SARS-CoV-2 と COVID-19 に関する備忘録 Vol.24――ブレインフォグなどの症状を負っている患者の脳に見られる灰白質変化などの微小構造変化が、感染後に長期障害がなかったと主観的に感じている患者の脳にも同様に…etc.

SARS-CoV-2 と COVID-19 に関するメモ・備忘録

Novel MRI reveals brain changes in long-COVID patients【EurekAlert 2023年11月22日】

CHICAGO – People with long COVID exhibit patterns of changes in the brain that are different from fully recovered COVID-19 patients, according to research being presented next week at the annual meeting of the Radiological Society of North America (RSNA).

“To the best of our knowledge, this is the first study comparing patients with long COVID to both a group without history of COVID-19 and a group that went through a COVID-19 infection but is subjectively unimpaired,” said one of the study’s lead authors, Alexander Rau, M.D., resident in the Departments of Neuroradiology and Diagnostic and Interventional Radiology at University Hospital Freiburg in Freiburg, Germany.


[IMAGE : BRAIN REGIONS IN WHICH THE MICROSTRUCTURE WAS ASSOCIATED WITH POST-COVID-CONDITION ASSOCIATED SYMPTOMS.]

After infection with COVID-19, as many as 10-25% of patients may develop a post-COVID condition commonly referred to as “long COVID.” People with long COVID may experience a wide variety of symptoms, including difficulty concentrating (“brain fog”), change in sense of smell or taste, fatigue, joint or muscle pain, shortness of breath, digestive symptoms, and more. These symptoms may persist for weeks, months, or—as is only now becoming apparent—years after COVID-19 infection.

However, the basis of this condition is poorly understood. Diffusion microstructure imaging (DMI), a novel MRI technique, is a promising approach to fill this gap.

DMI looks at the movement of water molecules in tissues. By studying how water molecules move in different directions and at various speeds, DMI can provide detailed information on the microstructure of the brain. It can detect even very small changes in the brain, not detectable with conventional MRI.

For this prospective, cross-sectional study, Dr. Rau and colleagues compared MRI brain scans of three groups: 89 patients with long COVID, 38 patients that had contracted COVID-19 but did not report any subjective long-term symptoms, and 46 healthy controls with no history of COVID-19.

The researchers first compared the cerebral macrostructure of these three groups to test for atrophy or any other abnormalities. Next, they used DMI to gain a deeper insight into the brain.

The three groups were compared to reveal group differences in the brain’s microstructure. DMI parameters were read for the gray matter in the brain. Additionally, whole brain analyses were employed to reveal the spatial distribution of alterations and associations with clinical data, including long-COVID symptoms like fatigue, cognitive impairment or impaired sense of smell.

The results showed no brain volume loss or any other lesions that might explain the symptoms of long COVID. However, COVID-19 infection induced a specific pattern of microstructural changes in various brain regions, and this pattern differed between those who had long COVID and those who did not.

“This study allows for an in vivo insight on the impact of COVID-19 on the brain,” Dr. Rau said. “Here, we noted gray matter alterations in both patients with long-COVID and those unimpaired after a COVID-19 infection. Interestingly, we not only noted widespread microstructural alterations in patients with long COVID, but also in those unimpaired after having contracted COVID-19.”

The findings also revealed a correlation between microstructural changes and symptom-specific brain networks associated with impaired cognition, sense of smell and fatigue.

“Expression of post-COVID symptoms was associated with specific affected cerebral networks, suggesting a pathophysiological basis of this syndrome” Dr. Rau said.

The researchers hope to reexamine the patients in the future, recording both clinical symptoms and changes to the brain’s microstructure.

Despite these brain imaging findings, it remains unclear why some people develop long COVID while others do not, although previous studies have identified risk factors including female sex, older age, higher body mass index, smoking, preexisting comorbidities, and previous hospitalization or intensive care unit admission.

 

Probable human origin of the SARS-CoV-2 polybasic furin cleavage motif【BMC Genomic Data 2023年11月21日】

Abstract

Background

The key evolutionary step leading to the pandemic virus was the acquisition of the PRRA furin cleavage motif at the spike glycoprotein S1/S2 junction by a progenitor of SARS-CoV-2. Two of its features draw attention: (i) it is absent in other known lineage B beta-coronaviruses, including the newly discovered coronaviruses in bats from Laos and Vietnam, which are the closest known relatives of the covid virus; and, (ii) it introduced the pair of arginine codons (CGG-CGG), whose usage is extremely rare in coronaviruses. With an occurrence rate of only 3%, the arginine CGG codon is considered a minority in SARS CoV-2. On the other hand, Laos and Vietnam bat coronaviruses contain receptor-binding domains that are almost identical to that of SARS-CoV-2 and can therefore infect human cells despite the absence of the furin cleavage motif.

