SARS-CoV-2 と COVID-19 に関する備忘録 Vol.23――去年始めにオミクロン株のBA.1かBA.2に感染してハイブリッド免疫を獲得した患者は、同年夏のBA.5に再感染した率が約30倍高かった…etc.

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SARS-CoV-2 と COVID-19 に関するメモ・備忘録

◆Early Omicron infection is associated with increased reinfection risk in older adults in long-term care and retirement facilities【THE LANCET eClinicalMedicine　2023年8月21日】

Summary

Background

Older adults are at increased risk of SARS-CoV-2 Omicron infection and severe disease, especially those in congregate living settings, despite high SARS-CoV-2 vaccine coverage. It is unclear whether hybrid immunity (combined vaccination and infection) after one Omicron infection provides increased protection against subsequent Omicron reinfection in older adults.

Methods

Incidence of SARS-CoV-2 Omicron infection was examined in 750 vaccinated residents of long-term care and retirement homes in the observational cohort COVID in Long-Term Care Study in Ontario, Canada, within a 75-day period (July to September 2022). Risk of infection was assessed by Cox proportional hazards regression. Serum anti-spike and anti-RBD SARS-CoV-2 IgG and IgA antibodies, microneutralization titres, and spike-specific T cell memory responses, were examined in a subset of 318 residents within the preceding three months.

Findings

133 of 750 participants (17.7%) had a PCR-confirmed Omicron infection during the observation period. Increased infection risk was associated with prior Omicron infection (at 9–29 days: 47.67 [23.73–95.76]), and this was not attributed to days since fourth vaccination (1.00 [1.00–1.01]) or residence outbreaks (>6 compared to ≤6: 0.95 [0.37–2.41]). Instead, reinfected participants had lower serum neutralizing antibodies to ancestral and Omicron BA.1 SARS-CoV-2, and lower anti-RBD IgG and IgA antibodies, after their initial Omicron infection.

Interpretation

Counterintuitively, SARS-CoV-2 Omicron infection was associated with increased risk of Omicron reinfection in residents of long-term care and retirement homes. Less robust humoral hybrid immune responses in older adults may contribute to risk of Omicron reinfection.

Funding

COVID-19 Immunity Task Force of the Public Health Agency of Canada.

Introduction

Infection with severe acute respiratory virus syndrome coronavirus 2 (SARS-CoV-2) has lasting and broad effects on cellular and humoral immunity. Hybrid immunity (i.e., immunity resulting from both vaccination and natural infection) generally provides transient protection against reinfection and longer-lasting protection from severe COVID-19. For older adults, their complex healthcare needs, multiple comorbidities, as well as age-associated changes to the immune system, may contribute to heterogenous and less durable hybrid immunity.

The emergence of the highly transmissible and immune evasive SARS-CoV-2 Omicron (B1.1.529) variant caused significant breakthrough infections globally in 2022. Older adults in congregate living facilities are disproportionately vulnerable to COVID-19 when community transmission is high. Accordingly, there were initial province-wide peaks in SARS-CoV-2 infection numbers in Ontario, Canada, in mid-January (BA.1) and mid-April (BA.1/BA.2), with concurrent outbreaks in many long-term care and retirement homes. Due to concerns about waning immunity, fourth monovalent mRNA vaccine doses were offered to those populations. We and others have found that recent monovalent vaccination was protective against symptomatic early Omicron BA.1/BA.2 infection. In addition, we found that infection with a pre-Omicron variant provided three months of protection against infection with Omicron BA.1/BA.2. Thus, recent monovalent vaccination and hybrid immunity protected some older adults against early Omicron infection.

As of July 2022, genomic surveillance showed that over half of COVID-19 cases in Ontario were caused by the Omicron subvariant BA.5 (B.1.1.529.5). Despite the high number of early Omicron infections, and presumed hybrid immune protection, there was a province-wide wave of Omicron BA.5 infections and outbreaks in long-term care homes. It was unclear whether less robust or waning protection from vaccination or hybrid immunity contributed to infection risk in older adults.

