SARS-CoV-2 と COVID-19 に関する備忘録 Vol.6――岩崎明子・イェール大教授の実績、コロナウイルスは心臓の動脈である冠動脈に直接感染できる…etc.

SARS-CoV-2 と COVID-19 に関するメモ・備忘録


Distinguishing features of long COVID identified through immune profiling【nature 2023年9月25日】


Post-acute infection syndromes may develop after acute viral disease. Infection with SARS-CoV-2 can result in the development of a post-acute infection syndrome known as long COVID. Individuals with long COVID frequently report unremitting fatigue, post-exertional malaise, and a variety of cognitive and autonomic dysfunctions. However, the biological processes that are associated with the development and persistence of these symptoms are unclear. Here 275 individuals with or without long COVID were enrolled in a cross-sectional study that included multidimensional immune phenotyping and unbiased machine learning methods to identify biological features associated with long COVID. Marked differences were noted in circulating myeloid and lymphocyte populations relative to the matched controls, as well as evidence of exaggerated humoral responses directed against SARS-CoV-2 among participants with long COVID. Furthermore, higher antibody responses directed against non-SARS-CoV-2 viral pathogens were observed among individuals with long COVID, particularly Epstein–Barr virus. Levels of soluble immune mediators and hormones varied among groups, with cortisol levels being lower among participants with long COVID. Integration of immune phenotyping data into unbiased machine learning models identified the key features that are most strongly associated with long COVID status. Collectively, these findings may help to guide future studies into the pathobiology of long COVID and help with developing relevant biomarkers.


Recovery from acute viral infections is heterogeneous and chronic symptoms may linger for months to years in some individuals. Moreover, persistent sequelae may develop after acute infection by a number of viruses from a diverse range of viral families. Post-acute infection syndromes (PAIS) following microbial infections have also been described for over a century. Yet despite their ubiquity, the basic biology underlying PAIS development, even for extensively studied PAIS such as myalgic encephalomyelitis/chronic fatigue syndrome, remains unclear.

SARS-CoV-2 is a Betacoronavirus that is responsible for almost 7 million deaths worldwide13. Infection causes COVID-19, which can manifest as a severe respiratory disease marked by extensive immunological and multiorgan system dysfunction. Recovery from COVID-19 is often complete; however, individuals (even those with initially mild disease courses) may have increased risks for adverse clinical events and abnormal clinical findings.

In addition to developing isolated dysfunctions, some patients recovering from COVID-19 may develop a group of new onset or aggravated sequelae known as long COVID (LC). Clinically, LC presents as a constellation of debilitating symptoms including unremitting fatigue, post-exertional malaise, cognitive impairment and autonomic dysfunction, alongside other less common manifestations. These persistent sequelae markedly impair physical and cognitive function and reduce quality of life. Estimates of LC prevalence vary substantially, but prospective studies suggest that about one in eight individuals with COVID-19 experience persistent somatic symptoms that are attributable to past SARS-CoV-2 infection. Although the underlying pathogenesis of LC remains unclear, current hypotheses include the persistence of virus or viral remnants in tissues; development or aggravation of autoimmunity; microbial dysbiosis; reactivation of non-SARS-CoV-2 latent viral infections; and tissue damage caused by chronic inflammation.

To investigate the biological underpinnings of LC, a cross-sectional study was designed (Mount Sinai–Yale long COVID; hereafter, MY-LC) involving 275 participants comprising five study groups: (1) healthcare workers infected with SARS-CoV-2 before vaccination (HCW); (2) healthy, uninfected, vaccinated controls (healthy control (HC) group); (3) previously infected, vaccinated controls without persistent symptoms (convalescent control (CCs) group); (4) individuals with persistent symptoms after acute infection (LC); and (5) a second group of individuals with persistent symptoms after acute infection from an independent study (external LC, hereafter EXT-LC). Among the CC and LC groups, enrolled participants had primarily mild (non-hospitalized) acute COVID-19 and samples for this study were acquired, on average, more than a year after their acute infection. The HC, CC and LC groups underwent systematic, multidimensional immunophenotyping and unbiased machine learning of aggregated data to identify potential LC biomarkers.


SARS-CoV-2 infects coronary arteries, increases plaque inflammation――NIH-funded research sheds light on link between COVID-19 infection and increased risk of cardiovascular disease and stroke.【NIH(アメリカ国立衛生研究所) 2023年9月28日】

SARS-CoV-2, the virus that causes COVID-19, can directly infect the arteries of the heart and cause the fatty plaque inside arteries to become highly inflamed, increasing the risk of heart attack and stroke, according to a study funded by the National Institutes of Health. The findings(link is external), published in the journal Nature Cardiovascular Research, may help explain why certain people who get COVID-19 have a greater chance of developing cardiovascular disease, or if they already have it, develop more heart-related complications.

