06/04/2020
COVID-19 – WE Have Questions ?
Over the past months, we have been told a lot about the COVID-19 pandemic and the SARS-CoV-2 virus that causes it. Also in the information space "flies" a lot of different rumors and alternative information - truthful and not.We learn a lot all the time - but is it really so?
The number of scientific articles on the SARS-CoV-2 virus is increasing and increasing, however, there are still many dark areas regarding its origin.
Let’s take into account only the official statements and see how everything will look from different angles. So. What animal species did this virus spread to humans?To us, some genetic scientists answered and showed evidence that the greatest likelihood of such a transmission is the path from the bat to people.
Other genetic scientists claim that the intermediate transmission occurred through palm civet or through lizards, or through ... another species of wild animal. All versions are good - the main thing is that the transmission path remains within the boundaries of the ANIMAL-HUMAN model.
Okay. If we take this model as a basis, then the possibility of spreading and transmitting the virus to humans through the market with wild animals (close contact or eating) is also understandable.Then another question, why in the Chinese province of Hubei, and not somewhere else?
Why didn’t this happen in another place where these animals also exist and the conditions for the possible spread of the NATURAL MUTING virus? From official data: in December 2019, 27 people from the first 41 hospitalized people (approximately 66% of people) were in a market located in the center of Wuhan in Hubei province, where wild animals are sold. However, they cannot provide us with medical data on the so-called primary patient (patient No. 0).
And to the real patient. Perhaps this state of affairs will become clear if this fact is taken into account: according to the initial study of the material, from the very first detected case of a human disease with the SARS-CoV-2 virus, with further elaboration of the movements, it will become clear that the patient of the Wuhan hospital with the “FIRST IDENTIFIED CASE "generally NEVER visited this market!
Moreover, an assessment of molecular dating based on the genomic sequences of SARS-CoV-2 indicates their rather STRANGE origin (part of the genome has a strange non-natural character - at least it is difficult to imagine the natural possibility of such a mutation), and in the period October-November 2019 year.This raises further questions about the reality of the link between the COVID-19 pandemic and wildlife.
Genomic data:
After laboratory samples were provided, the SARS-CoV-2 virus genome was sequenced. Comparative genomic analysis showed that SARS-CoV-2 belongs to the group of beta-coronaviruses and that it is very close to SARS-CoV, responsible for the epidemic of athepatic pneumonia that appeared in November 2002 in the Chinese province of Guangdong, after which it spread to 29 countries .
Then, as indeed now, it was argued that the source of transmission of the virus to humans was bats of the genus Rhinolophus (potentially indicating a possible pathway for mutating the virus in several species of cave bats). Bats are known to have been the reservoir of this virus.
However, a palm civet (Paguma larvata) could become a similar reservoir. Moreover, by sequential coincidence, palm civet could well serve as an intermediate host (at least in the first cases of human diseases). There are many beta coronaviruses. Some of them may be in people. But the interesting thing is that so far only 3 of them behave differently when in contact with a person.
They differ in the genome and mutational manifestations and even suggest an unnatural origin. Moreover, if we talk about SARS-CoV (2003-2004), then it was directly stated that the “clone” of this virus was isolated in several laboratories. Today it is said and confirmed that the SARS-CoV and SARS-CoV-2 viruses in the genome sequences are very similar to each other. Their identity, according to various experts, is about 96%.
The question arises:
If SARS-CoV could be artificial (at least with a repeated small outbreak of the SARS epidemic) and it is very similar to the current SARS-CoV-2, then what do we have today?
Let's go back to the natural carriers of coronaviruses. For example, it was discovered that another RaTG13 virus isolated from a bat was described as very similar to SARS-CoV-2. Consequently, animals of different species can be carriers of several very similar deadly viruses, while they only remain reservoir.
