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People suffering from COVID-19 could have several different SARS-CoV-2 variants hidden away from the immune system in different parts of the body, finds new research published in Nature Communications by an international research team. The study's authors say that this may make complete clearance of the virus from the body of an infected person, by their own antibodies, or by therapeutic antibody treatments, much more difficult. 
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Nature Reviews Immunology publie un document majeur concernant l'implication cruciale des cellules B germinales centrales (GC) dans le contrôle d
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Hyperactivation of the complement and coagulation systems is recognized as part of the clinical syndrome of COVID-19. Here we review systemic complement activation and local complement activation in response to the causative virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and their currently known relationships to hyperinflammation and thrombosis. We also provide an update on early clinical findings and emerging clinical trial evidence that suggest potential therapeutic benefit of complement inhibition in severe COVID-19. Hyperactivation of the complement system has been implicated in the pathology of COVID-19. Here the authors bring together the latest information on the role of complement in COVID-19 and progress in targeting complement components for treatment of severe disease.
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A proportion of patients surviving acute coronavirus disease 2019 (COVID-19) infection develop post-acute COVID syndrome (long COVID (LC)) lasting longer than 12 weeks. Here, we studied individuals with LC compared to age- and gender-matched recovered individuals without LC, unexposed donors and individuals infected with other coronaviruses. Patients with LC had highly activated innate immune cells, lacked naive T and B cells and showed elevated expression of type I IFN (IFN-β) and type III IFN (IFN-λ1) that remained persistently high at 8 months after infection. Using a log-linear classification model, we defined an optimal set of analytes that had the strongest association with LC among the 28 analytes measured. Combinations of the inflammatory mediators IFN-β, PTX3, IFN-γ, IFN-λ2/3 and IL-6 associated with LC with 78.5–81.6% accuracy. This work defines immunological parameters associated with LC and suggests future opportunities for prevention and treatment. Phetsouphanh and colleagues show that individuals with long COVID have persistent activation of the innate and adaptive immune system at 8 months after infection and define a set of analytes associated with long COVID. Via HAS-veille
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Generation of the C3a complement protein fragment by SARS-CoV-2 infection drives differentiation
Gilbert C FAURE's insight:
more covid information https://www.scoop.it/topic/immunology?q=covid more complement information https://www.scoop.it/topic/immunology?q=covid
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5 juillet 2021 Une équipe de scientifiques internationaux a récemment identifié des anticorps ultrapuissants anti-coronavirus 2 (SRAS-CoV-2) anti-syndrome respiratoire aigu sévère provenant de donneurs convalescents. Les anticorps sont capables de neutraliser une large gamme de variantes du SRAS-CoV-2, même à des concentrations sous-nanomolaires. De plus, les combinaisons de ces anticorps réduisent le risque de générer des mutants d'échappement in vitro. L'étude a été publiée le 13 août 2021 dans la revue Science. https://www.science.org/doi/full/10.112 ... ce.abh1766 Sur le fond Le coronavirus 2 du syndrome respiratoire aigu sévère (SRAS-CoV-2), l'agent pathogène responsable de la maladie à coronavirus 2019 (COVID-19), est un virus à ARN simple brin enveloppé de sens positif appartenant à la famille des bêta-coronavirus humains. La glycoprotéine de pointe sur l'enveloppe virale est composée de deux sous-unités S1 et S2. Dont, la sous-unité S1 se lie directement au récepteur de l'enzyme de conversion de l'angiotensine 2 (ACE2) de la cellule hôte via le domaine de liaison au récepteur (RBD) pour initier le processus d'entrée virale. La majorité des anticorps thérapeutiques contre le SRAS-CoV-2 