SARS-CoV-2 と COVID-19 に関する備忘録 Vol.7――血液脳関門（blood-brain barrier）、マスク、治療薬の有料化…etc.

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SARS-CoV-2 と COVID-19 に関するメモ・備忘録

下4ツイートを自動翻訳機能で和訳してみました

「SARS-CoV-2は侵入者である
血液脳関門は、施設（あなたの脳）を守る厳重なフェンスである。
通常、このフェンスは許可された人員（必要な栄養素や分子）しか通さない。
しかしこのウイルスは賢い」

「SARS-CoV-2は柵を突破するだけでなく、柵の構造にもダメージを与え、他の不要な侵入者（毒素や有害物質）の侵入を許す可能性がある。
もしSARS-CoV-2が血液脳関門を損なえば、オオカミが柵を越えて羊の放牧地に侵入するようなものである。」

「一旦中に入れば、オオカミは羊（ニューロンやその他の脳細胞）を攻撃することで直ちにダメージを与えることができるが、同時に他の捕食者や病気が安全な空間に入ってくる扉を開いてしまう。」

「長期的な影響は壊滅的で、慢性的な神経学的問題につながる可能性がある。フェンスが破られたことで、群れ全体が継続的な危険にさらされるのと同じことだ。」


◆Alteration of the blood-brain barrier by COVID-19 and its implication in the permeation of drugs into the brain【Frontiers in Cellular Neuroscience　2023年3月14日】

Diverse neurological symptoms have been reported in patients with SARS-CoV-2 disease (COVID-19), including stroke, ataxia, meningitis, encephalitis, and cognitive impairment. These alterations can cause serious sequelae or death and are associated with the entry of SARS-CoV-2 into the Central Nervous System (CNS). This mini-review discusses the main proposed mechanisms by which SARS-CoV-2 interacts with the blood-brain barrier (BBB) and its involvement in the passage of drugs into the CNS. We performed a search in PubMed with the terms “COVID-19” or “SARS-CoV-2” and “blood-brain barrier injury” or “brain injury” from the year 2019 to 2022. We found proposed evidence that SARS-CoV-2 infects neurovascular cells and increases BBB permeability by increasing the expression of matrix metalloproteinase-9 that degrades type IV collagen in the basement membrane and through activating RhoA, which induces restructuring of the cytoskeleton and alters the integrity of the barrier. The breakdown of the BBB triggers a severe inflammatory response, causing the cytokine storm (release of IL-1β, IL-6, TNF-α, etc.) characteristic of the severe phase of COVID-19, which includes the recruitment of macrophages and lymphocytes and the activation of astrocytes and microglia. We conclude that the increased permeability of the BBB would allow the passage of drugs that would not reach the brain in a normal physiological state, thus enhancing certain drugs’ beneficial or adverse effects. We hope this article will encourage research on the impact of drugs on patients with COVID-19 and recovered patients with sequelae, focusing mainly on possible dose adjustments and changes in pharmacokinetic parameters.

1. Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of coronavirus disease 2019 (COVID-19), which has caused more than 6.5 million deaths and more than 621 million positive cases worldwide (at least until October 17, 2022) as reported by the World Health Organization [WHO] (2022). According to a report by Visual Capitalist (with data from the WHO), COVID-19 is the pandemic with the seventh-highest number of deaths in modern history (Visual Capitalist, 2020).

SARS-CoV-2 is a positive-sense, single-stranded RNA virus with a spherical and spiked protein envelope of about 60-140 nm, belonging to the betacoronavirus genus (Welcome and Mastorakis, 2021). Among the main structural proteins, there is the spike (S) glycoprotein, which is a type I transmembrane protein, composed of the S1 subunit responsible for binding to the receptor on the surface of the host cell and the S2 subunit responsible for the fusion of membranes and viral penetration (Tizenberg et al., 2021; Takeda, 2022). SARS-CoV-1 and SARS-CoV-2 share 79% identity with each other (Lu et al., 2020; Chen Z. et al., 2021); however, SARS-CoV-2 has shown higher binding affinity to human angiotensin-converting enzyme 2 (ACE2), which has been identified as the primary mechanism of cellular infection (Tizenberg et al., 2021). Therefore, SARS-CoV-2 affects the lungs, kidneys, heart, liver, pharynx, brain, and all organs exhibiting ACE2 receptors expression (Puelles et al., 2020). Several neurological complications have been reported in COVID-19 patients, including seizures, Guillain-Barré syndrome, encephalitis, dizziness, headache, ageusia, anosmia, cognitive impairment, affective disorders, coordination deficit, and cerebrovascular injury (Asadi-Pooya and Simani, 2020; Berlit et al., 2020; Mao et al., 2020; Ermis et al., 2021; Papri et al., 2021). In this regard, brain involvement could occur through direct damage to the blood-brain barrier (BBB) that leads to the permeation and spread of the virus into the central nervous system (CNS) (Krasemann et al., 2022). It should be noted that there are other ways the virus can enter the brain, such as the olfactory nerve pathway, where SARS-CoV-2 binds to the olfactory bulb and sustentacular cells. Previous studies have shown that several viruses can enter the brain through this pathway, including SARS-CoV-1, MERS-CoV, and HCoV-OCR43 (Wang et al., 2020). The theory that SARS-CoV-2 can enter through the gastrointestinal system to invade the enteric nervous system and, finally, the brain has also been proposed (Wu and Tang, 2020). However, this review focuses on the BBB as the primary physical defense that regulates the transport of drugs and other substances to the brain.