How should this be understood and evaluated? In this case, a reservoir is one or several species of animals that are not very sensitive to a particular virus or not very sensitive to a group of viruses that are in them. In vivo, they somehow do not have any symptoms of the disease. Nevertheless, these same viruses in mutagenic manifestations in other organisms become quite dangerous and ultimately even fatal. Not the effect of the virus on a living organism (the host cell) is explained by one very important parameter - the efficiency of their immune system, which allows you to fight the excessive spread of the virus.
Recombination mechanism:
On February 7, 2020, as a result of research, scientists from China, with the assistance of Australian colleagues, discovered a virus very similar to SARS-CoV-2. However, a subsequent review study showed that the genome of a coronavirus isolated from Malaysian pangolin (Manis javanica) is similar to SARS-Cov-2, with only 90% genomic consistency. This is less than genomic consistency with the virus from the bat. This seems to indicate that the virus isolated from the lizard is not responsible for the COVID-19 epidemic, which is currently raging.
But...
96% of the similarities between bat coronaviruses and today's human coronavirus are in the entire genome. If we take specifically its S segment (the S gene encodes a protein located on the surface of the viral envelope and is responsible for the attachment of the virus to the host cell), then in this segment the similarity of bat and human coronaviruses will be 76.8%. However, coronavirus isolated from pangolin in a specific region of protein S is 99% similar to the same segment of human coronavirus. It also more closely matches the 74 amino acids involved in the binding domain of the ACE2 receptor (angiotensin-converting enzyme 2), which allows the virus to pe*****te human cells and infect them.This means that coronavirus isolated from pangolin is more able to pe*****te human cells, but is less identical to SARS-Cov-2 virus, while coronavirus isolated from bat is more identical to SARS-Cov-2 virus, but less able to pe*****te the cell person. There is such a paradoxical situation at first glance.
But this is only at first glance.
More detailed genomic comparisons in specific parts (segments) show that the SARS-Cov-2 virus is the result of recombination between two different viruses. Moreover, one area (replicative pattern) is close to the bat virus, and the other is closer to the pangolin virus. In other words, it is a chimera between two pre-existing viruses. The meaning of a chimera is usually used in a figurative sense, to mean something unreasonable or unrealizable. However, in the case of Novel Coronavirus (2019-nCoV) / COVID-19, it turned out to be POSSIBLE! It is also very important to understand that recombination leads to a new virus that is potentially capable of infecting a new host species. However, for such a recombination to occur under natural conditions, it is necessary that two, diverging viruses, SIMULTANEOUSly infect the host cell at the same time period in the same organism. It is VERY, VERY and VERY hard to believe in a natural mutation. However, in the laboratory, in an artificial way, this is completely possible!
So, the following two questions remain without an affirmative answer:In what organism did this “NATURAL” recombination take place? And, first of all, under what conditions did this "NATURAL" recombination take place, given that the bat and pangolin in natural nature have NOT MET EVER? To date, the “OFFICIAL” version of the primary source of the SARS-CoV-2 pandemic is that bats were the source.But in order for the virus to be transmitted from a bat to humans, an intermediate animal is necessary - this is a well-known fact. Moreover, in previous coronovirus epidemics (SARS-CoV and MERS-CoV), such intermediate animals were at least designated.
With the latest COVID-19 pandemic, a transitional animal species in which the SARS-CoV-2 virus would mutate to the “human” variant has not been found !!!
Officially answer like this: Since the market in Wuhan, which is associated with the outbreak of a new coronavirus infection, has been eliminated, the search for an intermediate animal carrier of the coronavirus is not possible.
A distinctive feature of the new SARS-CoV-2 coronavirus is its ability to rapidly spread. This also distinguishes him from the two previous pandemiological “brethren” (SARS-CoV and MERS). However, unlike them, it is not so dangerous, since it has a lower mortality rate (about 9.6%, for SARS-CoV, about 36%, for MERS, and so far about 5.4%, for COVID-19 (SARS-CoV-2 ) respectively).
