SARS-CoV-2 and HSV-1 Induce Amyloid Aggregation in Human CSF
The corona virus (SARS-CoV-2) pandemic and the resulting long-term neurological complications in patients, known as long COVID, have renewed the interest in the correlation between viral infections and neurodegenerative brain disorders. While many viruses can reach the central nervous system (CNS) causing acute or chronic infections (such as herpes simplex virus 1, HSV-1), the lack of a clear mechanistic link between viruses and protein aggregation into amyloids, a characteristic of several neurodegenerative diseases, has rendered such a connection elusive. Recently, we showed that viruses can induce aggregation of purified amyloidogenic proteins via the direct physicochemical mechanism of heterogenous nucleation (HEN). In the current study, we show that the incubation of HSV-1 and SARS-CoV-2 with human cerebrospinal fluid (CSF) leads to the amyloid aggregation of several proteins known to be involved in neurodegenerative diseases, such as: APLP1 (amyloid beta precursor like protein 1), ApoE, clusterin, α2-macroglobulin, PGK-1 (phosphoglycerate kinase 1), ceruloplasmin, nucleolin, 14-3-3, transthyretin and vitronectin. Importantly, UV-inactivation of SARS-CoV-2 does not affect its ability to induce amyloid aggregation, as amyloid formation is dependent on viral surface catalysis via HEN and not its ability to replicate. Our results show that viruses can physically induce amyloid aggregation of proteins in human CSF, and thus providing a potential mechanism that may account for the association between persistent and latent/reactivating brain infections and neurodegenerative diseases. ### Competing Interest Statement The authors have declared no competing interest.
SARS-CoV-2 generates amyloid in cerebral spinal fluid
In a recent study posted to the bioRxiv* preprint server, an international team of researchers demonstrated amyloid aggregation due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in human cerebrospinal fluid (CSF).
COVID-19: Lungen-MRT zeigt Langzeitschäden bei Kindern und...
Erlangen – Erkrankungen an COVID-19 können bei Kindern und Jugendlichen die Sauerstoffaufnahme in den Lungen auch über das Ende der akuten Phase hinaus... #COVID19 #Studie #Radiologie
An ACE2-dependent Sarbecovirus in Russian bats is resistant to SARS-CoV-2 vaccines
Author summary SARS-CoV-2, the sarbecovirus behind COVID-19, emerged in the human population after cross-species transmission from an animal source. While hundreds of sarbecoviruses have been discovered, predominantly in bats in Asia, the majority are not capable of infecting human cells. Khosta-2, a sarbecovirus discovered in Russia, has been shown to interact with the same entry receptor as SARS-CoV-2. In this study, we tested how well the spike proteins from these bat viruses infect human cells under different conditions. We found that the spike from virus, Khosta-2, could infect cells similar to human pathogens using the same entry mechanisms, but was resistant to neutralization by serum from individuals who had been vaccinated for SARS-CoV-2.
The rapid replacement of the SARS-CoV-2 Delta variant by Omicron (B.1.1.529) in England
The emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) B.1.1.529 (Omicron) variant caused international concern due to its rapid spread in Southern Africa. It was unknown whether this variant would replace or coexist with (either transiently or long term) the then-dominant Delta variant on its introduction to England. We developed a set of hierarchical logistic growth models to describe changes in the frequency of S gene target failure (SGTF) PCR tests, a proxy for Omicron. The doubling time of SGTF cases peaked at 1.56 days (95% CI: 1.49 to 1.63) on 5 December, whereas triple-positive cases were halving every 5.82 days (95% CI: 5.11 to 6.67) going into Christmas 2021. We were unable to characterize the replacement of Delta by Omicron with a single rate. The replacement rate decreased by 53.56% (95% CrI: 45.38 to 61.01) between 14 and 15 December, meaning the competitive advantage of Omicron approximately halved. Preceding the changepoint, Omicron was replacing Delta 16.24% (95% CrI: 9.72 to 23.41) faster in those with two or more vaccine doses, indicative of vaccine escape being a substantial component of competitive advantage. Despite the slowdown, Delta was almost entirely replaced in England within a month of the first sequenced domestic case. The synchrony of changepoints across regions at various stages of Omicron epidemics suggests that the growth rate advantage was not attenuated because of biological mechanisms related to strain competition. The step change in replacement could have resulted from behavioral changes, potentially elicited by public health messaging or policies, that differentially affected Omicron.