At the start of this BA.5-dominanted wave, within our COVID in Long-Term Care Study cohort of over 1000 residents of 27 long-term care and retirement homes, ∼90% of participants had received a fourth SARS-CoV-2 monovalent vaccination, and ∼35% had a prior SARS-CoV-2 infection. We thus retrospectively investigated the degree to which recent monovalent vaccination and/or infection provided protection against Omicron BA.5 infection. We found counterintuitively that recent Omicron BA.1/2 infection was associated with increased risk of Omicron BA.5 infection. Individuals with lower humoral hybrid immune responses after their initial Omicron infection had Omicron reinfections.

 

◆Prior COVID-19 infection is associated with persistent and higher thrombus burden in acute coronary syndromes【European Heart Journal　2023年11月9日】

Abstract

Background/Introduction

The COVID-19 pandemic challenged global healthcare systems by causing a multi-organ syndrome with a high mortality rate. COVID-19 infection is associated with a profound inflammatory response and hypercoagulability in the acute phase, however little is known on the persistence of endothelial dysfunction and hypercoagulability beyond this phase and its impact on acute coronary syndrome (ACS). 

Purpose

The purpose of this study was to investigate the effects of COVID-19 infection on the presentation and outcomes of coronary artery disease in patients with ACS.

Methods

A single centre prospective observational study was conducted from 10th of June 2020 to 6th of May 2021. Patients aged 18 or over presenting with ACS were included. Participants were excluded if they had active COVID-19 infection or if they did not undergo coronary angiography on admission.

Study participants were tested one presentation for SARS-CoV-2 nucleoprotein (N) antibody and SARS-CoV-2 spike protein receptor binding domain (RBD) antibody to determine whether the participants had prior COVID-19 infection, COVID-19 vaccination, or neither at the time of their presentation. Data was collected on their baseline demographics, angiographic findings, and treatments. Patients were followed up via telephone call and electronic case record review to assess outcomes at one year.

The primary end-point was all-cause mortality. Pre-specified secondary endpoints were cerebral infarction, repeat myocardial infarction or unplanned revascularisation and death (MACE) at one year, coronary artery ectasia, presence of thrombus, and thrombectomy requirement.

Results

280 patients were approached for the study. 5 refused participation, 8 were lost to follow-up, 2 did not undergo coronary angiography, and 98 had uninterpretable/insufficient blood samples for antibody analysis.

The remaining study population had 167 patients (median age 64 [43-85], 69.5% male). 22 (13.1%) had prior infection, 76 (45.5%) were antibody negative and 69 (41.3%) had a post COVID-19 immunisation response. 31.7% had diabetes mellitus, and 49.7% were smokers.

There was no difference in the primary endpoint between the groups. Patients with prior COVID-19 infection were more likely to have coronary ectasia/aneurysm compared to vaccinated and antibody negative patients (57.1% vs 27.5% and 30.3%, respectively p = 0.034). They were also more likely to have thrombosis (61.9% vs 33.3% and 52.6%, p = 0.019), and undergo thrombectomy (19.0% vs 4.3% and 3.9%, p=0.027).

Conclusions and Relevance

Our findings suggest that COVID-19 infection may lead to persistent endothelial dysfunction and hypercoagulability, portending increased severity of coronary artery ectasia and coronary thrombosis even after recovery from the initial infection.

 

◆Persistent cognitive slowing in post-COVID patients: longitudinal study over 6 months【SPLINGER LINK : Journal of Neurology　2023年11月7日】

Abstract

Background

Fatigue is a frequent and one of the most debilitating symptoms in post-COVID syndrome (PCS). Recently, we proposed that fatigue is caused by hypoactivity of the brain’s arousal network and reflected by a reduction of cognitive processing speed. However, it is unclear whether cognitive slowing is revealed by standard neuropsychological tests, represents a selective deficit, and how it develops over time.

Objectives

This prospective study assesses whether PCS patients show deficits particularly in tests relying on processing speed and provides the first longitudinal assessment focusing on processing speed in PCS patients.

Methods

Eighty-eight PCS patients with cognitive complaints and 50 matched healthy controls underwent neuropsychological assessment. Seventy-seven patients were subsequently assessed at 6-month follow-up. The Test for Attentional Performance measured tonic alertness as primary study outcome and additional attentional functions. The Neuropsychological Assessment Battery evaluated all key cognitive domains.