For reference:
The most transmitted virus between people is measles virus. One person can infect measles in the next 11-18 people. SARS-CoV-2 can be transmitted to 3-4 people.
How can COVID-19 Disease really occur?
Asymptomatic, mild, or bed-like form of the disease will be in 81.5% of peopleHospitalization will require about 13.8% of peopleIntensive care will be needed 4.7% Moreover, the disease mostly affects the oldest age-old category of people - more than 83% of sick people requiring medical intervention or intensive care are people aged 60+.
Where and how can a SARS coronavirus enter a host cell?The ACE2 gene encodes an angiotensin converting enzyme-2, which has been proven to be a receptor for both SARS-coronavirus (SARS-CoV) and human respiratory coronavirus NL63. Studies and analyzes show that ACE2 can be the host receptor for the new 2019-nCoV / SARS-CoV-2 coronavirus.
Although, based on official statements, a systematic analysis of coded-region variants in ACE2 and eQTL variants did not reveal direct, genetically confirmed evidence for the existence of ACE2 mutants that are resistant to the binding of coronavirus S-protein in different populations, in reality it is observed that, in populations of East Asia, AFs, Novel Coronavirus (2019-nCoV) / SARS-CoV-2 / COVID-19 in eQTL variants was much higher, and was associated with higher expression of ACE2 in tissues. This indicates that, in different populations under similar conditions, 2019-nCoV / SARS-CoV-2 has a different susceptibility and / or reaction. In certain parts of the SARS-CoV-2 viral genome, "natural oddities" of NOT NATURAL origin were observed. For example, in segments nsp3, nsp12, Orf8b, Orf9. By the way, these same "natural oddities" were observed in the last phase of the SARS epidemic in 2004.
QUESTIONS? QUESTIONS? QUESTIONS?
FOR REFERENCE:
Description of the action of viral genes and proteins, as well as cellular responses to their actionExplanation of the description: First, the nomenclature of the gene is given (the number of amino acid residues is indicated in parentheses), the gene product and / or its characteristics are described below, as well as the possible effect of this gene on the host cell response.
1. Orf1a / b. Not described
2.nsp1 (180). Expression promotes the degradation of endogenous host mRNA, which can inhibit host protein synthesis and prevent the accumulation of endogenous IFN-β mRNA. It induces the expression of CCL5, CXCL10 (IP10) and CCL3 in human lung epithelial cells by activation of NF-κB, and also enhances the degradation of cellular RNA, which can promote SARS-CoV replication or block immune responses.
3.nsp2 (638). Removal weakens the growth of the virus and subsequent RNA synthesis.
4.nsp3 (1922). Papain-like protease 2 provides proteolytic processing of viral polyprotein at 3 sites and takes part in the synthesis of the subgenomic RNA segment. Another action is via ADP-ribose-1-phosphatase (ADP-ribose 1-phosphatase), which dephosphorylates Appr-1 ‴ -p (a by-product of tRNA cell splicing), to ADP-ribose. The putative catalytic triad (Cys1651-His1812-Asp1826) and the zinc binding site have deubiquitinating activity; this unexpected activity in addition to its papain-like protease offers a new viral. a strategy for modulating the mechanism of ubiquitination of host cells.
5.nsp4 (500). Not described.
6.nsp5 (306). 3C-like protease, provides proteolytic processing of replicative polyprotein at 11 specific sites with the formation of key functional enzymes, such as replicase and helicase. In SARS-CoV, growth arrest and apoptosis using caspase-3 and caspase-9 activity were demonstrated in 3CLpro-expressing human promonocyte cells with increased activation of the nuclear factor κB-dependent reporter.
7.nsp6 (290). Not described.
8.nsp7 (83). Nuclear magnetic resonance research has discovered potential sites for protein interactions. So far, only a three-dimensional structure has been described.