COVID raises risk of long-term brain injury, large U.S. study finds
People who had COVID-19 are at higher risk for a host of brain injuries a year later compared with people who were never infected by the coronavirus, a finding that could affect millions of Americans, U.S. researchers reported on Thursday.
Updating information regarding convergent variants BA.2.3.20, BN.1, BA.2.10.4, BN.2.1, BA.4.6.1, BQ.1, BQ.1.1. In short, BA.2.75.2 and BQ.1.1 are the most antibody-evasive convergent variants tested, far exceeding BA.5 and approaching SARS-CoV-1 level. (1/4) https://t.co/BzknQBSF5e— Yunlong Richard Cao (@yunlong_cao) September 23, 2022
COVID-19 infection may increase risk of type 1 diabetes, suggests nationwide study of 1.2 million children
Testing positive for SARS-CoV-2, the virus that causes COVID-19, is associated with an increased risk of new-onset type 1 diabetes in children and adolescents, according to a new research at this year’s European Association for the Study of Diabetes (EASD) Annual Meeting in Stockholm, Sweden (19-23 Sept). The study is by Hanne Løvdal Gulseth and Dr German Tapia, Norwegian Institute of Public Health, Oslo, Norway, and colleagues.
Post-COVID-19 syndrome: retinal microcirculation as a potential marker for chronic fatigue
Post-COVID-19 syndrome (PCS) summarizes persisting sequelae after infection with the severe-acute-respiratory-syndrome-Coronavirus-2 (SARS-CoV-2). PCS can affect patients of all covid-19 disease severities. As previous studies revealed impaired blood flow as a provoking factor for triggering PCS, it was the aim of the present study to investigate a potential association of self-reported chronic fatigue and retinal microcirculation in patients with PCS, potentially indicating an objective biomarker. A prospective study was performed, including 201 subjects: 173 patients with PCS and 28 controls. Retinal microcirculation was visualized by OCT-Angiography (OCT-A) and quantified by the Erlangen-Angio-Tool as macula and peripapillary vessel density (VD). Chronic Fatigue (CF) was assessed with the variables ‘Bell score’, age and gender. The VD in the superficial vascular plexus (SVP), intermediate capillary plexus (ICP) and deep capillary plexus (DCP) were analyzed considering the repetitions (12 times). Taking in account of such repetitions a mixed model was performed to detect possible differences in the least square means between different groups of analysis. An age effect on VD was observed between patients and controls (p
Facing the Omicron variant – How well do vaccines protect against mild and severe COVID-19? Third interim analysis of a living systematic review
Background The SARS-CoV-2 Omicron variant is currently the dominant variant globally. This 3rd interim analysis of a living systematic review summarizes evidence on COVID-19 vaccine effectiveness (VE) and duration of protection against Omicron. Methods We systematically searched the COVID-19 literature for controlled studies evaluating the effectiveness of COVID-19 vaccines approved in the European Union up to 14/01/2022, complemented by hand-searches of websites and metasearch engines up to 11/02/2022. We considered the following comparisons: full primary immunization vs. no vaccination; booster immunization vs. no vaccination; booster vs. primary immunization. VE against any confirmed SARS-CoV-2 infection, symptomatic, and severe COVID-19 (i.e. COVID-19-related hospitalization, ICU-admission, or death) was indicated providing estimate ranges. Meta-analysis was not performed due to high study heterogeneity. Risk of bias was assessed with ROBINS-I, certainty of evidence evaluated using GRADE. Results We identified 26 studies, including 430 to 2.2 million participants. VE against any confirmed SARS-CoV-2 infection compared to no vaccination ranged between 0-62% after full primary immunization, and between 34-66% after a booster dose. VE-range for booster vs. primary immunization was 34-54.6%. Against symptomatic COVID-19, VE ranged between 6-76% after full primary immunization, and between 19-73.9% after booster immunization, if compared to no vaccination. When comparing booster vs. primary immunization VE ranged between 56-69%. VE against severe COVID-19 compared to no vaccination ranged between 3-84% after full primary immunization, and between 12-100% after a booster dose. One study compared booster vs. primary immunization (VE 100%, 95% CI 71.4-100). VE was characterized by a moderate to strong decline within three to six months for SARS-CoV-2 infections and symptomatic COVID-19. Against severe COVID-19 protection remained robust at least for up to six months. Waning immunity was more profound after primary than booster immunization. Risk of bias was moderate to critical across studies and outcomes. GRADE-certainty was very low for all outcomes. Author’s conclusions Under the Omicron variant, effectiveness of EU-licensed COVID-19 vaccines in preventing any SARS-CoV-2 infection or mild disease is low and only short-lasting after primary immunization, but can be improved by booster vaccination. VE against severe COVID-19 remains high and is long-lasting, especially after receiving the booster vaccination. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study did not receive any funding ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present work are contained in the manuscript
Household transmission of the SARS-CoV-2 Omicron variant in Denmark
Nature Communications - In this study, the authors compare the transmission dynamics of the Delta and Omicron SARS-CoV-2 variants using household data from Denmark. They find that Omicron has a...