Results

Patients showed cognitive slowing indicated by longer reaction times compared to control participants (r = 0.51, p < 0.001) in a simple-response tonic alertness task and in all more complex tasks requiring speeded performance. Reduced alertness correlated with higher fatigue (r =  − 0.408, p < 0.001). Alertness dysfunction remained unchanged at 6-month follow-up (p = 0.240) and the same was true for most attention tasks and cognitive domains. Conclusions

Hypoarousal is a core deficit in PCS which becomes evident as a selective decrease of processing speed observed in standard neuropsychological tests. This core deficit persists without any signs of amelioration over a 6-month period of time.

Introduction

It is now well established that post-COVID syndrome (PCS) represents a serious complication in a substantial number of patients following SARS-CoV-2 infection. PCS is diagnosed when COVID-19-related symptoms persist for more than 3 months. It can occur even after an initially mild to moderate course of infection, and comprise a large variety of symptoms. Around 30% of PCS patients show neurological and neuropsychiatric sequelae, such as fatigue, depressive symptoms, and cognitive dysfunction. These are experienced as particularly debilitating, as they have detrimental effects on daily functioning in PCS patients and hamper a successful return to their jobs.

Recently, we proposed that fatigue is caused by hypoactivity within the brain’s arousal network, reflected by a fundamental slowing of processing speed in PCS patients. In particular, the variance of (visual) processing speed in a laboratory task was explained by a neurophysiological measure of central nervous arousal, i.e., pupillary unrest, and the level of subjective mental fatigue. Thus, based on our data, processing speed not only seems to represent a reliable measure of the brain’s activation level, but it can also provide an objective proof of the subjective feeling of mental fatigue.

Although these results may represent an important step towards a better understanding of the neurocognitive deficits in PCS patients, a number of questions arise from this preceding study: first, it remains unclear whether a reduction of processing speed can be evidenced in standard neuropsychological assessment procedures as well. Given the high prevalence of PCS, the suitability of conventional, clinically established tests for disclosing processing speed deficits would be of great practical significance. Second, in our preceding study, we were not able to assess whether cognitive domains other than processing speed are also affected by the underlying arousal deficit. A demonstration that processing speed is selectively impaired in PCS patients would bear strong support for our hypoarousal model. Finally, it remains unknown whether hypoarousal is a temporary and transient, or a persisting problem in PCS patients. This is an important question for estimating the probability whether PCS patients are able to re-uptake their job in the near future. However, while subjective complaints of fatigue are known to prevail even after 2 years, follow-up observations including an objective measure of fatigue are still lacking. Hence, longitudinal assessment of processing speed is urgently required.

Thus, the first aim of the present study was to analyze whether a reduction of processing speed in PCS patients is evidenced in conventional neuropsychological tests as applied in a standard clinical setting. We compared PCS patients with cognitive complaints to sociodemographically matched healthy control participants and used tonic alertness, measured in a clinically established simple-response task, as our primary outcome. The second aim was to assess whether reduced processing speed is a selective deficit in PCS patients. We employed a computerized reaction time-based neuropsychological assessment procedure and a comprehensive test battery to explore whether the overall cognitive profile across different relevant cognitive domains would be indicative of particular deficits in tasks reliant on fast information processing speed. As secondary outcomes, we explored whether speed-dependent measures in general, such as reaction times and test scores relying on task completion times, were compromised in PCS patients. Additionally, we investigated whether test scores less dependent on processing speed were less affected. Third, to corroborate the relationship between hypoarousal and fatigue, we investigated whether performance in the primary outcome tonic alertness simple-response measure and the other measures that tapped processing speed was related to the degree of experienced fatigue. As a fourth aim of our study, we included a follow-up assessment after 6 months to evaluate whether processing speed deficits persist or ameliorate over time. To our knowledge, this is the first longitudinal study that particularly addresses processing speed, i.e., alertness dysfunction in PCS patients with cognitive complaints.

