转发 I've been up studying COVID-19 for the past few weeks for a substantial portion of every day, and I've come to a few very disturbing conclusions about the virus. It may have the potential to cause antibody-dependent enhancement of disease, like Dengue flavivirus. SARS had the same capability, and due to the genetic similarities between SARS-CoV and SARS-CoV-2, ADE can't be ruled out. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3019510/
Taken together, our data suggested that SARS-CoV is able to enter human immune cells via an antibody-mediated pathway and immunological consequences of such infection are under investigation (productive replication, cytokines secretion profile and cell death etc). Our data raise reasonable concerns regarding the use of SARS-CoV vaccine in humans and pave the way to further studies focusing on the role of immune-mediated infection phenomenon during SARS pathogenesis.
Our results showed 37 that mAb binds to the virus -surface spike, allowing it to undergo conformational changes 38 and become prone to proteolytic activation. Meanwhile, mAb binds to cell-surface IgG 39 Fc receptor, guiding viral entry through canonical viral-receptor-dependent pathways. 40 Our data suggest that the antibody/Fc-receptor complex functionally mimics viral 41 receptor in mediating viral entry. Moreover, we characterized mAb dosages in viral42 receptor-dependent, antibody-dependent, and both-receptors-dependent entry pathways, 43 delineating guidelines on mAb usages in treating viral infections. Our study reveals a 44 novel molecular mechanism for antibody-enhanced viral entry and can guide future 45 vaccination and antiviral strategies.
I keep hearing rumors about individuals "relapsing" with the disease and getting sicker and sicker with pneumonia before expiring. It may be a clue that the virus is actually hijacking immune cells by using weak or improper antibody response to hitch a ride into immune cells. Normally, with Dengue, that only happens if someone gets infected with a different strain. With COVID-19, it may be the case that it's doing this with the same strain, causing people to become reinfected and severely ill as a consequence. I confess that I don't understand how that could be possible, or what the exact mechanism behind this could be. It may be that I'm misreading this and misunderstanding the science behind it. I keep hearing reports of people having "weak antibodies" and not becoming properly immune, and if ADE is actually the culprit here, the consequences could be severe. https://www.usatoday.com/story/news/nation/2020/02/19/coronavirus-after-2000-deaths-can-you-get-virus-again/4804905002/ This would be terrible news if true, because it would mean that herd immunity would be difficult to develop, allowing the virus to be transmitted with impunity. It would also mean that China's plan to ease quarantine restrictions and send people back to work before their economy collapses would be doomed from the outset. People would start getting sick again almost immediately. It would be a disaster. It already is a disaster. I hear that Chinese doctors are using serum antibodies from recovered patients to cure critically sick people, with considerable success. This is another clue. Some people may possess the right characteristics to produce potent antibodies that are effective against the virus, while others may not. However, these phenomena have not been fully investigated or confirmed with SARS-CoV-2, yet, so all of this is just my own speculation coupled with what we already know about SARS-CoV. It would have to be studied experimentally. It may also be causing immune sensitization and cytokine storms, leading to a great deal of tissue damage. Some case studies of patients seem to indicate a highly overactive cytokine response that caused excess inflammation and basically obliterated a patient's alveoli. https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(20)30076-X/fulltext
Peripheral blood was prepared for flow cytometric analysis. We found that the counts of peripheral CD4 and CD8 T cells were substantially reduced, while their status was hyperactivated, as evidenced by the high proportions of HLA-DR (CD4 3·47%) and CD38 (CD8 39·4%) double-positive fractions (appendix p 3). Moreover, there was an increased concentration of highly proinflammatory CCR4+CCR6+ Th17 in CD4 T cells (appendix p 3). Additionally, CD8 T cells were found to harbour high concentrations of cytotoxic granules, in which 31·6% cells were perforin positive, 64·2% cells were granulysin positive, and 30·5% cells were granulysin and perforin double-positive (appendix p 3). Our results imply that overactivation of T cells, manifested by increase of Th17 and high cytotoxicity of CD8 T cells, accounts for, in part, the severe immune injury in this patient.