Beim #Formaldehyd kann man #Impfgegner auskontern, indem man ihnen sagt, dass sie täglich ca. 1g pro kg Körpergewicht selbst produzieren und die Konzentration an Formaldehyd im Körper höher ist als im #Impstoff. Weiß jemand wieviel mRNA wir jeden Tag produzieren?— Jeff Bergheim (@BergheimJeff) September 27, 2022
The Critical Contribution of Pseudouridine to mRNA COVID-19 Vaccines
The current COVID-19 pandemic is a massive source of global disruption, having led so far to two hundred and fifty million COVID-19 cases and almost five million deaths worldwide. It was recognized in the beginning that only an effective vaccine could ...
Detection of Messenger RNA COVID-19 Vaccines in Human Breast Milk
This cohort study investigates the presence of COVID-19 vaccine mRNA in the expressed breast milk of lactating individuals who received the vaccination within 6 months after delivery.
Reevaluation of antibody-dependent enhancement of infection in anti-SARS-CoV-2 therapeutic antibodies and mRNA-vaccine antisera using FcR- and ACE2-positive cells
Scientific Reports - Reevaluation of antibody-dependent enhancement of infection in anti-SARS-CoV-2 therapeutic antibodies and mRNA-vaccine antisera using FcR- and ACE2-positive cells
This situation, i.e., observed ADE without neutralization at a low dilution of serum, is unfavorable for protection against infection. However, it must be remembered that, in contrast to the above-mentioned Ab-involved adverse events, protective cellular immunity is also induced and is involved in anti-SARS-CoV-2 responses in vivo32. Therefore, as a whole, this Ab-mediated adverse potential during virus expansion and the opposing protective effects by T-cell immunity might make it more difficult to recognize the involvement of ADE in SARS-CoV-2 reinfection or resurrection in vivo12. Six volunteers treated with the mRNA vaccine in this study maintained an uninfected state for approximately 8 months after the second vaccination, and also had a third vaccination. Therefore, there is no suggestive information between the data based on in vitro analyses (Fig. 3, Supplemental Figs. 6 and 7) and the clinical observations. To make clear the relationship between clinical variations and ADE observed in in vitro analyses, further investigations using a larger number of samples will be required.
The latest from our team in @NatureMedicineThe long-term neurologic consequences of #COVID19A thread 🧵https://t.co/jmQMBvHAQnby @evanjxu @Biostayan @zalaly— Ziyad Al-Aly, MD (@zalaly) September 22, 2022
Anti-cardiac troponin antibodies in clinical human disease: a systematic review
Anti-cardiac troponin antibodies have been studied in different types of clinical diseases and in healthy populations. A systematic review of published data on anti-troponin antibodies was carried out (search performed on PubMed, ISI Web of Knowledge ...
The majority of severe COVID-19 patients develop anti-cardiac autoantibodies
GeroScience - Severe cases of COVID-19 are characterized by an inflammatory burst, which is accompanied by multiorgan failure. The elderly population has higher risk for severe or fatal outcome for...
