteomic and metabolomic profiles of 174 plasma samples from the 70 COVID-19 convalescents and 35 CONs.

Results

We performed a comprehensive molecular analysis of COVID-19 convalescents to investigate host changes up to 3 years after hospital discharge. Our multi-omics analysis revealed activation of cytoskeletal organization and glycolysis/gluconeogenesis, as well as suppression of gas transport and adaptive immune responses, in COVID-19 convalescents. Additionally, metabolites involved in glutathione metabolism; alanine, aspartate, and glutamate metabolism; and ascorbate and aldarate metabolism were significantly upregulated in COVID-19 convalescents. Pulmonary and molecular abnormalities persisted for 3 years in COVID-19 convalescents; impaired diffusing capacity for carbon monoxide (DLco) was the most prominent feature. We used this multi-omics profile to develop a model involving one protein (heterogeneous nuclear ribonucleoprotein K (HNRNPK)) and two metabolites (arachidonoyl-EA and 1-O-(2r-hydroxy-pentadecyl)-sn-glycerol)) for identification of COVID-19 convalescents with abnormal DLco.

Conclusions

These data provide insights concerning molecular sequelae among COVID-19 convalescents up to 3 years after hospital discharge, clarify mechanisms driving respiratory sequelae, and support the development of a novel model to predict reduced DLco. This longitudinal multi-omics analysis may illuminate the trajectory of altered lung function in COVID-19 convalescents.

◆Iron dysregulation and inflammatory stress erythropoiesis associates with long-term outcome of COVID-19【nature immunology　2025年3月1日】

Abstract

Persistent symptoms following SARS-CoV-2 infection are increasingly reported, although the drivers of post-acute sequelae (PASC) of COVID-19 are unclear. Here we assessed 214 individuals infected with SARS-CoV-2, with varying disease severity, for one year from COVID-19 symptom onset to determine the early correlates of PASC. A multivariate signature detected beyond two weeks of disease, encompassing unresolving inflammation, anemia, low serum iron, altered iron-homeostasis gene expression and emerging stress erythropoiesis; differentiated those who reported PASC months later, irrespective of COVID-19 severity. A whole-blood heme-metabolism signature, enriched in hospitalized patients at month 1–3 post onset, coincided with pronounced iron-deficient reticulocytosis. Lymphopenia and low numbers of dendritic cells persisted in those with PASC, and single-cell analysis reported iron maldistribution, suggesting monocyte iron loading and increased iron demand in proliferating lymphocytes. Thus, defects in iron homeostasis, dysregulated erythropoiesis and immune dysfunction due to COVID-19 possibly contribute to inefficient oxygen transport, inflammatory disequilibrium and persisting symptomatology, and may be therapeutically tractable.

◆Microglia dysfunction, neurovascular inflammation and focal neuropathologies are linked to IL-1- and IL-6-related systemic inflammation in COVID-19【nature immunology　2025年3月6日】

Abstract

COVID-19 is associated with diverse neurological abnormalities, but the underlying mechanisms are unclear. We hypothesized that microglia, the resident immune cells of the brain, are centrally involved in this process. To study this, we developed an autopsy platform allowing the integration of molecular anatomy, protein and mRNA datasets in postmortem mirror blocks of brain and peripheral organ samples from cases of COVID-19. We observed focal loss of microglial P2Y12R, CX3CR1–CX3CL1 axis deficits and metabolic failure at sites of virus-associated vascular inflammation in severely affected medullary autonomic nuclei and other brain areas. Microglial dysfunction is linked to mitochondrial injury at sites of excessive synapse and myelin phagocytosis and loss of glutamatergic terminals, in line with proteomic changes of synapse assembly, metabolism and neuronal injury. Furthermore, regionally heterogeneous microglial changes are associated with viral load and central and systemic inflammation related to interleukin (IL)-1 or IL-6 via virus-sensing pattern recognition receptors and inflammasomes. Thus, SARS-CoV-2-induced inflammation might lead to a primarily gliovascular failure in the brain, which could be a common contributor to diverse COVID-19-related neuropathologies.

◆Long Covid warning: ‘Silent organ damage is a real problem’【RNZ　2025年3月6日】

Public health experts are urging the government to protect people from Long Covid, which they say could have already affected a quarter of a million New Zealanders.