Lastly, and most disturbingly, the way the virus binds to ACE2 receptors may allow it to severely dysregulate the angiotensin-renin system of the body, potentially causing cardiopulmonary damage by directly affecting blood pressure. This is another thing that SARS-CoV does, which SARS-CoV-2 is most likely doing as well, given that it also binds to ACE2 receptors with a high degree of affinity in order to enter cells. https://www.futuremedicine.com/doi/10.2217/fvl.10.4
Viruses critically depend on host cell-encoded proteins and corresponding mechanisms to ensure their survival and replicative success. As a consequence, many host cell proteins are important contributors to the complex process of viral pathogenesis [15]. Cell surface components that are exploited as primary receptors to mediate viral entry represent the most obvious host cell proteins involved in establishment of a viral infection. Following target cell entry, several viruses are known to induce downmodulation of receptor expression. As a result, natural physiologic functions of these host cell components may be seriously impaired, with accompanying pathogenic consequences for infected cells, organ or individual. Paradoxically, viruses strongly benefit from downregulation of receptor expression [16], since it leads to controlled and productive infectious processes. Receptor downmodulation prevents infection of cells in which viral replication is already progressing [17], and is often needed to ensure efficient release of viral particles [18]. A number of viruses are known to induce cellular receptor modulation, including HIV, measles virus, influenza C virus and human herpes virus type 6 [19–22], as well as CoVs. Two integral proteases of the renin–angiotensin system (RAS), a major physiologic regulator of the cardiovascular system, facilitate cellular entry of several HCoVs: angiotensin-converting enzyme (ACE)2 and neutral aminopeptidase (aminopeptidase N [APN]) [23–26]. Here, we will discuss the interaction of SARS-CoV, HCoV-NL63 and HCoV-229E with renin–angiotensin proteases during their cellular entry, and the pathogenic consequences of HCoV-induced RAS dysregulation by receptor downmodulation at the primary site of infection.
The novel coronavirus 2019 (COVID-19) infected patients by binding human ACE2, leading to severe pneumonia and highly mortality rate in patients. At present, there is no definite and effective treatment for COVID-19. ACE2 plays an important role in the RAS, and the imbalance between ACE/Ang II/AT1R pathway and ACE2/Ang (1-7)/Mas receptor pathway in the RAS system will lead to multi-system inflammation.
Many SARS vaccines have been tested over the past 17 years, but most of them were failures. They provoked T-helper immunopathology, excess cytokine release, and organ damage. They sensitized the lab animals' immune systems, causing an over-exuberant immune response that damaged lung tissues. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0035421
An early concern for application of a SARS-CoV vaccine was the experience with other coronavirus infections which induced enhanced disease and immunopathology in animals when challenged with infectious virus [31], a concern reinforced by the report that animals given an alum adjuvanted SARS vaccine and subsequently challenged with SARS-CoV exhibited an immunopathologic lung reaction reminiscent of that described for respiratory syncytial virus (RSV) in infants and in animal models given RSV vaccine and challenged naturally (infants) or artificially (animals) with RSV [32], [33]. We and others described a similar immunopathologic reaction in mice vaccinated with a SARS-CoV vaccine and subsequently challenged with SARS-CoV [18], [20], [21], [28]. It has been proposed that the nucleocapsid protein of SARS-CoV is the antigen to which the immunopathologic reaction is directed [18], [21]. Thus, concern for proceeding to humans with candidate SARS-CoV vaccines emerged from these various observations.
My fear is that they may attempt to fast-track a vaccine, only to find that it fails in trials over and over again due to cytokine sensitization and/or ADE, leading to poor clinical outcomes and forcing them to go back to the drawing board. If that were to happen, and if sustained outbreaks were to occur in various places across the globe with no vaccine to counter them, the loss of life would be unbelievable. Without a vaccine, what do we have to fight this? Well, this is what I'm looking at right now: Remdesivir & Chloroquine. Inhibit RNA replication of the virus. Remdesivir seems to have potent activity against SARS-CoV-2 replication, but this has not been experimentally confirmed with good sample sizes and controls. CytoSorb. An adsorbent material consisting of special polymer pellets with tiny pores to trap excess cytokines. Filters blood extracorporeally. Losartan and Telmisartan. Angiotensin blockers to try and keep the virus away from ACE2 receptors. Vasodilators & Vasopressors to help regulate blood pressure in case of ACE2 dysregulation. There isn’t enough. There isn’t enough of any of this medication to deal with the number of infected we would have in a pandemic scenario. CytoSorb and similar extracorporeal blood therapies are extremely rare boutique therapies that are only available to a number of critically ill patients numbering in the hundreds worldwide. I am so afraid right now, you have no idea. I am experiencing unmanageable levels of distress from having delved into this. I only hope that this compiled information is useful to someone.
这也许能解释为啥 COVID-19 的病人 CD4 and CD8 T cells 都降低很多
因为抗体跟 COVID-19 的 S 蛋白结合
然後任何有 Fcγ receptor 的细胞都因为 antibody-mediated enhancement 而感染
原始 link 是:
https://www.reddit.com/r/China_Flu/comments/f8acpe/clinical_features_of_covid19_i_am_very_very/
谢谢分享!
最新文章说小孩和大人的危害性一样
理论依据是什么？