SARS-CoV-2 と COVID-19 に関する備忘録 Vol.59

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SARS-CoV-2 と COVID-19 に関するメモ・備忘録

◆Blood-Brain barrier disruption in long COVID and cognitive correlates: A cross-sectional MRI study【ScienceDirect　2025年7月28日】

Abstract

Disruption of the blood–brain barrier (BBB) may contribute to neuropsychiatric symptoms observed in Long COVID (LC). Using a non-contrast magnetic resonance imaging (MRI) technique, we investigated BBB permeability in individuals with LC and its relationship to cognitive function. We hypothesized that LC individuals would show greater BBB permeability than recovered individuals, and that higher permeability would correlate with poorer cognition. Ninety-seven participants meeting the 2024 NASEM definition of LC with at least one neuropsychiatric symptom and 31 recovered controls completed an MRI scan and cognitive testing. BBB permeability was assessed using water-extraction-with-phase-contrast-arterial-spin-tagging (WEPCAST) MRI, which estimates the permeability-surface-area product (PS) of arterially labeled water entering the brain. Cognitive performance was summarized into eight factor scores derived from principal components analysis. Compared to controls, the LC group was older (M = 47 vs. 39 years, P = 0.003), less educated (P = 0.02), more likely female (P = 0.04), and had higher hospitalization rates for COVID-19 (P = 0.02). PS was significantly elevated in the LC group after adjusting for age and sex (B = 18.59, SE = 6.11, β = 0.28, P = 0.003). No significant group differences were found in cerebral blood flow, extraction fraction (E), or brain volume. Within the LC group, higher PS was associated with poorer motor function, but not with other cognitive domains. These findings indicate subtle but persistent BBB disruption in LC individuals over two years post-infection, with a potential link to motor dysfunction. This supports prior evidence of BBB changes following severe COVID-19 and suggests that BBB integrity may be a long-term biomarker of neuropsychiatric complications in LC.

◆Sex differences in inflammation and markers of gut integrity in long COVID【SPRINGER NATURE　2025年7月28日】

Abstract

Endothelial damage represents an essential pathogenic mechanism of respiratory and multiorgan dysfunction as seen in the post-acute phase of COVID-19. Biological differences between male and female sex, inflammation, and gut integrity may have an integral role in endothelial damage and explain the residual effects of COVID-19 infection in long COVID, yet evidence is limited. Confirmed COVID-19 negative participants were 1:1 propensity-score matched to COVID-19 positive participants. Symptoms occurring at least one-month following COVID-infection and lasting more than three-months was defined as long COVID. Measures of endothelial function included reactive hyperemic index (RHI ≥ 1.67 = normal endothelial function) and augmentation index (higher AIx = worse arterial elasticity). A total of 89 COVID-19 negative participants was matched to 89 COVID-19 positive participants. Among the COVID-19 survivors, the median age was 42.92 years, 46.07% were female sex, and 57 (64%) had long COVID. Higher levels of inflammation (TNF-RI and oxLDL) and gut integrity (zonulin and BDG) was associated (P < 0.05) with a two-fold increase in the odds of long COVID. Female sex, independent of COVID-19 status, was 4x more likely to have worse AIx (P < 0.0001) compared to male sex. Among female sex with long COVID, higher levels of inflammation (IL-6, VCAM, hsCRP) and gut integrity (zonulin) was independently associated (P < 0.05) with higher AIx. Female sex with long COVID symptoms had the worse inflammation, gut integrity, and arterial stiffness among COVID-19 survivors. This reinforces the importance of continued, long-term follow-up care following COVID-19 infection, with special attention needed for female sex who may be at a higher cardiovascular disease risk.

◆Evidence of SARS-CoV-2 bacteriophage potential in human gut microbiota【National Library of Medicine　2025年4月23日】

Abstract

Background

In previous studies we have shown that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replicates in vitro in bacterial growth medium, that the viral replication follows bacterial growth, and it is influenced by the administration of specific antibiotics. These observations are compatible with a ‘bacteriophage-like’ behaviour of SARS-CoV-2.