A new Public Health Communication Centre briefing out on Thursday says the government must develop and implement a Long Covid strategy.

Massey University public health research Professor John Potter said the risk of Long Covid after an Omicron infection remained about 10 percent, and sufferers could be mildly impaired to severely disabled.

The briefing also says Long Covid can also lead to a ‘substantially increased’ risk of sudden death and ‘silent’ damage to cells and organs which can lead to later illness.

“Certainly the silent organ damage is a real problem, we think, for future development of disease. When you’re young and healthy, you can take a certain amount of damage to the system without it showing up.

“But as people age, their capacity to buffer against that particular set of damage might decline and we might see increased risk of other symptoms, particularly heart, lung, brain, emerging in people’s fifties and sixties.”

He said some estimates suggested that as many as 400 million people worldwide – about five percent of the global population – have Long Covid.

“Essentially every organ in our bodies can be involved in clinical Long Covid, and it can impact people of all ages, sex, and ethnicities. It reduces quality of life and can cause loss of ability to work and, in some cases, severe disability. This is a large burden of illness for our communities, healthcare system and the economy.”

Co-author Assoc Prof Amanda Kvalsvig from the University of Otago said New Zealand children were highly exposed to Covid-19.

“We know that infection and reinfection, even when mild, is linked to cell and organ damage that may harm their future health. More needs to be done to protect our children, and the first step is ensuring that our schools are safe.”

The NZ government’s response to Long Covid had been “inadequate”, said co-author University of Otago’s Prof Michael Baker.

“We have all the tools we need to protect people against Long Covid, including using proven public health measures to reduce exposure to the virus when indoors, and regular vaccination to reduce progression to Long Covid.

“The critical need is government leadership, with a coordinated, evidence-informed strategy that is resourced and implemented. This response would have many benefits including preventing other respiratory infections, improving our pandemic preparedness, protecting health, and maintaining productivity.”

In a statement to RNZ, Health Minister Simeon Brown said Covid-19 and Long Covid were now being managed as part of a ‘business as usual’ healthcare response, with the primary care sector largely taking the lead in patient care.

“In general, patients with Long Covid are cared for in the same way as people with other chronic conditions. This is largely through primary care, but they can be referred to specialist care when required.

Brown said the Ministry of Health continued to undertake evidence briefs, the most recent being around the way symptoms present in patients.

“This is to help clinicians in dealing with the complex issue of diagnosis as there is no definitive test to diagnose Long Covid. Officials have advised they will keep me updated with the latest evidence on Long Covid and other conditions.”

◆Macrophage peroxisomes guide alveolar regeneration and limit SARS-CoV-2 tissue sequelae【Science　2025年3月7日】

Structured Abstract

INTRODUCTION

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes both acute manifestations and long-term complications. These post acute sequelae (PASC) of SARS-CoV-2 infection or Long Covid have affected more than 60 million individuals worldwide. Similar chronic sequelae have also been observed after other respiratory viral infections, including influenza. Despite advances in antiviral and anti-inflammatory therapies, we lack effective interventions that target tissue regeneration and recovery after severe viral injury to minimize the development of chronic host conditions. Following alveolar damage, the emergence of epithelial progenitors—including transitional progenitor cells highly expressing cytokeratin 8 (KRT8)—is a hallmark of the lung repair process. However, dysregulated persistence of these cells can lead to pathological tissue remodeling and fibrosis, characteristics of post viral chronic lung sequelae. The immunological mechanisms regulating the development and persistence of dysplastic KRT8 cells after infection are not fully understood.

RATIONALE

Macrophages are critical in antiviral immunity, lung inflammation, and tissue repair after viral infection. Peroxisomes, cellular organelles involved in lipid metabolism and cellular redox balance, are often overlooked compared with other organelles such as mitochondria. Working in mouse models of infection, we examined the dynamic changes of macrophage peroxisome compartment in vivo after respiratory viral infection including SARS-CoV-2. We also investigated how peroxisomes regulate macrophage inflammatory and repair function in the lung after viral injury in vivo. Furthermore, we evaluated whether pharmacologically enhancing peroxisome biogenesis could serve as a pro-repair therapeutic approach to mitigate acute and chronic host conditions following infection.

