Hope everything is fine.

SARS-CoV-2 attacks human respiratory tract lining cells and get attached to ACE2 receptor mostly by it's spikes. Later on it pushes it's RNA genome inside the cell and reproduces. In response humans recognize the foreign pathogen binding with MHC-I and MHC-II, and hopes for the action of T-Cell antibodies.

Precisely, I am not a biologist, so pardon me for wrong informations, if any. Here I provide link for a paper which may be useful to read.

Article Genotype and phenotype of COVID-19: Their roles in pathogenesis

Also I attach my recent paper in the hope that you may find it interesting enough.

Conference Paper New Computational Analysis to Identify the Mutational Change...

I am agree with Tathagata

https://www.researchgate.net/publication/341654297_Covid-19_A_Silent_Killer

This paper has lot lot of information

Only few publications of COVID-19 Pathology including post-mortem studies have been published, including:

1. Article Histopathologic Changes and SARS–CoV-2 Immunostaining in the...

2. Preprint Pulmonary post-mortem findings in a large series of COVID-19...

3. Article Autopsy in suspected COVID-19 cases

4.Article COVID-19 Autopsies, Oklahoma, USA

5. Article Thromboembolic Findings in COVID-19 Autopsies: Pulmonary Thr...

In a nutshell: When the virus enters the cell, intracellular recognition complexes called RIG-1 and Nod-Like-Receptors recognize viral RNA, activates a kinase that relases Nuclear Factor - Kappa/Beta from iKappa/Betta, then this protein translocate to the nucleous to stimulate the expression of IL-1, TNF-alfa and INF-alfa/Beta. These Cytoquines attracts APC cells and naive T-Cells, then IL-6 expression starts and cytoquine strorm happens. After MHC-1 pressentation from APC cells, Cytotoxic T Cells and NK Lymphocites are recruited to the site of infection. IL-6 stimulates the expression of INF- γ that has a cytolytic effect on NK Lymphocytes, decreasing their survival, therefold eliminating the main regulator of this response resulting in the extensive lung compromise and cytoquine storm that characterises COVID19.

https://www.researchgate.net/publication/342165639_Covid_19_-A_General_Review_for_Dental_Care_Provider_and_Patient

