Transmissions & Cell Entry / Fusion
Dr Xxxxx : Transmission is not by biological vectors, but – depending on the virus species – via fomites or via aerogenes and/or faecal–oral routes. As CoVids primarily target epithelial cells, they are generally associated with gastrointestinal and respiratory infections that may be acute or become chronic with prolonged shedding of virus. In general, these infections are mild and often asymptomatic. This is the current focus of our infection control strategies.
Erasmus : I have seen reports suggesting that coronaviruses are able to infect stratified squamous epithelia, (of the non-recognising type).
Dr Xxxxx : Of the coronaviruses in particular the SARS – CoV (severe acute respiratory syndrome coronavirus) attacks cells via the human angiotensin converting enzyme receptors. Unfortunately most of our ACE (angiotensin-converting enzyme inhibiting) drugs target the type I ACE receptor whereas the SARS – CoV virus targets the type 2 ACE receptors. Type 2 ACE receptors are common in the human respiratory tissues.
Polyclonal antisera directed against ACE2 blocked virus infection and replication, suggesting that hACE2 is the primary receptor for SARS-CoV infection of HAE.
SARS-CoV structural proteins and Virions localized to ciliated epithelial cells. Infection was highly cytolytic, as infected ciliated cells were necrotic and shed over time onto the luminal surface of the epithelium.
Erasmus : We’re going to break with our usual practice of highlighting existing technology and the aspirations of human imagination springing from this framework. We’re going to promote a technology from our own team – home-grown expertise.
Not the sort of Intensive Care We Need.
IIPI: Intensive Infection Process Intervention
Dr Xxxxx : IIPI: Intensive Infection Process Intervention
The basic premise of this process is that by inhibiting viral growth at successive stages of colonisation and infection, progressively greater levels of viral inhibition can be attained.
If you reduce viral replication by 10%, this gives a factor of 0.9
If you reduce viral replication at 2 interlinked steps each by a factor of 10%, this gives a replication inhibition of .9×.9 = 0.81
If you reduce viral replication at 3 interlinked steps, each by a factor of 10%, this gives a replication inhibition of .9×.9×.9=.73
What this means is that progressive inhibition at interlinked viral replication steps can give a substantial change to the clinical outcome.
Erasmus : Can you tell us anything about CoVid’s special Infection Strategies
Kinkajou: (reading news article) Recent studies show that in seizing control of genes in the human cells it invades, the virus changes how segments of DNA are read, doing so in a way that might explain why the elderly are more likely to die of Covid-19 and why antiviral drugs might not only save sick patients’ lives but also prevent severe disease if taken before infection.
CoVid 19 blocks one virus-fighting set of genes but allows another set to launch, a unique infection success strategy amongst viruses.
Influenza and the original SARS virus (in the early 2000s), for instance, interfere with both arms of the body’s immune response — what can be described as “call to arms” genes and “call for reinforcement” genes.
The first group of genes produces interferons. These proteins, which infected cells release, are biological semaphores, signaling to neighboring cells to activate some 500 of their own genes that will slow down the virus’ ability to make millions of copies of itself if it invades them. This lasts seven to 10 days, controlling virus replication and thereby buying time for the second group of genes to act.
The second set of genes produce their own secreted proteins, called chemokines that emit a biochemical “come here!” alarm. When far-flung antibody-making B cells and virus-killing T cells sense the alarm, they race to its source. If all goes well, the first set of genes holds the virus at bay long enough for the lethal professional killers to arrive and start eradicating viruses.
Interferon Immune Actions
“Most other viruses interfere with some aspect of both the call to arms and the call for reinforcements”. “If they didn’t, no one would ever get a viral illness”: The one-two punch would pummel any incipient infection into submission.
SARS-CoV-2, however, uniquely blocks one cellular defense but activates the other. They found that within three days of infection, the virus induces cells’ call-for-reinforcement genes to produce cytokines. But it blocks their call-to-arms genes — the interferons that dampen the virus’ replication.