In the study, researchers focused on older people with fatty buildup, known as atherosclerotic plaque, who died from COVID-19. However, because the researchers found the virus infects and replicates in the arteries no matter the levels of plaque, the findings could have broader implications for anybody who gets COVID-19.

“Since the early days of the pandemic, we have known that people who had COVID-19 have an increased risk for cardiovascular disease or stroke up to one year after infection,” said Michelle Olive, Ph.D., acting associate director of the Basic and Early Translational Research Program at the National Heart, Lung, and Blood Institute (NHLBI), part of NIH. “We believe we have uncovered one of the reasons why.”

Though previous studies have shown that SARS-CoV-2 can directly infect tissues such as the brain and lungs, less was known about its effect on the coronary arteries. Researchers knew that after the virus reaches the cells, the body’s immune system sends in white blood cells known as macrophages to help clear the virus. In the arteries, macrophages also help remove cholesterol, and when they become overloaded with cholesterol, they morph into a specialized type of cell called foam cells.

The researchers thought that if SARS-CoV-2 could directly infect arterial cells, the macrophages that normally are turned loose might increase inflammation in the existing plaque, explained Chiara Giannarelli, M.D., Ph.D., associate professor in the departments of medicine and pathology at New York University’s Grossman School of Medicine and senior author on the study. To test their theory, Giannarelli and her team took tissue from the coronary arteries and plaque of people who had died from COVID-19 and confirmed the virus was in those tissues. Then they took arterial and plaque cells – including macrophages and foam cells – from healthy patients and infected them with SARS-CoV-2 in a lab dish. They found that the virus had also infected those cells and tissues.

Additionally, the researchers found that when they compared the infection rates of SARS-CoV-2, they showed that the virus infects macrophages at a higher rate than other arterial cells. Cholesterol-laden foam cells were the most susceptible to infection and unable to readily clear the virus. This suggested that foam cells might act as a reservoir of SARS-CoV-2 in the atherosclerotic plaque. Having more build-up of plaque, and thus a greater number of foam cells, could increase the severity or persistence of COVID-19.

The researchers then turned their attention to the inflammation they predicted might occur in the plaque after infecting it with the virus. They quickly documented the release of molecules, known as cytokines, that are known to increase inflammation and promote the formation of even more plaque. The cytokines were released by infected macrophages and foam cells. The researchers said this may help explain why people who have underlying plaque buildup and then get COVID-19 may have cardiovascular complications long after getting the infection.

“This study is incredibly important as it adds to the larger body of work to better understand COVID-19,” said Olive. “This is just one more study that demonstrates how the virus both infects and causes inflammation in many cells and tissues throughout the body. Ultimately, this is information that will inform future research on both acute and Long COVID.”

Though the findings conclusively show that SARS-CoV-2 can infect and replicate in the macrophages of plaques and arterial cells, they are only relevant to the original strains of SARS-CoV-2 that circulated in New York City between May 2020 and May 2021. The study was conducted in a small cohort of older individuals, all of whom had atherosclerosis and other medical conditions; therefore, the results cannot be generalized to younger, healthy individuals.

This work was funded by the NIH/NHLBI grants 1R01HL165258, R01HL153712, R35HL135799 and R01HL084312. NIAID and NIDDK also provided funding.


SARS-CoV-2 infection triggers pro-atherogenic inflammatory responses in human coronary vessels【nature:naturecardiovascular research 2023年9月28日】


Patients with coronavirus disease 2019 (COVID-19) present increased risk for ischemic cardiovascular complications up to 1 year after infection. Although the systemic inflammatory response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection likely contributes to this increased cardiovascular risk, whether SARS-CoV-2 directly infects the coronary vasculature and attendant atherosclerotic plaques remains unknown. Here we report that SARS-CoV-2 viral RNA is detectable and replicates in coronary lesions taken at autopsy from severe COVID-19 cases. SARS-CoV-2 targeted plaque macrophages and exhibited a stronger tropism for arterial lesions than adjacent perivascular fat, correlating with macrophage infiltration levels. SARS-CoV-2 entry was increased in cholesterol-loaded primary macrophages and dependent, in part, on neuropilin-1. SARS-CoV-2 induced a robust inflammatory response in cultured macrophages and human atherosclerotic vascular explants with secretion of cytokines known to trigger cardiovascular events. Our data establish that SARS-CoV-2 infects coronary vessels, inducing plaque inflammation that could trigger acute cardiovascular complications and increase the long-term cardiovascular risk.


Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is uniquely marked by extraordinary tissue tropism and an array of clinical presentations, from asymptomatic infection to acute respiratory distress, multi-organ failure and death. Ischemic cardiovascular events, such as acute myocardial infarction (AMI) and stroke, due to the underlying disruption of a chronically inflamed atherosclerotic plaque, are established clinical complications of COVID-19. AMI and stroke can be triggered by several acute respiratory viral infections, including influenza virus. However, patients with COVID-19 are >7-fold more likely to have a stroke than patients with influenza, and their risk for both AMI and stroke remains high for up to 1 year after infection. The extreme inflammatory response that occurs in severe cases of COVID-19, also known as cytokine storm, is likely a contributor to the increased risk for AMI and stroke. However, the possibility that SARS-CoV-2 directly affects the coronary vasculature, as documented for other distant organs (for example, kidney, gut, brain, adipose tissue and myocardium), remains largely unexplored. In the lungs, tissue damage is aggravated by potent inflammasome activation in macrophages sensing SARS-CoV-2 virus. A similar response in macrophages infiltrating arterial vessels affected by the virus could boost plaque inflammation and risk for AMI and stroke in patients with COVID-19. Here we show, in coronary autopsy specimens from patients with COVID-19, that infiltrating macrophages were infected by SARS-CoV-2. Lipid-laden macrophages (foam cells), a hallmark of atherosclerosis at all stages of the disease, were more susceptible to SARS-CoV-2 infection than other macrophages, and this was dependent on the receptor neuropilin-1 (NRP-1). SARS-CoV-2 induced a strong pro-atherogenic inflammatory response in both macrophages and foam cells, which was largely recapitulated in an ex vivo SARS-CoV-2 infection of human vascular explants. This response may contribute to the ischemic cardiovascular complications in patients with COVID-19.


SARS-CoV-2 Spike amyloid fibrils specifically and selectively accelerates amyloid fibril formation of human prion protein and the amyloid β peptide【bioRxiv 2023年9月1日】


An increasing number of reports suggest an association between COVID-19 infection and initiation or acceleration of neurodegenerative diseases (NDs) including Alzheimer’s disease (AD) and Creutzfeldt-Jakob disease (CJD). Both these diseases and several other NDs are caused by conversion of human proteins into a misfolded, aggregated amyloid fibril state. The fibril formation process is self-perpetuating by seeded conversion from preformed fibril seeds. We recently described a plausible mechanism for amyloid fibril formation of SARS-CoV-2 spike protein. Spike-protein formed amyloid fibrils upon cleavage by neutrophil elastase, abundant in the inflammatory response to COVID-19 infection.

We here provide evidence of significant Spike-amyloid fibril seeded acceleration of amyloid formation of CJD associated human prion protein (HuPrP) using an in vitro conversion assay. By seeding the HuPrP conversion assay with other in vitro generated disease associated amyloid fibrils we demonstrate that this is not a general effect but a specific feature of spike-amyloid fibrils. We also showed that the amyloid fibril formation of AD associated Aβ1-42 was accelerated by Spike-amyloid fibril seeds. Of seven different 20-amino acid long peptides, Spike532 (532NLVKNKCVNFNFNGLTGTGV551) was most efficient in seeding HuPrP and Spike601 (601GTNTSNQVAVLYQDVNCTEV620) was most effective in seeding Aβ1-42, suggesting substrate dependent selectivity of the cross-seeding activity.

Albeit purely in vitro, our data suggest that cross-seeding by Spike-amyloid fibrils can be implicated in the increasing number of reports of CJD, AD, and possibly other NDs in the wake of COVID-19.


Amyloids and viruses are each notorious for their detrimental effect on human health. There are also many ways in which cross-talk between these two disease causing entities resulting in increasing risk of harm to the host. Several neurodegenerative diseases (NDs) are intimately related to misfolding and amyloid formation of endogenously expressed proteins. However, research has to date failed to describe why some but not others fall victim to these diseases. In a retrospective study of 800 000 individuals from biobanks in Finland and the UK it was evident that infection from some of our most common viruses, e.g. Influenza and Herpes zoster was connected to an increased risk of some of the most common NDs such as Alzheimer’s disease (AD) and Parkinson’s disease (PD).

The neurological manifestations of COVID-19 both in the acute phase and as long term sequel of SARS-CoV-2 infection have been widely observed and described during the COVID-19 pandemic. The dominating explanation for this is neuroinflammation. Neuroinflammation is a common denominator of NDs. The specific roles of neuroinflammation in prion disease was recently reviewed.