Methods

We have further elaborated on these unusual findings and here we present the results of three different supplementary experiments: (1) an electron-microscope analysis of samples of bacteria obtained from a faecal sample of a subject positive to SARS-CoV-2; (2) mass spectrometric analysis of these cultures to assess the eventual de novo synthesis of SARS-CoV-2 spike protein; (3) sequencing of SARS-CoV-2 collected from plaques obtained from two different gut microbial bacteria inoculated with supernatant from faecal microbiota of an individual positive to SARS-CoV-2.

Results

Immuno-labelling with Anti-SARS-CoV-2 nucleocapsid protein antibody confirmed presence of SARS-CoV-2 both outside and inside bacteria. De novo synthesis of SARS-CoV-2 spike protein was observed, as evidence that SARS-CoV-2 RNA is translated in the bacterial cultures. In addition, phage-like plaques were spotted on faecal bacteria cultures after inoculation with supernatant from faecal microbiota of an individual positive to SARS-CoV-2. Bioinformatic analyses on the reads obtained by sequencing RNA extracted from the plaques revealed nucleic acid polymorphisms, suggesting different replication environment in the two bacterial cultures.

Conclusions

Based on these results we conclude that, in addition to its well-documented interactions with eukaryotic cells, SARS-CoV-2 may act as a bacteriophage when interacting with at least two bacterial species known to be present in the human microbiota. If the hypothesis proposed, i.e., that under certain conditions SARS-CoV-2 may multiply at the expense of human gut bacteria, is further substantiated, it would drastically change the model of acting and infecting of SARS-CoV-2, and most likely that of other human pathogenic viruses.

 

◆Brainstem Reduction and Deformation in the 4th Ventricle Cerebellar Peduncles in Long COVID Patients: Insights into Neuroinflammatory Sequelae and “Broken Bridge Syndrome”【medRxiv　2025年8月8日】

Abstract

Post-COVID Syndrome (PCS), also known as Long COVID, is characterized by persistent and often debilitating neurological sequelae, including fatigue, cognitive dysfunction, motor deficits, and autonomic dysregulation (Dani et al., 2021). This study investigates structural and functional alterations in the brainstem and cerebellar peduncles of individuals with PCS using diffusion tensor imaging (DTI) and volumetric analysis. Forty-four PCS patients (15 bedridden) and 14 healthy controls underwent neuroimaging. Volumetric analysis focused on 22 brainstem regions, including the superior cerebellar peduncle (SCP), middle cerebellar peduncle (MCP), periaqueductal gray (PAG), and midbrain reticular formation (mRt).

Significant volume reductions were observed in the SCP (p < .001, Hedges’ g = 3.31) and MCP (p < .001, Hedges’ g = 1.77), alongside decreased fractional anisotropy (FA) in the MCP, indicative of impaired white matter integrity. FA_Avg fractional anisotropy average tested by FreeSurfer Tracula, is an index of white matter integrity, reflecting axonal fiber density, axonal diameter and myelination. These neuroimaging findings correlated with clinical manifestations of motor incoordination, proprioceptive deficits, and autonomic instability. Furthermore, volume loss in the dorsal raphe (DR) and midbrain reticular formation suggests disruption of pain modulation and sleep-wake cycles, consistent with patient-reported symptoms. Post-mortem studies provide supporting evidence for brainstem involvement in COVID-19. Radtke et al. (2024) reported activation of intracellular signaling pathways and release of immune mediators in brainstem regions of deceased COVID-19 patients, suggesting an attempt to inhibit viral spread. While viral genetic material was detectable, infected neurons were not observed. Matschke et al. (2020) found that microglial activation and cytotoxic T lymphocyte infiltration were predominantly localized to the brainstem and cerebellum, with limited involvement of the frontal lobe. This aligns with clinical observations implicating the brainstem in PCS pathophysiology. Cell-specific expression analysis of genes contributing to viral entry (ACE2, TMPRSS2, TPCN2, TMPRSS4, NRP1, CTSL) in the cerebral cortex showed their presence in neurons, glial cells, and endothelial cells, indicating the potential for SARS-CoV-2 infection of these cell types. Associations with autoimmune diseases with specific autoantibodies, including beta-2 and M-2 against G-protein coupled alpha-1, beta-1, beta-2 adrenoceptors against angiotensin II type 1 receptor or M1,2,3-mAChR, among others, voltage-gated calcium channels (VGCC) are known (Blitshteyn et al. 2015 and Wallukat and Schminke et al. 2014). These findings support the “Broken Bridge Syndrome” hypothesis, positing that structural disconnections between the brainstem and cerebellum contribute to PCS symptomatology. Furthermore, we propose that chronic activation of the Extended Autonomic System (EAS), encompassing the hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system, may perpetuate these symptoms (Goldstein, 2020). Perturbations in this system may relate to the elevation of toxic autoantibodies AABs (Beta-2 and M-2), specific epitopes of the COVID virus’s SPIKE protein and Cytokine storm of IL-1, IL-6, and IL-8 in their increased numbers (1,000->10,000)