The BBB is a complex structure of endothelial cells (ECs) regulated by pericytes and end-feet of the astrocytes, as well as vascular smooth muscle cells that contribute to the integrity of the BBB, which dynamically control permeability and prevent the entry of harmful agents and pathogens into the brain. The ECs are connected by tight junctions (TJs) that limit the movement of substances through the paracellular space. Nonetheless, small lipophilic molecules with molecular weight <600 Da may diffuse across the BBB to enter the brain (Zhou et al., 2018). For greater effectiveness in drug delivery, temporary interruption of the BBB has been tried by various methods (Chen et al., 2022). However, this strategy has high risks, such as the invasion by immune cells, bacteria, viruses, toxins, or other molecules (including drugs) that may cause unwanted effects on the brain.

 


◆Consistent mask use and SARS-CoV-2 epidemiology: a simulation modelling study【WILEY Online Library　2023年7月10日】

Masks effectively reduce severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission.1 However, the impact of mask wearing over an extended period on morbidity and mortality at the population level is less clear, particularly given the interplay between mask effectiveness, population immunity, and other public health and social measures.

We recently reported the results of an integrated epidemiologic and economic agent-based model that assessed the costs and benefits of more than one hundred coronavirus disease 2019 (COVID-19) control policies used in Victoria, in combination with nine scenarios of SARS-CoV-2 variant emergence, during the eighteen months from April 2022.2 We included mask interventions implemented only during large epidemic waves that increased both general mask wearing and the proportion of mask wearing that involved respirators (eg, N95 masks). These policies had minimal impact on health outcomes.2 For this study, we extended these analyses to determine the impact of age-stratified consistent community-level mask wearing (ie, at all times when outside the home) on numbers of SARS-CoV-2 infections and COVID-19-related deaths.

We modelled different levels of consistent mask-wearing by people under 60 years of age (none, 20%, 35%, 50%; lower proportions were applied to people under 20 years of age: see footnote to Box 1) together with equal or greater levels of mask wearing by people aged 60 years or more (about 20% of the population),3 to a maximum of 75%. At each level of use, 80% of masks used were assumed to be cloth or surgical masks and 20% to be respirators. Other public health and social measures were fixed. The model began in April 2022 with Omicron BA.1 and BA.2 as the dominant SARS-CoV-2 variants, with the gradual emergence of BA.4 and BA.5 from May 2022. We calculated quarterly and cumulative median numbers of infections and deaths (from 500 model runs for each scenario, allowing for stochastic and input parameter uncertainty) during the twelve months from April 2022. Odds ratios for the relative risk of infection for people exposed to an infected person (wearing a mask v not wearing a mask) were set at 0.47 for cloth and surgical masks and 0.20 for respirators1 (further model details: Supporting Information, supplementary methods). As we used publicly available data, we did not seek formal ethics approval for our study.

 


◆Paxlovid Weaker Against Current COVID-19 Variants【Medscape：Ralph Ellis　2023年9月23日】

A real-world study published in JAMA Open Network found that Pfizer’s COVID-19 antiviral Paxlovid is now less effective at preventing hospitalization or death in high-risk patients as compared to earlier studies. But when looking at death alone, the antiviral was still highly effective.

Paxlovid was about 37% effective at preventing death or hospitalization in high-risk patients compared to no treatment. The study also looked at the antiviral Lagevrio, made by Merck, and found it was about 41% effective. In preventing death alone, Paxlovid was about 84% effective compared to no treatment and Lagevrio was about 77% effective, the study said.

The University of North Carolina Gillings School of Global Public Health and the Cleveland Clinic examined electronic health records of 68,867 patients at hospitals in Cleveland and Florida who were diagnosed with COVID from April 1, 2022, to Feb. 20, 2023.

For Paxlovid, the effectiveness against death and hospitalization was lower than the effectiveness rate of about 86% found in clinical trials in 2021, according to Bloomberg.