ont été conçus sur la base de la séquence de protéine de pointe native trouvée dans la souche Wuhan originale du SRAS-CoV-2. Ainsi, de nouvelles variantes virales avec de multiples mutations de la protéine de pointe peuvent probablement développer une résistance contre ces anticorps. Dans ce contexte, des études ont montré que les anticorps développés en réponse aux vaccins COVID-19 actuellement disponibles ont moins d'efficacité pour neutraliser les nouvelles variantes préoccupantes (COV) du SRAS-CoV, notamment B.1.1.7, B.1.351, P1 et B.1.617.2. Dans la présente étude, les scientifiques ont isolé et caractérisé des anticorps anti-pic RBD de patients guéris du COVID-19. Identification des anticorps Les anticorps ont été isolés de quatre donneurs convalescents infectés par la souche Washington-1 (WA-1) du SRAS-CoV-2. La séquence de pointe dans la souche WA-1 est similaire à la séquence de pointe dans la souche originale de Wuhan. Les cellules B isolées à partir d'échantillons de sang provenant de donneurs ont été triées pour l'identification des anticorps. Cela a conduit à l'identification de quatre anticorps neutralisants puissants ciblant le pic RBD. Ces anticorps ont montré une forte affinité pour le pic SRAS-CoV-2 même à des concentrations nanomolaires. Pour déterminer si les anticorps hautement puissants pouvaient bloquer l'ACE2 - la liaison aux pointes, des tests d'interférométrie par compétition ACE2 et de liaison à la surface cellulaire ont été effectués. Les résultats ont révélé que sur 4 anticorps, deux liés aux RBD en « position haute » et deux liés aux RBD en « position basse ». De plus, trois anticorps sur quatre bloquaient directement l'interaction RBD - ACE2, et un inhibait indirectement l'interaction par encombrement stérique - le ralentissement des réactions chimiques dû à l'encombrement stérique. Neutralisation médiée par les anticorps Tous les anticorps expérimentaux ont montré une puissance significativement plus élevée dans la neutralisation des variants contenant la mutation D614G que la souche WA-1. Une analyse plus poussée avec des particules lentivirales pseudotypées avec des variantes à pointes a indiqué que les anticorps maintiennent une puissance élevée pour neutraliser un ensemble diversifié de 10 variantes à pointes. Il est important de noter que trois des quatre anticorps expérimentaux ont montré une grande efficacité pour neutraliser 13 variantes circulantes préoccupantes/intéressantes du SRAS-CoV-2, notamment B.1.1.7, B.1.351, B.1.427, B.1.429, B.1.526, P.1, P.2, B.1.617.1 et B.1.617.2. Analyse structurale et fonctionnelle des anticorps Des analyses au microscope cryoélectronique des structures du complexe anticorps-antigène ont révélé que deux anticorps avec le pouvoir de neutralisation le plus élevé se lient à la protéine de pointe avec tous les RBD en « position haute ». D'autres analyses structurelles ont révélé que les modes de liaison à l'épitope des anticorps sont responsables d'un pouvoir neutralisant élevé contre les COV du SRAS-CoV-2. La capacité de liaison et de neutralisation des anticorps a été affectée négativement par trois mutations de pointe, dont F486R, N487R et Y489R. Résistance aux anticorps Une pression de sélection d'anticorps a été appliquée à la souche WA-1 pour identifier les mutations potentielles d'échappement qui peuvent apparaître au cours de l'infection virale. La pression de sélection positive a été appliquée en incubant le virus avec des concentrations croissantes des anticorps pour déclencher la résistance aux anticorps. Dans deux des anticorps les plus puissants, l'un était affecté négativement par une seule mutation F486S et l'autre était affecté par les mutations F486L, N487D et Q493R. Cependant, la mutation Q493R a montré un impact négligeable sur la liaison et la neutralisation. Une analyse plus poussée a révélé que ces mutations d'échappement sont principalement absentes dans les variantes virales circulantes, indiquant l'absence de pression de sélection. En effectuant plusieurs cycles de sélection à l'aide de traitements combinés avec deux anticorps, il a été observé que les combinaisons d'anticorps pourraient réduire le risque d'acquisition de mutations d'échappement et le développement ultérieur de variantes virales résistantes. Source: News Medical et merci à QcLiLi, dans Twitter En référence à "Wang L. 2021. Anticorps ultrapuissants contre des variantes diverses et hautement transmissibles du SRAS-CoV-2. Sciences". -- -- --
