SARS-CoV-2 と COVID-19 に関する備忘録 Vol.5――東北大教授の押谷仁には要警戒、人間がどうやっても実現できない『真の無秩序』だけどコロナウイルスは自分の中で真の無秩序を飼い慣らしている？！…etc.

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SARS-CoV-2 と COVID-19 に関するメモ・備忘録


◆Molecular Diagnosis of COVID-19 Sudden and Unexplained Deaths: The Insidious Face of the Pandemic【MDPI　2023年9月18日】

Abstract

The COVID-19 epidemic has led to a significant increase in the number of deaths. This has resulted in forensic autopsies focusing on additional diagnostic possibilities. The following article is a summary of 23 autopsies of sudden and unexplained deaths. Particularly noteworthy are the described cases of children whose deaths were originally classified as SIDS (sudden infant death syndrome). All tests were performed at the Department of Forensic Medicine and Forensic Genetics, Pomeranian Medical University in Szczecin. Autopsy analyses were extended to include diagnostics of the SARS-CoV-2 virus using molecular methods and a detailed histopathological analysis of lung tissue. The material for molecular tests consisted of a nasopharyngeal swab taken postmortem and a lung tissue homogenate. In both cases, the RT-PCR method with CT cut-off point analysis was used for diagnosis. In all analyzed cases, the lungs showed massive congestion and increased fragility and cohesion. The tested material showed the presence of the SARS-CoV-2 virus, which indicated various stages of infection. It was observed that the higher the virus expression in the lungs, the lower or undetectable it was in the nasopharyngeal swab. This may explain false negative results during life in swabs. An interesting finding is that child deaths classified as SIDS also showed the presence of the virus. This may constitute a new direction of research.

 


◆Age-dependence of the 1918 pandemic【Cambridge University Press：British actuarial Journal　2019年2月12日】

Abstract

A well-known feature of the great H1N1 influenza pandemic of a century ago is that the highest mortality rate was amongst young adults. The general explanation has been that they died from an over-reaction of their active immune systems. This explanation has never been very satisfactory because teenagers also have very active immune systems. Recent virological research provides a new perspective, which is important for life and health insurers. There is now strong recent scientific evidence for the principle of antigenic imprinting, where the highest antibody response is against influenza virus strains from childhood. The peak ages of 1918 pandemic mortality correspond to a cohort exposed to the H3N8 1889–1890 Russian influenza pandemic. The vulnerability of an individual depends crucially on his or her exposure to influenza during their lifetime, especially childhood. Date of birth is thus a key indicator of pandemic vulnerability. An analysis of the implications is presented, with focus on those now in their fifties, who were exposed to the H3N2 1968 Hong Kong influenza.

1. Introduction

In the century that has passed since the great 1918 influenza pandemic, there have been three further influenza pandemics in 1957, 1968 and 2009, but the combined death toll from these lesser pandemics is only a small percentage of the tens of millions who died in the 1918 pandemic, which stands as the deadliest in history. More died from the 1918 pandemic than in the First World War. The catastrophic death toll depends partly on the specific lethality characteristics of the 1918 H1N1 virus, partly on the vulnerability of individuals to the H1N1 virus, and also partly on the dynamics of its contagion. To begin, a review is given of the contagion of the 1918 pandemic.

 


◆Antigenicity and receptor affinity of SARS-CoV-2 BA.2.86 spike【bioRxiv　2023年9月24日】

Abstract

Although the COVID-19 pandemic has officially ended, SARS-CoV-2 continues to spread and evolve. Recent infections have been dominated by XBB.1.5 and EG.5.1 subvariants. A new subvariant designated BA.2.86 has just emerged, spreading to 21 countries in 5 continents. This virus contains 34 spike mutations compared to its BA.2 predecessor, thereby raising concerns about its propensity to evade existing antibodies. We examined its antigenicity using human sera and monoclonal antibodies (mAbs). Reassuringly, BA.2.86 was not more resistant to human sera than XBB.1.5 and EG.5.1, indicating that the new subvariant would not have a growth advantage in this regard. Importantly, sera from patients who had XBB breakthrough infection exhibited robust neutralizing activity against all viruses tested, suggesting that upcoming XBB.1.5 monovalent vaccines could confer added protection. The finding that the longer genetic distance of BA.2.86 did not yield a larger antigenic distance was partially explained by the mAb data. While BA.2.86 showed greater resistance to mAbs to subdomain 1 (SD1) and receptor-binding domain (RBD) class 2 and 3 epitopes, it was more sensitive to mAbs to class 1 and 4/1 epitopes in the “inner face” of RBD that is exposed only when this domain is in the “up” position. We also identified six new spike mutations that mediate antibody resistance, including E554K that threatens SD1 mAbs in clinical development. The BA.2.86 spike also had a remarkably high receptor affinity. The ultimate trajectory of this new SARS-CoV-2 variant will soon be revealed by continuing surveillance, but its worldwide spread is worrisome.