Bivalent SARS-CoV-2 mRNA vaccines increase breadth of neutralization and protect against the BA.5 Omicron variant
The emergence of SARS-CoV-2 variants in the Omicron lineage with large number of substitutions in the spike protein that can evade antibody neutralization has resulted in diminished vaccine efficacy and persistent transmission. One strategy to broaden vaccine-induced immunity is to administer bivalent vaccines that encode for spike proteins from both historical and newly-emerged variant strains. Here, we evaluated the immunogenicity and protective efficacy of two bivalent vaccines that recently were authorized for use in Europe and the United States and contain two mRNAs encoding Wuhan-1 and either BA.1 (mRNA-1273.214) or BA.4/5 (mRNA-1273.222) spike proteins. As a primary immunization series in BALB/c mice, both bivalent vaccines induced broader neutralizing antibody responses than the constituent monovalent vaccines (mRNA-1273 [Wuhan-1], mRNA-1273.529 [BA.1], and mRNA-1273-045 [BA.4/5]). When administered to K18-hACE2 transgenic mice as a booster at 7 months after the primary vaccination series with mRNA-1273, the bivalent vaccines induced greater breadth and magnitude of neutralizing antibodies compared to an mRNA-1273 booster. Moreover, the response in bivalent vaccine-boosted mice was associated with increased protection against BA.5 infection and inflammation in the lung. Thus, boosting with bivalent Omicron-based mRNA-1273.214 or mRNA-1273.222 vaccines enhances immunogenicity and protection against currently circulating SARS-CoV-2 strains. ### Competing Interest Statement M.S.D. is a consultant for Inbios, Vir Biotechnology, Senda Biosciences, Moderna, and Immunome. The Diamond laboratory has received unrelated funding support in sponsored research agreements from Vir Biotechnology, Emergent BioSolutions, and Moderna. G.-Y.C., G.S.-J., A.N., K.W., D.L., D.M.B., L.A., H.J., P.M., N.J.A., A.C., S.E. and D.K.E. are employees of and shareholders in Moderna Inc.
Nanomolar inhibition of SARS-CoV-2 infection by an unmodified peptide targeting the prehairpin intermediate of the spike protein
Variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) challenge currently available coronavirus disease 2019 vaccines and monoclonal antibody therapies through epitope change on the receptor binding domain of the viral spike glycoprotein. Hence, there is a specific urgent need for alternative antivirals that target processes less likely to be affected by mutation, such as the membrane fusion step of viral entry into the host cell. One such antiviral class includes peptide inhibitors, which block formation of the so-called heptad repeat 1 and 2 (HR1HR2) six-helix bundle of the SARS-CoV-2 spike (S) protein and thus interfere with viral membrane fusion. We performed structural studies of the HR1HR2 bundle, revealing an extended, well-folded N-terminal region of HR2 that interacts with the HR1 triple helix. Based on this structure, we designed an extended HR2 peptide that achieves single-digit nanomolar inhibition of SARS-CoV-2 in cell-based and virus-based assays without the need for modifications such as lipidation or chemical stapling. The peptide also strongly inhibits all major SARS-CoV-2 variants to date. This extended peptide is ∼100-fold more potent than all previously published short, unmodified HR2 peptides, and it has a very long inhibition lifetime after washout in virus infection assays, suggesting that it targets a prehairpin intermediate of the SARS-CoV-2 S protein. Together, these results suggest that regions outside the HR2 helical region may offer new opportunities for potent peptide-derived therapeutics for SARS-CoV-2 and its variants, and even more distantly related viruses, and provide further support for the prehairpin intermediate of the S protein.
Do you keep getting colds after COVID? Here's what we know about how COVID changes your immune system
It's early days yet. But growing evidence suggests COVID causes changes to your immune system that may put you at risk of other infectious diseases, writes Lara Herrero.
Nasal Vaccines Are Commercially High Risk, Perhaps High Reward
Dozens of intranasally delivered vaccines targeting SARS-CoV-2 are in development. Could they pave the way for widespread nasal vaccination in the future?
Severe COVID-19 impairs the immune system for longer than 6 months
The immune cells of patients who received hospital care for COVID-19 early in the pandemic were still affected six months later, shows a study conducted by researchers at Linköping University.