9. nsp8 (198). The putative RNA-dependent RNA polymerase is the crystal structure of the nsp7-nsp8 hexadecamera and has a central channel with positive electrostatic properties and sizes favorable for nucleic acid binding. This is probably another unique RNA-dependent RNA polymerase of the large genome.
10.nsp9 (113). The three-dimensional crystal structure of a dimer that binds viral RNA and interacts with nsp8.
11. nsp10 (139). A crystalline structure that has the function of nucleic acid binding in a larger complex of RNA-binding proteins for transcription and replication of viral genes. Specifically interacts with the NADH 4L subunit and cytochrome oxidase II with depolarization of the inner mitochondrial membrane of a transfected human lung fibroblast. It has a pronounced cytopathic effect.
12. nsp11 (13). Not described.
13. nsp12 (932). RNA-dependent RNA polymerase replicates and transcribes to produce RNA, the bipolar dimension of the gene with the subgene.
14. nsp13 (601). Helicase (dNT phase and RNA 5'-triphosphatase activity).
15. nsp14 (527). 3 '→ 5'-exoribonuclease. Its unusual 3 ′ → 5′-exoribonuclease activity complements the endoribonuclease activity in the replication of the giant RNA genome.
16. nsp15 (346). Uridylate-specific RNA endonuclease that is critically involved in the coronavirus replication cycle.
17. nsp16 (298). Alleged 2'-O-ribose methyltransferase (2'-O-ribose methyltransferase).
18. Orf2 (1.255). Spike protein. It binds to the ACE2 host cell receptor and other coreceptors, mediates the pe*******on of the virus into host cells as a type 1 viral fusion protein. However, endosome acidification is required for effective S-mediated viral pe*******on. For fusion, protease activation and proteolytic cleavage by abundantly expressing factor Xa is required to bind to the membranes of the virus and infected cells (S1 and S2). T cells (after IL-2 activation) respond to transfected ACE2, which can form a bond with an expressing viral spike followed by a significant accumulation of protein S in the endoplasmic reticulum, which can modulate virus replication, thereby increasing acute pulmonary failure.
19. Orf3a (274). Forms an ion channel sensitive to potassium, contributing to budding and subsequent isolation of the virus. Overexpression of Orf3a in the cell line can cause apoptosis. Its expression in lung epithelial cells A549 increases the level of mRNA and the intracellular and secreted levels of all three subunits - alpha, beta and gamma, as well as fibrinogen. With overexpression of Orf3a, an increase in the production of inflammatory chemokines is also observed (in large quantities, they are activated by SARS-CoV infection).
20. Orf3b (154). It is mainly localized in the nucleolus of various transfected cells. Orf3b inhibits IFN-β expression in signal synthesis and transmission. With the expression of Orf3b, cells can undergo simultaneous necrosis and apoptosis within 6 hours after transfection, but this action can occur at later times.
21. Orf4 (76). The shell protein, which in flat lipid bilayers creates ion channels that become more permeable to monovalent cations, compared with the permeability of monovalent anions. Presumably involved in the nucleation and release of the virus. Over time, it induces apoptosis in transfected Jurkat T cells, especially in the absence of growth factors.
22. Orf5 (221). Membrane surface protein responsible for viral assembly and budding. M-protein induces apoptosis in cells, which can be suppressed by caspase inhibitors.
23. Orf6 (63). A membrane protein that accelerates the replication and virulence of recombinant murine coronavirus. Inhibits synthesis and IFN signaling. Inhibits nuclear translocation, but not phosphorylation of STAT1. Orf6 is localized in the endoplasmic reticulum / Golgi membrane of infected cells, binds and disrupts the formation of a nuclear import complex, linking karyopherin alpha 2 and karyopherin beta 1 to the membrane. This retention of the complex leads to the loss of STAT1 transport to the nucleus, despite the induced viral RNA IFN signaling. Thus, Orf6 blocks the expression of STAT1-activated genes, which are necessary for establishing the antiviral state.