Introduction

A highly mutated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron subvariant, designated BA.2.86, was first reported only a few weeks ago, and it is genetically distinct from the prevailing viruses in the XBB sublineage. The genetic distance to its predecessor, BA.2, is equivalent to that between BA.1 and the Delta variant, raising the same antibody evasion concerns when the first Omicron variant emerged in late 2021. Over 190 sequences of BA.2.86 has been found in 21 countries already despite limited surveillance nowadays. A recent outbreak due to the new subvariant in a nursing facility in England with high attack rate among residents and staff shows BA.2.86 is readily transmissible. At present, there is little clinical evidence to address its pathogenicity.

Compared with the spike of BA.2, BA.2.86 possesses 34 additional mutations, including 13 mutations in the N-terminal domain (NTD), 14 in RBD, 2 in SD1, 3 in the subdomain 2 (SD2), and 2 in the S2 region. Mutations H69V70 deletion (H69V70△), Y144 deletion (Y144△), G446S, N460K, F486P, and R493Q have been identified previously, but mutations V445H, N450D, N481K, V483 deletion (V483△), and E554K have been seldom observed in circulating viruses (Figure 1C). This extensive array of spike mutations in BA.2.86 is alarming because of the heightened potential for the virus to evade serum antibodies elicited by prior infections and/or vaccinations or mAbs intended for clinical use. The present study addresses this concern by characterizing the antigenicity of BA.2.86 spike using multiple collections of human sera and a large panel of mAbs.

 


◆Prion Disease After COVID-19: A Case Report【American Journal of Case reports　2023年9月21日】

Abstract

BACKGROUND: Prion disease (PrD) is one of the rapidly progressive dementias. It typically requires several diagnostic criteria to fulfill a probable diagnosis, as definite diagnosis is based on isolated brain biopsy. There has been much debate on a possible infectious etiology of PrD. Viral infections are commonly pathologic in most neurodegenerative conditions. In PrD, misfolded proteins can be contagious and act as infective proteins, regardless of the pathologic agent. There is evidence that COVID-19 can result in neurologic manifestations, and neurodegeneration has been reported in the literature. There are several case reports describing parkinsonism after COVID-19, with Parkinson’s disease in particular noted in COVID-19. Few cases of PrD were reported after COVID-19 infection. We identified 1 case of PrD in the setting of COVID-19 at our hospital.

CASE REPORT: We report the case of a 62-year-old man admitted to Mount Sinai Queens Hospital Center, who presented with rapidly progressive dementia along with difficulty walking and myoclonus. All workup results were negative. He underwent MRI brain, but results were not revealing. Due to the high clinical suspicion, CSF protein 14-3-3 testing was ordered and was positive. Clinically, he experienced worsening neurological function after having been COVID-19-positive on admission. The case fulfilled the probable diagnostic criteria for diagnosing PrD. The patient continued to deteriorate and died due to the rapid progression of his condition.

CONCLUSIONS: Our case demonstrates the potential correlation of COVID with neurodegenerative conditions, especially prion disorders. While such cases are highly likely to be due to COVID-19, there is no definite evidence beyond coincidental findings. Future studies might be required to establish this correlation.

 


◆Incidence of Diabetes Among Youth Before and During the COVID-19 Pandemic【JAMA Network　2023年9月21日】

Key Points

Question Did new-onset type 1 and type 2 diabetes increase among US youth between 2016 and 2021?

Findings In this cohort study of individuals 19 years and younger, type 1 diabetes slightly increased overall and type 2 diabetes significantly increased after the beginning of the COVID-19 pandemic, in particular among non-Hispanic Black and Hispanic youth.