 

◆SARS-CoV-2 infection and spontaneous spinal hemorrhage: a systematic review【SPLINGER LINK : Neurosurgical Review　2023年11月15日】

Abstract

The neurological manifestations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, including spontaneous spinal hemorrhage (SSH), are diverse. SSH is a detrimental neurosurgical event requiring immediate medical attention. We aimed to investigate the association between SARS-CoV-2 and SSH and delineate a rational clinical approach. The authors searched PubMed, Scopus, Web of Science, and Google Scholar for studies published up to January 25, 2023, on SSH and SARS-CoV-2 infection. For each dataset, the authors performed pooled estimates examining three outcomes of interest: (1) early post-intervention neurological status, (2) mortality, and (3) post-intervention neurological rehabilitation outcomes. After reviewing 1341 results, seven datasets were identified for the final analysis. Fifty-seven percent of patients were females. Twenty-eight percent of the patients experienced severe systemic infection. The mean interval between the SARS-CoV-2 infection and neurological presentation was 18 days. Pain and sensorimotor deficits were the most common (57%). Spinal epidural hematoma (EDH) was the most common presentation (71.4%). Three patients were treated conservatively, while 4 received neurosurgical intervention. Pain and sensorimotor deficits had the best treatment response (100%), while the sphincter had the worst response (0%). Long-term follow-up showed that 71% of patients had good recovery. SARS-CoV-2-associated SSH is a rare complication of infection, with an often insidious presentation that requires high clinical suspicion. Patients with SARS-CoV-2 infection and new neurological symptoms or disproportionate neck or back pain require a neuroaxis evaluation. Neurosurgical intervention and conservative management are both viable options to treat SSH following COVID-19. Still, a homogenous approach to the treatment paradigm of SSH cannot be obtained, but lesions with space-occupying effects are suitable for neurosurgical evacuation-decompression while more indolent lesions could be treated conservatively. These options should be tailored individually until larger studies provide a consensus.

 

 

◆Men experience a long-term drop in semen quality after COVID infection – even if the infection was mild【EurekAlert : EUROPEAN SOCIETY OF HUMAN REPRODUCTION AND EMBRYOLOGY　2023年6月26日】

More than three months after suffering from mild COVID infection, men have lower sperm concentrations and fewer sperm that are able to swim, according to new findings presented today (Monday) at the 39th annual meeting of the European Society of Human Reproduction and Embryology (ESHRE) [1].

Professor Rocio Núñez-Calonge, scientific advisor at UR International Group at the Scientific Reproduction Unit, Madrid (Spain), said that after an average of 100 days following SARS-CoV-2 infection there appeared to be no improvement in sperm quality and concentration, even though new sperm would have been produced in that time.

“There have been previous studies that show semen quality is affected in the short term following a COVID infection but, as far as we are aware, none that have followed men for a longer period of time,” she said. “We assumed that semen quality would improve once new sperm were being generated, but this was not the case. We do not know how long it might take for semen quality to be restored and it may be the case that COVID has caused permanent damage, even in men who suffered only a mild infection.”

Prof. Núñez-Calonge and colleagues had observed that, in some men attending clinics in Spain for assisted reproduction treatment, semen quality was worse after COVID infection than before the infection even though they had recovered and the infection was mild. So they decided to investigate if COVID had influenced the decline in quality.

“Since it takes approximately 78 days to create new sperm, it seemed appropriate to evaluate semen quality at least three months after recovery from COVID,” said Prof. Núñez-Calonge.

Between February 2020 and October 2022, the researchers recruited 45 men attending six reproductive clinics in Spain to the study. All had a confirmed diagnosis of mild COVID, and the clinics had data from analysis of semen samples taken before the men were infected. Another semen sample was taken between 17 and 516 days after infection. The median (average) age of the men was 31, and the amount of time that elapsed between the pre- and post-COVID samples was a median of 238 days. The researchers analysed all the samples taken up to 100 days after infection, and then analysed a subset of samples taken more than 100 days later.

They found a statistically significant difference in semen volume (down 20% from 2.5 to 2 millilitres), sperm concentration (down 26.5% from 68 to 50 million per ml of ejaculate), sperm count (down 37.5% from 160 to 100 million per millilitre of semen), total motility i.e. being able to move and swim forwards (down 9.1% from 49% to 45%) and numbers of live sperm (down 5% from 80% to 76%).