The difference in effectiveness in the real-world and clinical studies may have occurred because the early studies were conducted with unvaccinated people. Also, the virus has evolved since those first studies, Bloomberg reported.

Researchers said Paxlovid and Lagevrio are recommended for use because they reduce hospitalization and death among high-risk patients who get COVID, even taking recent Omicron subvariants into account.

“These findings suggest that the use of either nirmatrelvir (Paxlovid) or molnupiravir (Lagevrio) is associated with reductions in mortality and hospitalization in patients infected with Omicron, regardless of age, race and ethnicity, virus strain, vaccination status, previous infection status, or coexisting conditions,” the study says. “Both drugs can, therefore, be used to treat non-hospitalized patients who are at high risk of progressing to severe COVID-19.”

Both drugs should be taken within 5 days of the onset of COVID symptoms.

 


◆Effects of tea, catechins and catechin derivatives on Omicron subvariants of SARS-CoV-2【nature：scientific reports　2023年10月3日】

Abstract

The Omicron subvariants of SARS-CoV-2 have multiple mutations in the S-proteins and show high transmissibility. We previously reported that tea catechin (−)-epigallocatechin gallate (EGCG) and its derivatives including theaflavin-3,3’-di-O-digallate (TFDG) strongly inactivated the conventional SARS-CoV-2 by binding to the receptor binding domain (RBD) of the S-protein. Here we show that Omicron subvariants were effectively inactivated by green tea, Matcha, and black tea. EGCG and TFDG strongly suppressed infectivity of BA.1 and XE subvariants, while effect on BA.2.75 was weaker. Neutralization assay showed that EGCG and TFDG inhibited interaction between BA.1 RBD and ACE2. In silico analyses suggested that N460K, G446S and F490S mutations in RBDs crucially influenced the binding of EGCG/TFDG to the RBDs. Healthy volunteers consumed a candy containing green tea or black tea, and saliva collected from them immediately after the candy consumption significantly decreased BA.1 virus infectivity in vitro. These results indicate specific amino acid substitutions in RBDs that crucially influence the binding of EGCG/TFDG to the RBDs and different susceptibility of each Omicron subvariant to EGCG/TFDG. The study may suggest molecular basis for potential usefulness of these compounds in suppression of mutant viruses that could emerge in the future and cause next pandemic.

Introduction

The B.1.1.529 lineage of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified in South Africa in November 2021, and designated as the Omicron variant by the World Health Organization (WHO). In comparison with the original strain, the Omicron BA.1 variant harbored 30 amino acid substitutions, deletion of six amino acid residues and an insertion of three amino acid residues in the spike protein that plays key roles in the viral attachment and entry into cells. Due to these heavy mutations, the Omicron variant was recognized as a variant of concern (VOC) with high transmissibility and potential to cause breakthrough infection in vaccinated individuals. Indeed, infection of this variant spread worldwide in 2022, replacing previous variants of SARS-CoV-2. Thereafter, sublineages of the Omicron variant including BA.2, BA.5, BA.2.75 and XBB.1 evolved with additional mutations and caused widespread infection.

SARS-CoV-2 is mainly transmitted by saliva of COVID-19 patients and asymptomatic infected persons, because SARS-CoV-2 infects, and propagates in, salivary glands and oral mucosa in human. Saliva containing the virus may be scattered by speaking, sneezing and coughing and forms droplets and aerosols that could reach nasal and oral mucosa of nearby persons who may subsequently get infected. We considered that inactivation of virus in saliva should be important, and explored various foods and food ingredients that inactivate the conventional strain of SARS-CoV-2. We reported that exposure of the virus to green tea, roasted green tea, oolong tea and black tea in vitro resulted in significant reduction of the virus infectivity. We also found that the tea catechin compound (−)- epigallocatechin gallate (EGCG) powerfully and rapidly inactivated the virus, which was also reported by other groups. Similar effects were also seen in black tea ingredients, galloylated theaflavins (theaflavin-3-O-gallate (TF3G), theaflavin-3’-O-gallate (TF3’G), and theaflavin-3,3’-O-digallate (TFDG)), and theasinensin A (TSA) that are derivatives of tea catechins. We also reported that the EGCG, TFDG and TSA interfered with the interaction between viral spike protein and ACE2 by binding to the spike protein receptor binding domain (RBD). However, it remains to be clarified whether these tea ingredients also inactivate the Omicron variants of SARS-CoV-2. Moreover, it has not been elucidated which amino acid substitutions in the Omicron subvariants may influence the binding of EGCG and TFDG to the spike protein.

In this study we examined the efficiencies of tea, tea catechins and catechin derivatives to inactivate the Omicron subvariant strains of the SARS-CoV-2. We also assessed whether saliva from healthy volunteers who consumed a candy containing green tea or black tea inactivates BA.1 in vitro.