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Virus entry, consisting of attachment to and penetration into the host target cell, is the first step of the virus life cycle and is a critical ‘do or die’ event that governs virus emergence in host populations. Most antiviral vaccines induce neutralizing antibodies that prevent virus entry into cells. However, while the prevention of virus invasion by humoral immunity is well appreciated, considerably less is known about the immune defences present within cells (known as intrinsic immunity) that interfere with virus entry. The interferon-induced transmembrane (IFITM) proteins, known for inhibiting fusion between viral and cellular membranes, were once the only factors known to restrict virus entry. However, the progressive development of genetic and pharmacological screening platforms and the onset of the COVID-19 pandemic have galvanized interest in how viruses infiltrate cells and how cells defend against it. Several host factors with antiviral potential are now implicated in the regulation of virus entry, including cholesterol 25-hydroxylase (CH25H), lymphocyte antigen 6E (LY6E), nuclear receptor co-activator protein 7 (NCOA7), interferon-γ-inducible lysosomal thiol reductase (GILT), CD74 and ARFGAP with dual pleckstrin homology domain-containing protein 2 (ADAP2). This Review summarizes what is known and what remains to be understood about the intrinsic factors that form the first line of defence against virus infection. Besides neutralizing antibodies, viruses face a range of cell-intrinsic inhibitors that are specialized to limit virus entry into host cells. Majdoul and Compton describe the mechanisms of action of the cellular factors providing this important first line of defence against virus infection, including infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
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The introduction of vaccines has inspired new hope in the battle against SARS-CoV-2. However, the emergence of viral variants, in the absence of potent antivirals, has left the world struggling wit...
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Immunocompromised individuals, such as patients with haematological malignancies who have recently undergone haematopoietic stem cell transplantation, may not be protected effectively from COVID-1
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Abstract Autopsies of patients who have died from COVID-19 have been crucial in delineating patterns of injury associated with SARS-CoV-2 infection. Despite their utility, comprehensive autopsy stu...
Gilbert C FAURE's insight:
at last....
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Les variants qui apparaissent toujours plus différenciés et plus tenaces sont-ils un péril pour la sortie du tunnel ?
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Patients with cancer have higher COVID-19 morbidity and mortality. Here we present the prospective CAPTURE study, integrating longitudinal immune profiling with clinical annotation. Of 357 patients with cancer, 118 were SARS-CoV-2 positive, 94 were symptomatic and 2 died of COVID-19. In this cohort, 83% patients had S1-reactive antibodies and 82% had neutralizing antibodies against wild type SARS-CoV-2, whereas neutralizing antibody titers against the Alpha, Beta and Delta variants were substantially reduced. S1-reactive antibody levels decreased in 13% of patients, whereas neutralizing antibody titers remained stable for up to 329 days. Patients also had detectable SARS-CoV-2-specific T cells and CD4+ responses correlating with S1-reactive antibody levels, although patients with hematological malignancies had impaired immune responses that were disease and treatment specific, but presented compensatory cellular responses, further supported by clinical recovery in all but one patient. Overall, these findings advance the understanding of the nature and duration of the immune response to SARS-CoV-2 in patients with cancer. Turajlic and colleagues assess longitudinal antibody and cellular immune responses against SARS-CoV-2 variants of concern in patients with cancer, following either recovery from SARS-CoV-2 infection or vaccination, in two back-to-back reports from the CAPTURE study.