The result is essentially no brakes on the virus’s replication, but a storm of inflammatory molecules in the lungs, which can be described as a “unique” and “aberrant” consequence of how SARS-CoV-2 manipulates the genome of its target.
Dr Xxxxx : In summary, CoVid produces a protein / chemical that blocks a cell’s capacity to respond to interferon. Interferon is not able to block viral replication ensuring increased severity and duration for CoVid infections- giving them a distinct nature, much different to the average cough or cold.
The Real Mechanism of Interferon Action.
This also means that the immune system gets pulled into the infection, exacerbating inflammation : giving the “cytokine storm” effect. This is responsible for the late stage damage and lung scarring in CoVid infections. It is probably the basis whereby dexamethasone and Hydroxychloroquine save lives ; by minimizing immune response damage and scarring to the lungs in particular. ( Fibrosing alveolitis , which is lung scarring from excess inflammation following the CoVid infection, is responsible for late deaths from CoVid). Reducing late immune damage through immunomodulation with hydroxychloroquine or immune suppression with dexamethasone would be a useful though a “late stage only” strategy.
Poor health and homeless is a big risk for health.
NEWS EXCERPT 2
In another new study, scientists in Japan last week identified how SARS-CoV-2 accomplishes that genetic manipulation. Its ORF3b gene produces a protein called a transcription factor that has “strong anti-interferon activity,” Kei Sato of the University of Tokyo and colleagues found — stronger than the original SARS virus or influenza viruses. The protein basically blocks the cell from recognizing that a virus is present, in a way that prevents interferon genes from being expressed.
In fact, the Icahn School team found no interferons in the lung cells of Covid-19 patients. Without interferons, “There is nothing to stop the virus from replicating and festering in the lungs forever.”
That causes lung cells to emit even more “call-for-reinforcement” genes, summoning more and more immune cells. Now the lungs have macrophages and neutrophils and other immune cells “everywhere,” causing such runaway inflammation “that you start having inflammation that induces more inflammation.”
At the same time, unchecked viral replication kills lung cells involved in oxygen exchange. “And suddenly you’re in the hospital in severe respiratory distress,” he said.
Diagram of the Respiratory Tree:
the primary COVID / Corona Virus target.
In elderly people, as well as those with diabetes, heart disease, and other underlying conditions, the call-to-arms part of the immune system is weaker than in younger, healthier people, even before the coronavirus arrives. That reduces even further the cells’ ability to knock down virus replication with interferons, and imbalances the immune system toward the dangerous inflammatory response.
In a study of human cells growing in lab dishes, described in a preprint (not peer-reviewed or published in a journal yet), he and his colleagues also found that SARS-CoV-2 “prevents the vast amount” of interferon genes from turning on. But when cells growing in lab dishes received the interferon IFN-1 before exposure to the coronavirus, “the virus has a difficult time replicating.”
After a few days, the amount of virus in infected but interferon-treated cells was 1,000- to 10,000-fold lower than in infected cells not pre-treated with interferon. (The original SARS virus, in contrast, is insensitive to interferon.)
Ending the pandemic and preventing its return is assumed to require an effective vaccine to prevent infection and antiviral drugs such as remdesivir to treat the very sick, but the genetic studies suggest a third strategy: preventive drugs.
It’s possible that treatment with so-called type-1 interferon “could stop the virus before it could get established,” Menachery said.
The vaccine: One Day ?
Giving drugs to healthy people is always a dicey proposition, since all drugs have side effects — something considered less acceptable than when a drug is used to treat an illness. “Interferon treatment is rife with complications,” Menachery warned. The various interferons, which are prescribed for hepatitis, cancers, and many other diseases, can cause flu-like symptoms. (Really nasty flu- like symptoms).
But the risk-benefit equation might shift, both for individuals and for society, if interferons or antivirals or other medications are shown to reduce the risk of developing serious Covid-19 or even make any infection nearly asymptomatic.
Interferon “would be warning the cells the virus is coming,” Menachery said, so such pretreatment might “allow treated cells to fend off the virus better and limit its spread.” Determining that will of course require clinical trials, which are underway.