Meaning These findings suggest the need for further evaluation of physiologic and behavioral risk factors preceding new-onset diabetes during the COVID-19 pandemic.

Abstract

Importance Prior research found increases in diabetes among youth during the COVID-19 pandemic, but few studies examined variation across sociodemographics.

Objective To examine diabetes incidence rates among a diverse population of youth in the US before and during the COVID-19 pandemic.

Design, Setting, and Participants This cohort study included data from Kaiser Permanente Southern California (KPSC) between January 1, 2016, and December 31, 2021. KPSC members aged from birth to 19 years with no history of diabetes were included. Individuals were followed up using electronic health records for diabetes incidence defined using diagnoses, laboratory values, and medications. Analyses were conducted between November 2022 and January 2023.

Main Outcome and Measures Age- and sex-standardized annual and quarterly incidence rates per 100 000 person-years (PYs) were calculated for type 1 diabetes and type 2 diabetes between 2016 and 2021. Rates were calculated within strata of age (<10 and 10-19 years), sex, and race and ethnicity (Asian/Pacific Islander, Hispanic, non-Hispanic Black, non-Hispanic White, and other/multiple/unknown). Using Poisson regression with robust error variances, incidence rate ratios (IRR) comparing 2020 to 2021 with 2016 to 2019 were calculated by diabetes type and within age, sex, and race and ethnicity strata and adjusting for health care utilization. Results Between 2016 to 2021, there were 1200, 1100, and 63 patients with type 1 diabetes (mean [SD] age, 11.0 [4.5] years; 687 [57.3%] male), type 2 diabetes (mean [SD] age, 15.7 [2.7] years; 516 [46.9%] male), and other diabetes, respectively. Incidence of type 1 diabetes increased from 18.5 per 100 000 PYs in 2016 to 2019 to 22.4 per 100 000 PYs from 2020 to 2021 with increased IRRs among individuals aged 10 to 19 years, male individuals, and Hispanic individuals. Incidence of type 2 diabetes increased from 14.8 per 100 000 PYs from 2016 to 2019 to 24.7 per 100 000 PYs from 2020 to 2021 with increased IRRs among individuals aged 10 to 19 years, male and female individuals, and those with Black, Hispanic, and other/unknown race and ethnicity.

Conclusions and Relevance In this cohort study of youth in KPSC, incidence of diabetes increased during the COVID-19 pandemic and was more pronounced in specific racial and ethnic groups. Future research to understand differential impacts of physiologic and behavioral risk factors is warranted.

Introduction

Youth-onset diabetes is a serious chronic health condition, placing individuals at risk for early complications, comorbidities, and excess mortality, in particular among those who develop type 2 diabetes and those from racial and ethnic minority groups such as non-Hispanic Black individuals. Prior research from the SEARCH for Diabetes in Youth study showed increases in the incidence of type 1 diabetes and type 2 diabetes in the US between 2002 and 2018, with significant variability between racial and ethnic groups. Prior studies have reported that, in addition to traditional risk factors, respiratory viruses including influenza may influence susceptibility and trigger autoimmune responses in individuals manifesting clinical symptoms of type 1 diabetes. However, findings have been mixed depending on the population composition, self-report vs laboratory-confirmed infections, and duration of study follow-up for assessing diabetes risk. Further, there is less research examining the impacts of respiratory viruses on type 2 diabetes. Of more recent interest, research has shown that coronavirus-binding via angiotensin-converting enzyme 2 receptors damages islet cells and may cause acute diabetes, and hyperglycemia and insulin resistance have been noted in patients with COVID-19 infection without prior indicators of diabetes risk. Additionally, diabetes risk factors may have been exacerbated during the COVID-19 pandemic including limited physical activity, increased sedentary behaviors, sleep disturbances, and increased intake of processed foods.

Recent studies have shown increased rates of newly diagnosed type 1 diabetes and type 2 diabetes in children and young adults during the COVID-19 pandemic compared with time periods prior with higher levels of glucose, hemoglobin A1c (HbA1c), and more severe diabetic ketoacidosis. For example, a study examining pediatric diabetes between April 1, 2020, and March 31, 2021, compared with the prior 2 years found a 48% and 231% increase in the number of patients with type 1 diabetes and type 2 diabetes, respectively. However, these prior studies have been limited in examining variation by age, sex, or race and ethnicity or have been limited to shorter time periods. For the current study, we aimed to describe the incidence of new-onset type 1 diabetes and type 2 diabetes among individuals younger than 20 years in Kaiser Permanente Southern California (KPSC) between 2016 and 2021.