Prof. Núñez-Calonge said motility and the total sperm count were the most severely affected. Half of the men had total sperm counts that were 57% lower after COVID compared to their pre-COVID samples. The shape of the sperm was not significantly affected.

When the researchers looked at the group of men who provided a sample later than 100 days after COVID, they found that sperm concentration and motility had still not improved over time.

“The continuing effect of COVID infection on semen quality in this later period may be caused by permanent damage due to the virus, even in mild infection. We believe clinicians should be aware of the damaging effects of SARS-CoV-2 virus on male fertility. It is particularly interesting that this decrease in semen quality occurs in patients with mild COVID infection, which means that the virus can affect male fertility without the men showing any clinical symptoms of the disease,” said Prof. Núñez-Calonge.

It is known that the SARS-CoV-2 virus can affect the testicles and sperm, but the mechanism is still unknown. Prof. Núñez-Colange says that inflammation and damage to the immune system that is seen in patients with long COVID might be involved.

“The inflammatory process can destroy germ cells by infiltrating the white blood cells involved in the immune system, and reduce testosterone levels by affecting the interstitial cells that produce the male hormone,” she said.

“It should be mentioned that impairment of semen parameters may not be due to a direct effect of the SARS-CoV-2 virus. There are likely to be additional factors that contribute to long-term sperm parameters decrease, but whose identity is currently unknown. Furthermore, we did not measure hormonal levels in this study: intense changes in testosterone, a key player involved in male reproductive health, has previously been reported in COVID-infected male patients.”

The researchers plan to continue to study the men to measure both semen quality and hormonal status over time. They believe there should be more research into the reproductive functions of men after COVID infection to see if their fertility is affected temporarily or permanently.

The chair of ESHRE, Professor Carlos Calhaz-Jorge from the Northern Lisbon Hospital Centre and the Hospital de Santa Maria in Lisbon (Portugal), was not involved in this research. He commented: “This is interesting research by Prof. Núñez-Calonge and her colleagues and shows the importance of long-term follow-up of fertility patients after a COVID infection, even if it’s a mild infection. However, it’s important to note that the semen quality in these patients after a COVID infection is still within the World Health Organization’s criteria for ‘normal’ semen and sperm. So, it is unclear whether these reductions in semen quality after a COVID infection translate into impaired fertility and this should be the subject of further research.”

(ends)

[1] Presentation no: O-020, “What is the recovery time for sperm parameters in men who have suffered a mild Covid-19 infection?” presented by Professor Rocio Núñez-Calonge, Session 04: Factors influencing sperm (dys)function, Hall D1, 11.15 hrs CEST, Monday 26 June 2023.

 

 

◆Dysregulations in hemostasis, metabolism, immune response, and angiogenesis in post-acute COVID-19 syndrome with and without postural orthostatic tachycardia syndrome: a multi-omic profiling study【nature scientific reports　2023年11月19日】