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The entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into human cells is an essential step for virus transmission and development of COVID 19. Although the lung epithelial cells are its initial target, SARS-CoV-2 also can infect endothelial cells. Endothelial cells are the major constituents of the vascular system and cardiovascular complication is a hallmark of severe COVID-19. Angiotensin-converting enzyme 2 (ACE2) is the entry receptor for SARS-CoV-2. However, the possible involvement of other cellular components in the viral entry is not fully understood. A team of researchers from the Boston University School of Medicine (BUSM) has identified extracellular vimentin as an attachment factor that facilitates SARS-CoV-2 entry into human cells. Vimentin is a structural protein that is widely expressed in the cells of mesenchymal origin such as endothelial cells and a potential novel target against SARS-CoV-2, which could block the infection of the SARS-CoV-2. "Severe endothelial injury, vascular thrombosis, and obstruction of alveolar capillaries (tiny air sacs scattered throughout the lungs) are common features of severe COVID-19.
Identification of vimentin as a host attachment factor for SARS-CoV-2 can provide new insight into the mechanism of SARS-CoV-2 infection of the vascular system and can lead to the development of novel treatment strategies," said corresponding author Nader Rahimi, Ph.D., associate professor of pathology & laboratory medicine at BUSM. The researchers used liquid chromatography–tandem mass spectrometry (LC-MS/MS) and identified vimentin as a protein that binds to the SARS-CoV-2 spike (S) protein and facilitates SARS-CoV-2 infection. They also found that depletion of vimentin significantly reduces SARS-CoV-2 infection of human endothelial cells. In contrast, over-expression of vimentin with ACE2 significantly increased the infection rate. "More importantly, we saw that the CR3022 antibody inhibited the binding of vimentin with CoV-2-S-protein, and neutralized SARS-CoV-2 entry into human cells," explained Rahimi.
Findings Published in P.N.A.S. (Jan. 25, 2022): https://doi.org/10.1073/pnas.2113874119 Via Juan Lama
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Cross-reactive immune responses to SARS-CoV-2 have been observed in pre-pandemic cohorts and proposed to contribute to host protection. Here we assess 52 COVID-19 household contacts to capture immune responses at the earliest timepoints after SARS-CoV-2 exposure. Using a dual cytokine FLISpot assay on peripheral blood mononuclear cells, we enumerate the frequency of T cells specific for spike, nucleocapsid, membrane, envelope and ORF1 SARS-CoV-2 epitopes that cross-react with human endemic coronaviruses. We observe higher frequencies of cross-reactive (p = 0.0139), and nucleocapsid-specific (p = 0.0355) IL-2-secreting memory T cells in contacts who remained PCR-negative despite exposure (n = 26), when compared with those who convert to PCR-positive (n = 26); no significant difference in the frequency of responses to spike is observed, hinting at a limited protective function of spike-cross-reactive T cells. Our results are thus consistent with pre-existing non-spike cross-reactive memory T cells protecting SARS-CoV-2-naïve contacts from infection, thereby supporting the inclusion of non-spike antigens in second-generation vaccines. While cross-reactive immunity between human coronavirus and SARS-CoV-2 may contribute to host protection, validating evidences are still scarce. Here the authors assess a cohort of 52 donors with immediate-early contact with SARS-CoV-2 to correlate higher frequency of cross-reactive T cells with lower infection rate.
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Author summary In this work we describe the prognostic value of early detection of SARS-CoV-2-specific T cell response in acute COVID-19, as patients without a prompt SARS-CoV-2-specific T cell response progress to severe COVID-19. We also show that the presence of specific T cells against SARS-CoV-2 when patients arrive to the emergency room is a protective factor against developing severe COVID-19, independently of the age and gender of the patient, which are two major known contributors to disease outcome. In addition, we show robust cellular and humoral immune responses persist 3 months after real-world vaccination.