 


◆Tonsils are major sites of persistence of SARS-CoV-2 in children【ASM Journal：Microbiology Spectrum　2023年9月22日】

ABSTRACT

In the present study, we show that SARS-CoV-2 can infect palatine tonsils, adenoids, and secretions in children without symptoms of COVID-19, with no history of recent upper airway infection. We studied 48 children undergoing tonsillectomy due to snoring/OSA or recurrent tonsillitis between October 2020 and September 2021. Nasal cytobrushes, nasal washes, and tonsillar tissue fragments obtained at surgery were tested by RT-qPCR, immunohistochemistry (IHC), flow cytometry, and neutralization assay. We detected the presence of SARS-CoV-2 in at least one specimen tested in 27% of patients. IHC revealed the presence of the viral nucleoprotein in epithelial surface and in lymphoid cells in both extrafollicular and follicular regions, in adenoids and palatine tonsils. Also, IHC for the SARS-CoV-2 non-structural protein NSP-16 indicated the presence of viral replication in 53.8% of the SARS-CoV-2-infected tissues. Flow cytometry showed that CD20+ B lymphocytes were the most infected phenotypes, followed by CD4+ lymphocytes and CD123 dendritic cells, CD8+ T lymphocytes, and CD14+ macrophages. Additionally, IF indicated that infected tonsillar tissues had increased expression of ACE2 and TMPRSS2. NGS sequencing demonstrated the presence of different SARS-CoV-2 variants in tonsils from different tissues. SARS-CoV-2 antigen detection was not restricted to tonsils but was also detected in nasal cells from the olfactory region. Palatine tonsils and adenoids are sites of prolonged RNA presence by SARS-CoV-2 in children, even without COVID-19 symptoms.

IMPORTANCE

This study shows that SRS-CoV-2 of different lineages can infect tonsils and adenoids in one quarter of children undergoing tonsillectomy. These findings bring advancement to the area of SARS-CoV-2 pathogenesis, by showing that tonsils may be sites of prolonged infection, even without evidence of recent COVID-19 symptoms. SARS-CoV-2 infection of B and T lymphocytes, macrophages, and dendritic cells may interfere with the mounting of immune responses in these secondary lymphoid organs. Moreover, the shedding of SARS-CoV-2 RNA in respiratory secretions from silently infected children raises concern about possible diagnostic confusion in the presence of symptoms of acute respiratory infections caused by other etiologies.

 


◆Is neuropilin-1 the neuroimmune initiator of multi-system hyperinflammation in COVID-19?【ScienceDirect　2023年9月23日】

Highlights

  • Despite in-depth inflammation research, a major initiator of cytokine network activation in COVID-19 is yet to be found.
  • Neuropilin-1 (NRP-1) is an inflammation mediator and a host entry element for direct viral invasion of cells by SARS-CoV2.
  • NRP-1 may be implicated in hyperinflammatory damage of the CNS and lungs, as well as other body systems in COVID-19.
  • Neuroimmunological interactions of NRP-1 make it suitable for pharmacotherapeutic targeting in COVID-19.
  • Clinical trials have explored anti-NRP1/VEGF in cancer, but their safety and utility in COVID-19 requires further research.

Abstract

A major immunopathological feature of Coronavirus disease-2019 (COVID-19) is excessive inflammation in the form of “cytokine storm”. The storm is characterized by injurious levels of cytokines which form a complicated network damaging different organs, including the lungs and the brain. The main starter of “cytokine network” hyperactivation in COVID-19 has not been discovered yet. Neuropilins (NRPs) are transmembrane proteins that act as neuronal guidance and angiogenesis modulators. The crucial function of NRPs in forming the nervous and vascular systems has been well-studied. NRP1 and NRP2 are the two identified homologs of NRP. NRP1 has been shown as a viral entry pathway for SARS-CoV2, which facilitates neuroinvasion by the virus within the central or peripheral nervous systems. These molecules directly interact with various COVID-19-related molecules, such as specific regions of the spike protein (major immune element of SARS-CoV2), vascular endothelial growth factor (VEGF) receptors, VEGFR1/2, and ANGPTL4 (regulator of vessel permeability and integrity). NRPs mainly play a role in hyperinflammatory injury of the CNS and lungs, and also the liver, kidney, pancreas, and heart in COVID-19 patients. New findings have suggested NRPs good candidates for pharmacotherapy of COVID-19. However, therapeutic targeting of NRP1 in COVID-19 is still in the preclinical phase. This review presents the implications of NRP1 in multi-organ inflammation-induced injury by SARS-CoV2 and provides insights for NRP1-targeting treatments for COVID-19 patients.