Abstract

Post-acute COVID-19 (PACS) are associated with cardiovascular dysfunction, especially postural orthostatic tachycardia syndrome (POTS). Patients with PACS, both in the absence or presence of POTS, exhibit a wide range of persisting symptoms long after the acute infection. Some of these symptoms may stem from alterations in cardiovascular homeostasis, but the exact mechanisms are poorly understood. The aim of this study was to provide a broad molecular characterization of patients with PACS with (PACS + POTS) and without (PACS-POTS) POTS compared to healthy subjects, including a broad proteomic characterization with a focus on plasma cardiometabolic proteins, quantification of cytokines/chemokines and determination of plasma sphingolipid levels. Twenty-one healthy subjects without a prior COVID-19 infection (mean age 43 years, 95% females), 20 non-hospitalized patients with PACS + POTS (mean age 39 years, 95% females) and 22 non-hospitalized patients with PACS-POTS (mean age 44 years, 100% females) were studied. PACS patients were non-hospitalized and recruited ≈18 months after the acute infection. Cardiometabolic proteomic analyses revealed a dysregulation of ≈200 out of 700 analyzed proteins in both PACS groups vs. healthy subjects with the majority (> 90%) being upregulated. There was a large overlap (> 90%) with no major differences between the PACS groups. Gene ontology enrichment analysis revealed alterations in hemostasis/coagulation, metabolism, immune responses, and angiogenesis in PACS vs. healthy controls. Furthermore, 11 out of 33 cytokines/chemokines were significantly upregulated both in PACS + POTS and PACS-POTS vs. healthy controls and none of the cytokines were downregulated. There were no differences in between the PACS groups in the cytokine levels. Lastly, 16 and 19 out of 88 sphingolipids were significantly dysregulated in PACS + POTS and PACS-POTS, respectively, compared to controls with no differences between the groups. Collectively, these observations suggest a clear and distinct dysregulation in the proteome, cytokines/chemokines, and sphingolipid levels in PACS patients compared to healthy subjects without any clear signature associated with POTS. This enhances our understanding and might pave the way for future experimental and clinical investigations to elucidate and/or target resolution of inflammation and micro-clots and restore the hemostasis and immunity in PACS.

Introduction

The SARS-CoV-2 virus causes COVID-19 which has affected hundreds of millions of people worldwide since it first emerged in late 2019. While most infected individuals recover fully within a few weeks, some experience symptoms that persist for months after acute infection or develop symptoms after a short period of recovery. This novel condition is referred to as post-acute COVID-19 syndrome (PACS) and is defined as persisting symptoms > 12 weeks after contracting an acute SARS-CoV-2 infection. It is estimated that the prevalence of PACS is approximately 10% among non-hospitalized patients with a mild acute infection. PACS is a complex and multi-faceted condition that can affect various organ systems, including the respiratory, cardiovascular, neurological and musculoskeletal systems1. Some of the most common symptoms of PACS include fatigue, shortness of breath, chest pain, joint and muscle pain, palpitations and cognitive impairment. However, the pathophysiology underlying PACS is to this date incompletely understood and needs further investigation. We were among the first to report that PACS can be associated with postural orthostatic tachycardia syndrome (POTS) and have highlighted the importance of cardiovascular dysautonomia in this patient population. A recent study estimates the prevalence of POTS to be 30% in severely affected PACS patients referred to a tertiary specialist center. More recently we have shown that POTS associated with PACS is accompanied with microvascular endothelial dysfunction which translates into reduced endothelial dependent cardiac stress perfusion.

The pathophysiological mechanisms underlying PACS remain unknown but proposed causes are persisting SARS-CoV-2 virus, immune system dysregulation, autoimmunity, endothelial cell inflammation (endotheliitis) associated with micro clot formation or neurological dysregulation. The clinical and pathophysiological association between PACS and POTS also remain elusive. While the prevalence of POTS in PACS has been reported in case series, detailed studies exploring pathological mechanisms underlying PACS-related POTS are lacking. Possible overlap, but also distinctions among various PACS phenotypes, including POTS and other forms of cardiovascular complications, might exist. Thus, additional knowledge regarding alterations in key signaling pathways is needed to improve our understanding of this complex condition.

Therefore, we sought to provide a foundation for future mechanistic studies by applying an unbiased, multi-omic approach analyzing cardiometabolic plasma proteins, proinflammatory cytokines/chemokines and sphingolipids in patients with PACS with and without POTS compared to healthy controls. Our hypothesis posits significant molecular changes in PACS, particularly in cases associated with POTS, aiming to lay a foundation for future mechanistic studies and enhance our understanding of these intricate conditions.