24. Orf7a (122). A unique type I transmembrane protein that participates in the assembly of the virus by interacting with M and E (necessary for the formation of virus-like particles when co-expressed with S and N). Expression of Orf7a induces apoptosis via a caspase-3-dependent pathway in cell lines originating from different organs, but especially in the lungs, kidneys and liver.
25. Orf7b (44). Not described.
26. Orf8a (39). Orf8a was localized in the mitochondria, and its overexpression led to an increase in the mitochondrial transmembrane potential, production of reactive oxygen species, caspase-3 activity, and cell apoptosis. Orf8a enhances virus replication and induces apoptosis via the mitochondrial dependent pathway.
27. Orf8b (84). May modulate virus replication.
28. Orf9 (422). Nucleocapsid protein. Binding and packaging of viral RNA in the assembly of the virion, N-antagonized IFN by inhibiting the synthesis of IFN-β. It can cause pneumonia by activating COX-2 gene expression by binding directly to the promoter, leading to inflammation through numerous COX-2 signaling cascades. It leads to induced reorganization of actin in cells lacking growth factors.
29. Orf9b (98). The crystal structure of Orf9b can participate in attachment to the membrane and associate with intracellular vesicles, which indicates that Orf9b plays one of the roles in the assembly of the virion.
Mortality from Covid19 has not yet affected the statistics on total annual mortality in Europe.
In recent years, official statistics for 24 European countries show that not only the overall mortality rate does not increase, but, for now, is actually much lower than the latest average annual and intermediate indicators.
The statistics are compiled by the European Monitoring of Excess Mortality for Public Health Action (EuroMOMO - European Mortality Monitoring Agency). The data presented resulted from an international partnership of institutions from 24 European countries. The purpose of this data collection is declared to be to promote public health emergency preparedness.
This project tracks “excess mortality,” that is, the number of officially registered deaths compared to average mortality. Each country is disaggregated by age demography.
As we see at the 12th week of 2020 (March 19-25) in the vast majority of European countries there is no excess mortality. This means that mortality is at the expected level.
The one obvious exception is Italy. But note that mortality is classified as "high" (High 5; 7), but not "very high" (Very high> 7), as, for example, it was in Europe in previous years.
So today, in Europe, Italy is the country most affected by the coronavirus pandemic. Events in Italy give rise to harsh quarantine conditions, not only in Italy but also in other European countries. The main reason for this is high mortality and the rapid spread of the virus.
However, for comparison, let's look at the same mortality map, only in previous years (please note this is the statistics of the same agency)
In 2019, in a global sense, Europe was much worse.
France has a "very high" mortality rate (Very high> 7)
In Spain and Portugal, mortality is classified as "high" (High 5; 7) - at the same level as today in Italy
In several other countries, mortality is classified as “above average”
Nevertheless, in 2019 there was no quarantine and no blocking of movement.
DO YOU HAVE QUESTIONS?
It was the height of the huge flu season 2017-2018. As you can see, Europe then also suffered rather badly in terms of "excess mortality."
However, in 2018 there was nothing similar in terms of blocking movement. And no one declared a global epidemic.
ARE ANY QUESTIONS?
According to the results of “excess mortality”, the 2nd week of 2017 was probably even worse than the situation now, because almost the entire western part of Europe and especially the Mediterranean countries had a huge surge in “excess mortality”
And in 2017, the flu virus or “excess mortality” as a result of “something”, otherwise, did not lead to the announcement of an epidemic or the closure of borders
The question naturally arises:
Or maybe "excess mortality" is just a NORMAL PHENOMENON for this period of the year?
For example, in its current form, so far, the indicators of "excess mortality" in 2020 are lower than the indicators of "excess mortality" in 2017.
Then the question is:
IF THERE WAS NO QUARANTINE AND FREEDOM OF MOVEMENT IN THE FIRST MONTHS OF 2017, NOT IN 2018, NOT IN 2019 - SO WHY DO WE ALL HAVE IT TODAY?