Results

Based on these data, the aim of this work is to provide a detailed sequence analysis between the SARS-CoV-2 S gene insert encoding PRRA and the human mRNA transcripts. The result showed a 100% match to several mRNA transcripts. The set of human genes whose mRNAs match this S gene insert are ubiquitous and highly expressed, e.g., the ATPase F1 (ATP5F1) and the ubiquitin specific peptidase 21 (USP21) genes; or specific genes of target organs or tissues of the SARS-CoV-2 infection (e.g., MEMO1, SALL3, TRIM17, CWC15, CCDC187, FAM71E2, GAB4, PRDM13). Results suggest that a recombination between the genome of a SARS-CoV-2 progenitor and human mRNA transcripts could be the origin of the S gene 12-nucleotide insert encoding the S protein PRRA motif.

Conclusions

The hypothesis of probable human origin of the SARS-CoV-2 polybasic furin cleavage motif is supported by: (i) the nature of human genes whose mRNA sequence 100% match the S gene insert; (ii) the synonymous base substitution in the arginine codons (CGG-CGG); and (iii) further spike glycoprotein PRRA-like insertions suggesting that the acquisition of PRRA may not have been a single recombination event.

 

Isolation may select for earlier and higher peak viral load but shorter duration in SARS-CoV-2 evolution【nature communications 2023年11月21日】

Abstract

During the COVID-19 pandemic, human behavior change as a result of nonpharmaceutical interventions such as isolation may have induced directional selection for viral evolution. By combining previously published empirical clinical data analysis and multi-level mathematical modeling, we find that the SARS-CoV-2 variants selected for as the virus evolved from the pre-Alpha to the Delta variant had earlier and higher peak in viral load dynamics but a shorter duration of infection. Selection for increased transmissibility shapes the viral load dynamics, and the isolation measure is likely to be a driver of these evolutionary transitions. In addition, we show that a decreased incubation period and an increased proportion of asymptomatic infection are also positively selected for as SARS-CoV-2 mutated to adapt to human behavior (i.e., Omicron variants). The quantitative information and predictions we present here can guide future responses in the potential arms race between pandemic interventions and viral evolution.

Introduction

The human impact of population densities and activities on the global environment has increased so dramatically that the current geological era has been termed the Anthropocene. Human-mediated selection constitutes one of the most significant and pervasive selective pressures on Earth, changing at a pace that requires rapid evolution of adaptive responses by all organisms. COVID-19-related restrictions and the resultant changes in human activities created a phenomenon termed “anthropause,” that is, a considerable global slowing of human activities and the effects of human activity on nature.

Human history has always been interwoven with viruses. Viruses debilitate many people and can have large-scale demographic effects on human populations according to immunity and prior disease exposure. On the other hand, humans are an essential arena in which viruses evolve. Changes in human population size, immunity, and behavior based on public health policy can facilitate the rapid evolution of viruses.

We are facing the ongoing rapid emergence and adaptation of SARS-CoV-2. The virus was initially discovered in Wuhan, China, in late December 2019 (B lineage, strain Wuhan-Hu-1) and spread worldwide. Virus bearing the D614G substitution on the surface of the spike protein emerged in 2020 and became dominant among the circulating SARS-CoV2 variants. The Alpha variant (B.1.1.7), first detected in the UK at the end of 2020, displayed a 43–90% higher reproduction number than pre-existing variants. Interestingly, however, Alpha faded away with the rise of the more transmissible Delta variant (B.1.617.2), which was first documented in India in October 2020. Then, the Omicron variant (originally B.1.1.529), which was first isolated in South Africa on October 2021, spread aggressively. A range of Omicron subvariants (BA.1, BA.2, BA.4, and BA.5) eclipsed the Delta variant, and the Omicron variant became the predominant variant worldwide after February 2022. Currently, several new Omicron subvariants (BQ.1, XBB, and others) are emerging and are reported to be more transmissible and resistant to immunity generated by previous variants or vaccinations. Collectively, these observations indicate that SARS-CoV-2 has continuously been evolving and variants have continued to emerge to replace existing viral strains worldwide, as observed with influenza.

An understanding of the epidemiological and clinical characteristics of current and future emerging infectious diseases is important for developing adaptive treatments, including antivirals and vaccinations, and screening and isolation strategies. Thus, evaluating and predicting how viral dynamics changes throughout infection through evolution is essential. An unprecedentedly large volume of high-quality data have accumulated during the COVID-19 pandemic, and here we analyze the data on SARS-CoV-2 variants to benefit preparedness for future pandemics. As we discuss elsewhere, quantifying and comparing the timing and height of peak viral load and the duration of viral shedding among SARS-CoV-2 variants are of critical importance. In addition, understanding the driving forces behind viral evolution is also required, given the different selective pressures acting on the virus. In general, the infection- and/or vaccine-induced immune response to antiviral drugs (i.e., pharmaceutical interventions: PIs) leads to virus evolution. The strongest evidence for selection based on human intervention is the rapid evolution of immune-escaping mutations in the Omicron variant, which often occur in parallel and can be predicted ahead of time19. In contrast, nonpharmaceutical interventions (NPIs), such as isolation, quarantine, social distancing, and wearing a face covering, efficiently prevent close contact, in particular, in symptomatic patients, given that most cases are the result of community transmission. NPIs have proven effective in reducing the spread of SARS-CoV-2 in many contexts. The introduction of strong selection pressure by NPIs and the evolutionary impact of this has been the focus of much attention, but how viral load dynamics are altered in vivo has not yet been explored. We were thus interested in the role of isolation as a strong NPI and explored the possible impact of such human behavioral changes on SARS-CoV-2 evolution.