NDs are specifically associated with the misfolding and amyloid formation of intracerebral proteins. AD is linked to formation of extracellular amyloid plaques with the Aβ peptide as main constituent and intracellular neurofibrillary tangles composed of Tau protein. Prion diseases are caused by the misfolding and aggregation of the prion protein, PrP, that is abundant on the extracellular surface of all neuronal cells in mammals. Although each distinct disease is associated with its own set of misfolded proteins, more and more evidence is pointing towards the possibility of cross-seeding, that is that amyloids formed of one type of protein can induce amyloid formation of another protein.

Several SARS-CoV-2 proteins are known to form amyloid. The proteins translated from viral open reading frame genes (ORFs) are often intrinsically disordered and/or fold only in the context of the viral particle. SARS-CoV-2 ORF6 and ORF10 are amyloidogenic and the resulting amyloids exhibit neurotoxic properties on cultured cells. Nucleocapsid proteins (NCAPs) are crucial for the assembly of viral particles. These proteins contain low complexity domains that are important for the self-assembly of the virus particle but the complementarity between adjacent polypeptide chains can also promote the formation of amyloid structure. The low complexity domain of SARS-CoV-2 NCAP forms amyloid in vitro and this amyloid was recently suggested as a drug candidate for treatment of COVID-19.

The SARS-CoV-2 Spike proteins forms amyloid when cleaved by neutrophil elastase. Elastase is abundant in covid induced inflammation. Amyloid derived from SARS-CoV-2 spike protein has the potential to hamper fibrinolysis of seeded fibrin and hence might be one explanation for microclot formation in severe and long COVID-19. Data from Brogna and colleagues demonstrate that Spike protein produced in the host as response to mRNA vaccine, as deduced by specific amino acid substitutions, persists in blood samples from 50% of vaccinated individuals for between 67 and 187 days after mRNA vaccination. Such prolonged Spike protein exposure has previously been hypothesized to stem from residual virus reservoirs, but evidently this can occur also as consequence of mRNA vaccination.

Other viruses from different families comprise amyloidogenic proteins. As an example, several proteins of Influenza A, causing seasonal flu, are known to be amyloidogenic. Recombinant expressed Pb1-F2 protein forms amyloid in vitro and in experimentally infected cells. Influenza A non-structured protein 1 (NS1) can also from amyloid in vitro. Influenza A infection has been shown to induce misfolding of PrP.

During the past 3 years, several case reports of Creutzfeldt-Jakob disease (CJD) manifestation in parallel with COVID-19 infection or vaccination have been published. Recently it was suggested by Stefano et al that the conversion of PrPC to PrPSc and the subsequent mitochondrial dysfunction should be considered when addressing the etiology of long COVID-19.

Although AD is a very slowly progressing disease, there are already indications that suggest a connection between COVID-19 infection and downstream risk of AD. Brain atrophy was prevalent in patients infected post COVID-19 for early strains. Aβ aggregates were found postmortem in brains of young COVID-19 infected patients. COVID-19 imposed 1.69 increased risk for new diagnosis of AD within 360 days at age >65 years.

A recent in vitro study showed augmented Aβ1-42 fibril formation induced by preformed seeds from SARS-CoV-2 Spike-protein peptide 1058-1068. We herein follow up the concept of cross-seeding of ND proteins with SARS-CoV-2 Spike amyloid fibrils. Cross-seeding is a testable hypothesis and we addressed it in our well-established in vitro seeding assays by cross-seeding of human prion protein and Aβ1-42 peptide with seven different amyloid fibrils from peptides of the SARS-CoV-2 spike protein.


T cell cross-reactivity in autoimmune-like hepatitis triggered by COVID-19【ScienceDirect 2023年9月28日】

Over 1000 cases of pediatric hepatitis of unknown etiology have been reported worldwide since the first case was reported in the UK. To date, the etiology of pediatric hepatitis remains unknown and controversial. Adenovirus was first suspected to be the cause as it was present in the blood samples of the majority of cases. Partial cases have also been tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, it is still unclear how these viruses contribute to pediatric hepatitis. In the case of a pediatric patient with SARS-CoV-2 infection, the liver biopsy showed acute submassive hepatocyte necrosis, accompanied by a significant increase in T cell infiltration. Furthermore, CD8+ T cell dominant hepatitis induced by coronavirus disease 2019 (COVID-19) vaccination has also been recently reported. Although it is known that T cell receptors (TCRs) can discriminate between self- and non-self-antigens, it is now well-accepted that TCRs exhibit cross-reactivity toward similar and even distinct antigen peptides. Thus, we hypothesized that following SARS-CoV-2 infection or vaccination, T cells carrying TCRs that recognize self-antigens undergo clonal expansion, which could eventually result in the onset of autoimmune-like hepatitis.