Graphical Abstract

 


◆Evidence of antigenic drift in the fusion machinery core of SARS-CoV-2 spike【bioRxiv　2023年9月27日】

ABSTRACT

Antigenic drift of SARS-CoV-2 is typically defined by mutations in the N-terminal domain and receptor binding domain of spike protein. In contrast, whether antigenic drift occurs in the S2 domain remains largely elusive. Here, we perform a deep mutational scanning experiment to identify S2 mutations that affect binding of SARS-CoV-2 spike to three S2 apex public antibodies. Our results indicate that spatially diverse mutations, including D950N and Q954H, which are observed in Delta and Omicron variants, respectively, weaken the binding of spike to these antibodies. Although S2 apex antibodies are known to be non-neutralizing, we show that they confer partial protection in vivo. We further demonstrate that such in vivo protection activity is diminished by the natural mutation D950N. Overall, this study indicates that the S2 domain of SARS-CoV-2 spike can undergo antigenic drift, which represents a potential challenge for the development of more universal coronavirus vaccines.

INTRODUCTION

As the major antigen of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the spike (S) glycoprotein has undergone extensive antigenic drift since the beginning of the COVID-19 pandemic. SARS-CoV-2 S protein is a homotrimer with an N-terminal domain (NTD), a receptor-binding domain (RBD), and an S2 domain. S protein facilitates virus entry by engaging the host receptor angiotensin-converting enzyme II (ACE2) via RBD and mediating virus-host membrane fusion through the fusion machinery in S2. While all three domains in S can elicit antibody responses during infection or vaccination, the neutralizing potency of antibodies to RBD and NTD are typically much higher than those to S2. Consistently, mutations in RBD and NTD are key determinants of SARS-CoV-2 antigenic drift. Although mutations in S2 have also emerged in circulating SARS-CoV-2 variants, they are thought to mainly affect the stability and fusogenicity of S protein. As a result, whether S2 mutations play a role in the antigenic drift of SARS-CoV-2 remain largely elusive.

Due to the relatively high sequence conservation of S2, human antibodies to S2 can achieve exceptional breadth. For example, human antibodies to the S2 fusion peptide can neutralize coronavirus strains from different genera (α, β, γ and δ). Besides, human antibodies to the S2 stem helix can neutralize diverse β-coronavirus strains. Additionally, a public clonotype to the apex of S2 can cross-react with multiple sarbecoviruses. This public clonotype is encoded by IGHV1-69/IGKV3-11 with complementarity determining region (CDR) H3 and L3 lengths of 15 and 11 amino acids (IMGT numbering), respectively. Although S2 antibodies usually have weak neutralizing activity, antibodies to fusion peptide and stem helix have been shown to confer in vivo protection against SARS-CoV-2 infection. Given that S2 antibodies are commonly observed in both vaccinated and infected individuals, they likely exert selection pressure on the circulating SARS-CoV-2.

In this study, we showed that the IGHV1-69/IGKV3-11 public clonotype to the apex of S2 confers partial in vivo protection, despite their lack of neutralizing activity. Subsequently, a deep mutational scanning experiment was performed to probe the effects of S2 mutations on the cell-surface binding activity of three IGHV1-69/IGKV3-11 S2 antibodies, namely COVA1-07, COVA2-14, and COVA2-18. Specifically, we focused on single amino acid mutations within the first heptad repeat (HR1) and central helix (CH). Our results revealed that D950N and Q954H, which are observed in Delta and Omicron variants, respectively, weakened binding of SARS-CoV-2 S to all three IGHV1-69/IGKV3-11 S2 antibodies. Additional in vivo experiment further suggested that protection mediated by COVA2-18 was weakened by D950N. Collectively, these results indicate that S2 mutations contribute to SARS-CoV-2 antigenic drift.