Sustained cellular immune dysregulation in individuals recovering from SARS-CoV-2 infection
SARS-CoV-2 causes a wide spectrum of clinical manifestations and significant mortality. Studies investigating underlying immune characteristics are needed to understand disease pathogenesis and inform vaccine design. In this study, we examined immune cell subsets in hospitalized and nonhospitalized individuals. In hospitalized patients, many adaptive and innate immune cells were decreased in frequency compared with those of healthy and convalescent individuals, with the exception of an increase in B lymphocytes. Our findings show increased frequencies of T cell activation markers (CD69, OX40, HLA-DR, and CD154) in hospitalized patients, with other T cell activation/exhaustion markers (PD-L1 and TIGIT) remaining elevated in hospitalized and nonhospitalized individuals. B cells had a similar pattern of activation/exhaustion, with increased frequency of CD69 and CD95 during hospitalization followed by an increase in PD1 frequencies in nonhospitalized individuals. Interestingly, many of these changes were found to increase over time in nonhospitalized longitudinal samples, suggesting a prolonged period of immune dysregulation after SARS-CoV-2 infection. Changes in T cell activation/exhaustion in nonhospitalized patients were found to positively correlate with age. Severely infected individuals had increased expression of activation and exhaustion markers. These data suggest a prolonged period of immune dysregulation after SARS-CoV-2 infection, highlighting the need for additional studies investigating immune dysregulation in convalescent individuals.
Impaired function and delayed regeneration of dendritic cells in COVID-19
Author summary Dendritic cells (DCs) recognize viral infections and trigger innate and adaptive antiviral immunity. COVID-19 severity is greatly influenced by the host immune response and modulation of DC generation and function after SARS-CoV-2 infection could play an important role in this disease. This study identifies a long-lasting reduction of DCs in the blood of COVID-19 patients and a functional impairment of these cells. Downregulation of costimulatory molecule CD86 and upregulation of inhibitory molecule PD-L1 in conventional DCs correlated with disease severity and were accompanied by a reduced ability to stimulate T cells. A higher frequency of CD163+ CD14+ cells in the DC3 subpopulation correlated with systemic inflammation suggesting that these cells may play a role in inflammatory responses of COVID-19 patients. Depletion and functional impairment of DCs beyond the acute phase of the disease may have consequences for susceptibility to secondary infections and clinical management of COVID-19 patients.
Long-term perturbation of the peripheral immune system months after SARS-CoV-2 infection - BMC Medicine
Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly infectious respiratory virus which is responsible for the coronavirus disease 2019 (COVID-19) pandemic. It is increasingly clear that recovered individuals, even those who had mild COVID-19, can suffer from persistent symptoms for many months after infection, a condition referred to as “long COVID”, post-acute sequelae of COVID-19 (PASC), post-acute COVID-19 syndrome, or post COVID-19 condition. However, despite the plethora of research on COVID-19, relatively little is known about the molecular underpinnings of these long-term effects. Methods We have undertaken an integrated analysis of immune responses in blood at a transcriptional, cellular, and serological level at 12, 16, and 24 weeks post-infection (wpi) in 69 patients recovering from mild, moderate, severe, or critical COVID-19 in comparison to healthy uninfected controls. Twenty-one of these patients were referred to a long COVID clinic and 50% reported ongoing symptoms more than 6 months post-infection. Results Anti-Spike and anti-RBD IgG responses were largely stable up to 24 wpi and correlated with disease severity. Deep immunophenotyping revealed significant differences in multiple innate (NK cells, LD neutrophils, CXCR3+ monocytes) and adaptive immune populations (T helper, T follicular helper, and regulatory T cells) in convalescent individuals compared to healthy controls, which were most strongly evident at 12 and 16 wpi. RNA sequencing revealed significant perturbations to gene expression in COVID-19 convalescents until at least 6 months post-infection. We also uncovered significant differences in the transcriptome at 24 wpi of convalescents who were referred to a long COVID clinic compared to those who were not. Conclusions Variation in the rate of recovery from infection at a cellular and transcriptional level may explain the persistence of symptoms associated with long COVID in some individuals.