Further research is warranted to elucidate the underlying neuroinflammatory mechanisms, EAS dysregulation, and potential therapeutic interventions for PCS.

◆Risk of neuropsychiatric and related conditions associated with SARS-CoV-2 infection: a difference-in-differences analysis【nature communications　2025年7月24日】

Abstract

The COVID-19 pandemic has been associated with increased neuropsychiatric conditions in children and youths, with evidence suggesting that SARS-CoV-2 infection may contribute additional risks beyond pandemic stressors. This study aims to assess the full spectrum of neuropsychiatric conditions in COVID-19 positive children (ages 5–12) and youths (ages 12–20) compared to a matched COVID-19 negative cohort, accounting for factors influencing infection risk. Using EHR data from 25 institutions in the RECOVER program, we conduct a retrospective analysis of 326,074 COVID-19 positive and 887,314 negative participants matched for risk factors and stratified by age. Neuropsychiatric outcomes are examined 28 to 179 days post-infection or negative test between March 2020 and December 2022. SARS-CoV-2 positivity is confirmed via PCR, serology, or antigen tests, while negativity requires negative test results and no related diagnoses. Risk differences reveal higher frequencies of neuropsychiatric conditions in the COVID-19 positive cohort. Children face increased risks for anxiety, OCD, ADHD, autism, and other conditions, while youths exhibit elevated risks for anxiety, suicidality, depression, and related symptoms. These findings highlight SARS-CoV-2 infection as a potential contributor to neuropsychiatric risks, emphasizing the importance of research into tailored treatments and preventive strategies for affected individuals.

◆Spike RBD drives sustained Parkinson’s disease progression via microglia-neuron crosstalk-mediated RTP801 upregulation【ScienceDirect　2025年8月5日】

Abstract

Introduction

Emerging evidence highlights the exacerbation and sustained Parkinson’s disease (PD) progression following COVID-19. The SARS-CoV-2 spike receptor-binding domain (RBD), which can persist in the brain post-infection, is a likely contributor, but how it drives this neuropathology is unclear.

Objectives

To elucidate the underlying mechanisms of long COVID’s impact on PD and identify mechanism that contribute to the continuous progression of PD.

Methods

The SARS-CoV-2 spike RBD was stereotactically injected into the substantia nigra pars compacta of α-synuclein (αSyn) A53T mice within a chronic stress-genetic susceptibility model. We characterized the pathological impact of RBD using motor and non-motor behavioral tests, fMRI-based functional connectivity, in vivo electrophysiology, immunofluorescence, and αSyn aggregate analysis. To elucidate the underlying mechanisms, we then employed RNA-sequencing, transmission electron microscopy, microglial depletion, and comparative studies in αSyn A53T mice lacking RTP801 (αSyn A53T+; RTP801−/−).