◆Tumor Hypoxia Regulates Immune Escape/Invasion: Influence on Angiogenesis and Potential Impact of Hypoxic Biomarkers on Cancer Therapies【Frontiers in Immunology　2021年1月20日】

The environmental and metabolic pressures in the tumor microenvironment (TME) play a key role in molding tumor development by impacting the stromal and immune cell fractions, TME composition and activation. Hypoxia triggers a cascade of events that promote tumor growth, enhance resistance to the anti-tumor immune response and instigate tumor angiogenesis. During growth, the developing angiogenesis is pathological and gives rise to a haphazardly shaped and leaky tumor vasculature with abnormal properties. Accordingly, aberrantly vascularized TME induces immunosuppression and maintains a continuous hypoxic state. Normalizing the tumor vasculature to restore its vascular integrity, should hence enhance tumor perfusion, relieving hypoxia, and reshaping anti-tumor immunity. Emerging vascular normalization strategies have a great potential in achieving a stable normalization, resulting in mature and functional blood vessels that alleviate tumor hypoxia. Biomarkers enabling the detection and monitoring of tumor hypoxia could be highly advantageous in aiding the translation of novel normalization strategies to clinical application, alone, or in combination with other treatment modalities, such as immunotherapy.

 

◆Human microbiota is a reservoir of SARS-CoV-2 advantageous mutations【bioRxiv　2023年11月17日】

Abstract

SARS-CoV-2 mutations are rapidly emerging, in particular advantageous mutations in the spike (S) protein, which either increase transmissibility or lead to immune escape, are posing a major challenge to pandemic prevention and treatment. However, how the virus acquires a high number of advantageous mutations in a short time remains a mystery. Here, we show that the human microbiota may contribute to mutations in variants of concern (VOCs). We identified a mutation and adjacent 6 amino acids (aa) in a viral mutation fragment (VMF) and searched for homologous fragments (HFs) in the National Center for Biotechnology Information (NCBI) database. Among the approximate 8000 HFs obtained, 61 mutations in S and other outer membrane proteins were found in bacteria, accounting for 62% of all mutation sources, which is a 12-fold higher than the natural variable proportion. Approximately 70% of these bacterial species belong to the human microbiota, are primarily distributed in the gut or lung and exhibit a composition pattern similar to that of COVID-19 patients. Importantly, SARS- CoV-2 RNA-dependent RNA polymerase (RdRp) replicates corresponding bacterial mRNAs harboring mutations, producing chimeric RNAs. Collectively, SARS-CoV-2 may acquire mutations from the human microbiota, resulting in alterations in the binding sites or antigenic determinants of the original virus. Our study sheds light on the evolving mutational mechanisms of SARS-CoV-2.

 

◆SARS-CoV-2 infects neurons, astrocytes, choroid plexus epithelial cells and pericytes of the human central nervous system【bioRxiv　2023年11月22日】

Abstract

SARS-CoV-2, the coronavirus responsible for the COVID-19 pandemic, is associated with a range of neurological manifestations including haemorrhage, thrombosis and ischaemic necrosis and encephalitits. However, the mechanism by which this occurs is unclear. Neurological disease associated with SARS-CoV-2 infection has been proposed to occur following direct infection of the central nervous system and/or indirect sequelae as a result of peripheral inflammation. We profiled ACE2 and TMPRSS2 in brain tissue from five healthy human donors, and observed expression of these proteins in astrocytes, neurons and choroid plexus epithelium within frontal cortex and medulla. Primary human astrocytes, neurons and choroid plexus epithelial cells supported productive SARS-CoV-2 infection in an ACE2- dependent manner. Infected cells supported the full viral lifecycle, releasing infectious virus particles. In contrast, primary brain microvascular endothelial cells, pericytes and microglia were refractory to SARS-CoV-2 infection. These data support a model whereby SARS-CoV-2 is neurotropic, and this may in part explain the neurological sequelae of infection.

Importance A subset of patients with COVID-19 develop neurological symptoms, but the underlying cause is poorly understood. We observed that cells within normal human brain express the SARS-CoV-2 entry factors ACE-2 and TMPRRS2, with expression mainly observed within astrocytes, neurons and choroid plexus epithelium. Primary human astrocytes, neurons and choroid plexus epithelial cells cultured in vitro supported the full SARS-CoV-2 life cycle with a range of SARS-CoV-2 variants. This study demonstrates that cells of the human central nervous system express SARS-CoV-2 entry factors in vivo and support viral infection in vitro, thus supporting a model where neurological symptoms seen in some COVID-19 patients may be as a result of direct viral infection of the central nervous system. Furthermore, these data highlight the importance of investigating the ability of therapeutics to clear virus from this potential reservoir of infection.