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It is not fully understood why COVID-19 is typically milder in children1–3. To examine differences in response to SARS-CoV-2 infection in children and adults, we analysed paediatric and adult COVID-19 patients and healthy controls (total n=93) using single-cell multi-omic profiling of matched nasal, tracheal, bronchial and blood samples. In healthy paediatric airways, we observed cells already in an interferon-activated state, that upon SARS-CoV-2 infection was further induced especially in airway immune cells. We postulate that higher paediatric innate interferon-responses restrict viral replication and disease progression. The systemic response in children was characterised by increases in naive lymphocytes and a depletion of natural killer cells, while in adults cytotoxic T cells and interferon-stimulated subpopulations were significantly increased. We provide evidence that dendritic cells initiate interferon signaling in early infection, and identify novel epithelial cell states that associate with COVID-19 and age. Our matching nasal and blood data showed a strong interferon response in the airways with the induction of systemic interferon-stimulated populations, which were massively reduced in paediatric patients. Together, we provide several mechanisms that explain the milder clinical syndrome observed in children.
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Immunological memory is a hallmark of adaptive immunity and facilitates an accelerated and enhanced immune response upon re-infection with the same pathogen1,2. Since the outbreak of the ongoing coronavirus disease 19 (COVID-19) pandemic, a key question has focused on which severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cells stimulated during acute infection give rise to long-lived memory T cells3. Using spectral flow cytometry combined with cellular indexing of transcriptomes and T cell receptor (TCR) sequencing we longitudinally characterize individual SARS-CoV-2-specific CD8+ T cells of COVID-19 patients from acute infection to one year into recovery and find a distinct signature identifying long-lived memory CD8+ T cells. SARS-CoV-2-specific memory CD8+ T cells persisting one year after acute infection express CD45RA, interleukin-7 receptor α (CD127), and T cell factor-1 (TCF1), but they maintain low CCR7, thus resembling CD45RA+ effector-memory T (TEMRA) cells. Tracking individual clones of SARS-CoV-2-specific CD8+ T cells, we reveal that an interferon signature marks clones giving rise to long-lived cells, whereas prolonged proliferation and mammalian target of rapamycin (mTOR) signaling are associated with clonal disappearance from the blood. Collectively, we describe a transcriptional signature that marks long-lived, circulating human memory CD8+ T cells following an acute virus infection.
Irène Cai Yi's curator insight,
December 8, 2021 10:55 AM
des suggestion pour production de vaccination forte
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A defence response malfunctions in people with severe COVID-19.
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The viral receptor on human cells plays a critical role in disease progression
Gilbert C FAURE's insight:
You should know where virus attacks to fight against it
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Among the many activities attributed to the type I interferon (IFN) multigene family, their roles as mediators of the antiviral immune response have emerged as important components of the host response to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection.
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COVID-19 can involve persistence, sequelae, and other medical complications that last weeks to months after initial recovery. This systematic review and meta-analysis aims to identify studies assessing the long-term effects of COVID-19. LitCOVID and Embase were searched to identify articles with original data published before the 1st of January 2021, with a minimum of 100 patients. For effects reported in two or more studies, meta-analyses using a random-effects model were performed using the MetaXL software to estimate the pooled prevalence with 95% CI. PRISMA guidelines were followed. A total of 18,251 publications were identified, of which 15 met the inclusion criteria. The prevalence of 55 long-term effects was estimated, 21 meta-analyses were performed, and 47,910 patients were included (age 17–87 years). The included studies defined long-COVID as ranging from 14 to 110 days post-viral infection. It was estimated that 80% of the infected patients with SARS-CoV-2 developed one or more long-term symptoms. The five most common symptoms were fatigue (58%), headache (44%), attention disorder (27%), hair loss (25%), and dyspnea (24%). Multi-disciplinary teams are crucial to developing preventive measures, rehabilitation techniques, and clinical management strategies with whole-patient perspectives designed to address long COVID-19 care.