Results

Severe COVID-19 significantly remodeled the peroxisome compartment, reducing the number of peroxisomes in mouse lung macrophages, as revealed by bioinformatic and immunofluorescence analyses. We found that increased interferon signaling, especially IFNγ signaling, inhibited peroxisome biogenesis and promoted peroxisome degradation through pexophagy (autophagy of peroxisomes) in macrophages. Mouse models with selective depletion of macrophage peroxisomes demonstrated that peroxisomes were essential for resolving inflammation and promoting alveolar regeneration after severe viral injury. Mechanistically, peroxisomes exhibited cell type–specific modulation of lipid metabolism, enhancing mitochondrial health and supporting macrophage repair programs for the self-renewal of alveolar type 2 (AT2) cells. Macrophage peroxisome dysfunction, however, led to increased inflammasome activation and excessive IL-1β release by means of the Gasdermin D pore. Persistent IL-1β production subsequently caused the accumulation of dysplastic KRT8 transitional epithelial progenitors in the lung, driving chronic tissue pathology and fibrotic remodeling following acute SARS-CoV-2 infection. Chronic peroxisome impairment was observed in the lungs from human patients with PASC pulmonary fibrosis and relevant mouse models. Notably, in our mouse models, pharmacological enhancement of peroxisome biogenesis using sodium 4-phenylbutyrate (4-PBA) restored peroxisome function in macrophages, mitigated lung inflammation and fibrosis, and enhanced alveolar regeneration after viral infection.

CONCLUSION

This study suggests that severe respiratory viral infections can reduce peroxisome biogenesis and promote peroxisome degradation in response to raised interferon levels. Our findings reveal that peroxisomes act as essential regulators of macrophage-mediated lung inflammation resolution and tissue regeneration following viral injury. Thus, peroxisomal dysfunction in macrophages contributes to the development of severe acute morbidity and chronic tissue sequelae post-COVID-19. Targeting peroxisome biogenesis or enhancing peroxisomal metabolic function represents a promising therapeutic approach for mitigating the long-term consequences of respiratory viral infections, with potential for improving health outcomes for patients with PASC.

◆Analysis of 977 Long COVID Patients Reveals Prevalent Neuropathy and Association with Anti-Ganglioside Antibodies【medRxiv　2025年3月5日】

Abstract

Background Long COVID (LC) is a novel condition that is characterized by persistent symptoms that last from months to years following a SARS-CoV-2 infection. While LC symptoms vary widely, neuropathy is one of the most prevalent symptoms and drastically affects quality of life. However, the underlying pathophysiology of LC neuropathy remains poorly understood. Here, we investigated the prevalence and potential mechanisms of LC neuropathy in the largest LC neuropathy cohort to date.

Methods We conducted an observational study of 977 adults with LC at Dell Medical School. Participants underwent clinical assessments, skin punch biopsy, and comprehensive metabolic, endocrine and immunological profiling. A subset of patients received treatment with intravenous immunoglobulin (IVIG) treatment.

Findings Neuropathic symptoms were reported by 55% (534/977) participants, with skin biopsy confirming small fiber neuropathy in 56.5% (48/85) cases, affecting both epidermal and autonomic nerve fibers. Common risk factors for neuropathy, including metabolic and endocrine disorders, did not fully explain neuropathic symptoms. While general immunological markers (lymphocyte, T cell, and B cell count and CRP) were unremarkable, unexpectedly, we detected anti-ganglioside antibodies (AGAs) in 25% of patients with LC neuropathy, a comparable rate to other AGA-associated neuropathies. Longitudinal testing revealed persistent AGA positivity, and multiple elevated AGAs in a subset of patients. In a pilot treatment cohort of eight patients, IVIG treatment resulted in improvement of patient reported neuropathic symptoms.

Interpretation Our findings reveal a high prevalence of small fiber neuropathy in LC, with evidence suggesting an autoimmune mechanism involving AGAs in one in four LC neuropathy patients. The therapeutic response to IVIG further supports an autoimmune pathophysiology, suggesting potential benefits of immunomodulation in LC neuropathy patients.