Results

RBD accelerated PD-related motor and non-motor symptom deterioration, impaired brain functional connectivity, and reduced neuronal excitability. It exacerbated dopaminergic neuron degeneration and αSyn aggregation. RTP801 was identified as a critical mediator of RBD-induced PD progression, with its sustained upregulation in dopaminergic neurons dependent on microglial activation. Mechanistically, initially activates microglia induced an increase in neuronal RTP801 via IL-6 and IL-8. RBD leaded to mitochondrial dysfunction, mtDNA release, and activation of the cGAS-STING pathway between neurons and microglia, triggering a mtDNA-cGAS-STING-IFNβ/RTP801 feedback loop, driving neurodegeneration.

Conclusions

Our findings demonstrate that SARS-CoV-2 RBD exacerbates PD progression through a pathogenic crosstalk between microglia and neurons. This neurotoxic signaling is mediated by a mitochondrial mtDNA-cGAS-STING-IFNβ/RTP801 axis. Targeting RTP801 or the STING pathway may therefore represent a promising therapeutic strategy to mitigate long COVID-associated progression of PD.

◆Aggregation potency and proinflammatory effects of SARS-CoV-2 proteins【nature : scientific reports　2025年8月4日】

Abstract

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, is primarily known as a respiratory disease. The continued study of the disease has shown that long-term COVID-19 symptoms include persisting effects of the virus on the brain when the infection is over, possibly even leading to neurodegeneration. However, the exact mechanisms of nervous system damage induced by SARS-CoV-2 are still unclear. In this study, we focused on two possibly shared pathways of SARS-CoV-2-induced neural dysfunction and neurodegeneration: protein aggregation, which is associated with impaired protein clearance, and inflammatory responses, which involve a hyper-active immune status. We observed distinct expression and distribution patterns of ten SARS-CoV-2 proteins in the two cell lines, meanwhile forming aggregation puncta and inducing pro-inflammatory responses. We found that the ER stress was induced and that the autophagy-lysosome pathway was inhibited upon viral protein expression. Boosting autophagy function attenuated protein aggregation, suggesting that modulation of autophagy might be a valid strategy for inhibiting cytotoxic effects of SARS-CoV- 2 proteins. Our study provides potential explanations of SARS-CoV-2-induced cell damage, based on shared cellular mechanisms and furthermore, suggests that modulation of proteostasis may serve as therapeutic strategies for preventing long-lasting SARS-CoV-2 cytotoxic effects.

◆Covid-19 linked with spike in long term digestive disorders, new study reveals【Sky News Australia : Jennifer Shahin　2025年8月5日】

Covid-19 has led to a sharp increase in digestive problems including irritable bowel syndrome and chronic indigestion, new research has revealed.

Emerging research continues to uncover long-term health impacts linked to Covid-19, with impacts ranging from brain ageing and lung complications to a significant rise in digestive disorders.

In 2020, early findings from the Wuhan Medical Treatment Expert Group for Covid-19 in China identified gastrointestinal symptoms such as diarrhoea and nausea as common consequences of the virus.

Recent studies are unveiling more information about the ongoing digestive issues affecting both adults and children in the post-pandemic period.

A 2023 study published in Clinical Gastroenterology and Hepatologyreported a sharp increase in digestive disorders following the pandemic.

The study found that overall gut-related disorders increased from 38.3 percent to 42.6 percent.

Using data collected before and after the pandemic, in 2017 and 2023, researchers noted a significant rise in gut-brain interaction disorders, including irritable bowel syndrome (IBS) and functional dyspepsia, which is chronic indigestion.

IBS cases rose by 28 percent, while functional dyspepsia increased by nearly 44 percent.

Adults who had Covid-19 were also more likely to develop gastrointestinal problems such as acid reflux, ulcers and indigestion within a year of infection.

Research involving children showed similar results.

Children who had previously contracted Covid-19 faced a 25 to 28 percent higher risk of developing new gastrointestinal symptoms compared to those who had not been infected.

Meanwhile, those who experienced long Covid, meaning symptoms lasting for more than three months after infection, were significantly more likely to suffer from gut-brain disorders.

The symptoms linked to long Covid included nausea, diarrhoea, stomach pain and loss of appetite.

These individuals also reported higher levels of anxiety, depression and a lower quality of life.