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Epstein-Barr virus (EBV) reactivation resulting from the inflammatory response to coronavirus infection may be the cause of previously unexplained long COVID symptoms—such as fatigue, brain fog, and rashes—that occur in approximately 30% of patients after recovery from initial COVID-19 infection. The first evidence linking EBV reactivation to long COVID, as well as an analysis of long COVID prevalence, is outlined in a new long COVID study published in the journal Pathogens. "We ran EBV antibody tests on recovered COVID-19 patients, comparing EBV reactivation rates of those with long COVID symptoms to those without long COVID symptoms," said lead study author Jeffrey E. Gold of World Organization. "The majority of those with long COVID symptoms were positive for EBV reactivation, yet only 10% of controls indicated reactivation." The researchers began by surveying 185 randomly selected patients recovered from COVID-19 and found that 30.3% had long term symptoms consistent with long COVID after initial recovery from SARS-CoV-2 infection. This included several patients with initially asymptomatic COVID-19 cases who later went on to develop long COVID symptoms.
The researchers then found, in a subset of 68 COVID-19 patients randomly selected from those surveyed, that 66.7% of long COVID subjects versus 10% of controls were positive for EBV reactivation based on positive EBV early antigen-diffuse (EA-D) IgG or EBV viral capsid antigen (VCA) IgM titers. The difference was significant (p < 0.001, Fisher's exact test). "We found similar rates of EBV reactivation in those who had long COVID symptoms for months, as in those with long COVID symptoms that began just weeks after testing positive for COVID-19," said coauthor David J. Hurley, Ph.D., a professor and molecular microbiologist at the University of Georgia. "This indicated to us that EBV reactivation likely occurs simultaneously or soon after COVID-19 infection." The relationship between SARS-CoV-2 and EBV reactivation described in this study opens up new possibilities for long COVID diagnosis and treatment. The researchers indicated that it may be prudent to test patients newly positive for COVID-19 for evidence of EBV reactivation indicated by positive EBV EA-D IgG, EBV VCA IgM, or serum EBV DNA tests. If patients show signs of EBV reactivation, they can be treated early to reduce the intensity and duration of EBV replication, which may help inhibit the development of long COVID. "As evidence mounts supporting a role for EBV reactivation in the clinical manifestation of acute COVID-19, this study further implicates EBV in the development of long COVID," said Lawrence S. Young, Ph.D., a virologist at the University of Warwick, and Editor-in-Chief of Pathogens. "If a direct role for EBV reactivation in long COVID is supported by further studies, this would provide opportunities to improve the rational diagnosis of this condition and to consider the therapeutic value of anti-herpesvirus agents such as ganciclovir."
Original findings published in Pathogens (June 10, 2021): https://doi.org/10.3390/pathogens10060763 Via Juan Lama
Clarisse Staehlé's curator insight,
December 5, 2022 11:11 AM
L’infection par le virus d’Epstein-Barr peut être une des causes de longs symptômes de COVID tes que : la fatigue, les éruptions cutanées …
Cela permettrait de traiter tôt les patients afin de réduire l’intensité et la durée de la réplication de l’EBV, ce qui peut aider à inhiber le développement d'un long COVID.
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The release of neutrophil extracellular traps (NETs), a process termed NETosis, avoids pathogen spread but may cause tissue injury. NETs have been found in severe COVID-19 patients, but their role in disease development is still unknown. The aim of this study is to assess the capacity of NETs to drive epithelial-mesenchymal transition (EMT) of lung epithelial cells and to analyze the involvement of NETs in COVID-19. Bronchoalveolar lavage fluid of severe COVID-19 patients showed high concentration of NETs that correlates with neutrophils count; moreover, the analysis of lung tissues of COVID-19 deceased patients showed a subset of alveolar reactive pneumocytes with a co-expression of epithelial marker and a mesenchymal marker, confirming the induction of EMT mechanism after severe SARS-CoV2 infection. By airway in vitro models, cultivating A549 or 16HBE at air-liquid interface, adding alveolar macrophages (AM), neutrophils and SARS-CoV2, we demonstrated that to trigger a complete EMT expression pattern are necessary the induction of NETosis by SARS-CoV2 and the secretion of AM factors (TGF-β, IL8 and IL1β). All our results highlight the possible mechanism that can induce lung fibrosis after SARS-CoV2 infection.
Michael Craver 's curator insight,
June 17, 2021 8:09 PM
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