So far, statistical analyses have shown that SARS-CoV-2 viral kinetics are mainly dominated by individual-level variation, but the kinetics may be partly determined by immunity and variant. Here, to explore the isolation-driven viral evolution, we first quantified the viral dynamics from existing data on the viral load over the course of SARS-CoV-2 infection for the pre-Alpha (non-variants of interest/variants of concern [VOI/VOCs] types), Alpha, and Delta variants (i.e., individual-level virus infection model) considering both individual and variant-specific variations in kinetics. Then, to explain and predict the evolutionary patterns of SARS-CoV-2 variants in terms of the time-series pattern of viral load, we developed a multi-level population dynamics model by coupling a population-level virus transmission model with the individual-level virus infection model. Under different clinical phenotypes for COVID-19 patients, defined here as the incubation period and the proportion of symptomatic infections, we evaluated how the time-series patterns of viral load and, therefore, SARS-CoV-2, evolve under isolation of infected individuals. We interestingly demonstrate that NPIs may select for earlier and higher peak viral load but shorter duration of infection in SARS-CoV-2. Although there are multiple ways to cause the recent evolutionary trajectory, the concepts and variables that affect the current transition can be anticipated. We discuss the potential evolution of SARS-CoV-2 as it adapts to maximize transmissibility in the presence of a human behavior change.

 

Study on brain damage patterns of COVID-19 patients based on EEG signals【Frontiers in Human Neuroscience 2023年11月24日】

Objective: The coronavirus disease 2019 (COVID-19) is an acute respiratory infectious disease caused by the SARA-CoV-2, characterized by high infectivity and incidence. Clinical data indicates that COVID-19 significantly damages patients’ perception, motor function, and cognitive function. However, the electrophysiological mechanism by which the disease affects the patient’s nervous system is not yet clear. Our aim is to investigate the abnormal levels of brain activity and changes in brain functional connectivity network in patients with COVID-19.

Methods: We compared and analyzed electroencephalography signal sample entropy, energy spectrum, and brain network characteristic parameters in the delta (1–4 Hz), theta (4–8 Hz), alpha (8–13 Hz), and beta (13–30 Hz) bands of 15 patients with COVID-19 and 15 healthy controls at rest.

Results: At rest, energy values of the four frequency bands in the frontal and temporal lobes of COVID-19 patients were significantly reduced. At the same time, the sample entropy value of the delta band in COVID-19 patients was significantly increased, while the value of the beta band was significantly decreased. However, the average value of the directed transfer function of patients did not show any abnormalities under the four frequency bands. Furthermore, node degree in the temporal lobe of patients was significantly increased, while the input degree of the frontal and temporal lobes was significantly decreased, and the output degree of the frontal and occipital lobes was significantly increased.

Conclusion: The level of brain activity in COVID-19 patients at rest is reduced, and the brain functional network undergoes a rearrangement. These results preliminarily demonstrate that COVID-19 patients exhibit certain brain abnormalities during rest, it is feasible to explore the neurophysiological mechanism of COVID-19’s impact on the nervous system by using EEG signals, which can provide a certain technical basis for the subsequent diagnosis and evaluation of COVID-19 using artificial intelligence and the prevention of brain nervous system diseases after COVID-19 infection.

 

 

SARS-CoV-2 omicron BA.5 and XBB variants have increased neurotropic potential over BA.1 in K18-hACE2 mice and human brain organoids【Frontiers in Microbiology 2023年11月23日】

The reduced pathogenicity of the omicron BA.1 sub-lineage compared to earlier variants is well described, although whether such attenuation is retained for later variants like BA.5 and XBB remains controversial. We show that BA.5 and XBB isolates were significantly more pathogenic in K18-hACE2 mice than a BA.1 isolate, showing increased neurotropic potential, resulting in fulminant brain infection and mortality, similar to that seen for original ancestral isolates. BA.5 also infected human cortical brain organoids to a greater extent than the BA.1 and original ancestral isolates. In the brains of mice, neurons were the main target of infection, and in human organoids neuronal progenitor cells and immature neurons were infected. The results herein suggest that evolving omicron variants may have increasing neurotropic potential.