Look at my 1983 articles (J. of Trauma and JCI) on animal models of acute lung injury that involve compliment activation and activation of wbc NADPH oxidase to produce superoxide, O2 dot minus. With superoxide comes hydrogen peroxide. With presence of "free iron". Fe+++ comes the opportunity for superoxide to reduce the iron to Fe++. Fe++ is a thermodynamically appropriate catalyst of the reduction of the O-O bond to OH minus (H2O) and OH dot, the hydroxyl radical, a most highly oxidizing molecule that cannot easily be quenched stoichiometrically in vivo; and it has no enzyme adversary as superoxide and catalase do. SARS activates NF-kB that is a transcription (not translation) factor that when activated migrates to the nucleus and binds onto promotor genes responsible for cytokine and oxidative stress storms. The common view is that the pathophysiology is a "cytokine storm". In my two articles the animal models of acute lung injury disease are inhibited by PEG catalase and iron chelators. My clinical experience is that early to moderate COVID-19 disease can be treated with 1) NF-kB downregulators; 2) Nrf2 uprregulators, 3) pentose shunt facilitators, this last rx being due to the glucose metabolite dependency in Pentose Shunt pathways of Nrf2 upregulation, facilitation of survival of endothelial progenitor cells, counteraction of vasocontrictive properties of peroxynitrite (superoxide + NO ---> ONOO minus or peroxynitrite, a vasoconstrictant). I contacted Joe M. McCord in January to suggest that his Nrf2 like NF-kB is a transcription factor but when activated or upregulated it migrates to the nucleus and binds onto the promotor genes that result in anti-cytokine storm and anti-oxidative stress storm related effects + others as mentioned below. Nrf2 upregulator, PB125, should be a inhibitor of COVID-19. He subsequently found that PB125 downregulates the gene responsible for the membrane peptidase necessary for spike protein modification so the spike fits the ACE2 lock; PB125 activate PAI-1 inhibition of spike protein binding; it counteracts virus induced redox imbalance that assists the virus in taking over cell replication machinery; it helps dampen down the cytokine storm; it induces superoxide dismutase, catalase, glutathione peroxidase; it protect Nrf2 from deactivation by an activated NF-kB. So my model is one of: 1) an oxidative stress storm (It is the hydroxyl radical, not superoxide, STUPID as my mental reminder); 2) there is a microangiopathy in which there is endothelial dysregulation and damage such that inflammatory fluid goes into the alveolar space and there is activation of fibroblasts to produce fibrosis; 3) the hydroxyl radical polymerizes VWF to create microemboli that contribute (plus the microangiopathy) to multiorgan damage and failure. In a limited number of patients with active disease I have seen APPARENT success in using my three component set of therapies. In reserve, I have an inhibitor of NADPH oxidase (and Angiotensin I) that does lower blood pressure in humans. The link with the comorbidities of Diabetes, Obesity, Cardiovascular disease as active hypertension is via the involvement of oxidative stress in all three of these clinical entities that feeds into the oxidative stress caused by the virus. My model emphasizes the two "master switches" of redox balance, NF-kB and Nrf2 that play a role in the pathophysiology of diabetes, hypertension, congestive heart failure, angina, obesity induced inflammation and oxidative stress, arteriosclerosis, lipoprotein E related disease, reperfusion injury, ARDS, other acute lung injuries that evade labeling as ARDS, some DNA damage disease, activated macrophage, neutrophil, microglial....disease, other cardiovascular disease as arrhythmias (H2O2 is an ambient signal in arrhythmia signaling pathways), microvascular angina, heart disease that is the greatest killer of postmenopausal women, apoptosis (Nrf2 upregulation good in good cells, bad in bad cells), miscarriages, premature births, infant motality, disparities in outcomes (AN (not THE) explanation for disparities in outcome between indigenous peoples, African Americans, Hispanic peoples, Asian peoples, Pacific Islanders, Caucasians, men and women...), degenerative neurological diseases including MS (dimethyl fumarate is a Nrf2 upregulator that helps prevent flares), Parkinson's Disease (explanation given in Scientific American about iron and hydroxyl radical involvement in pathophysiology), Alzheimer's disease (amyloid is a byproduct not THE pathophysiology of a fundamentally microvascular and atrophying (due to ischemia) disease, Huntington's Chorea, Rheumatoid Arthritis & Psoriasis increased cardiovascular mortalities, photoaging (it can be inhibited by antioxidants that decrease reperfusion injury (why does sunburn burn?), ALL RNA virus disease, systemic inflammatory reaction disease, disease causing multi-organ failure, eye disease including age-related macular degeneration, glaucoma, keratoacanthosis, cataracts, diabetic retinopathy - remember there are a lot of endothelial cells in the eye, a component of diabetes complications as renal disease, peripheral neuropathy (a neurovascular disease), diabetic cardiomyopathy, diabetic retinopathy, diabetic gastroparesis...., some carcinogenic events including those associated with chronic inflammatory infiltrates as ulcerative colitis, the lingering pathophysiologies of long departed critters as with "chronic Lyme disease", the CNS side effects of malaria, contributory toward sickle cell disease pain and syndromes, some "lifespan diseases" including those involving declining mitochondrial function in high energy production with shift of production to the glycolytic cycles that produce far less efficient energy and more chaotic glucose metabolism outside the pentose shunt that produces beaucoup oxidative stress, sepsis induced vascular dysregulation, erectile dysfunction (remember ED can cause ED)......etc....etc....etc

Oxidative stress, out of sight out of mind to most all physicians, but oh so important. We are all rusting, some faster and some slower than others.

Hi all participants and have a nice week. In the following RG open question I attempt to search causes of the Lombardia hyper cluster of COVID19,

https://www.researchgate.net/post/The_novel_Coronavirus_in_N_Italy_Lombardia_COVID19_2019nCoV_SARSCoV2_shows_a_fatality_rate_compatible_with_SARS-MERS_Why

a very worst case.

In order to obtain data, there are extensive bibliographical lists about

--oral-fecal contagion

--chemicals vs. SARS-CoV/2

--receptor ecosystem

--animal reservoirs

--Guillain-Barrè syndrome

-- co-infection (other local CoV)

-- comparative data vs. others world hyper clusters

I hope this is an interesting point to obtain data for this dramatic situation in N. Italy (and Central Europe), in order to prevent similar evolution in the next future.

-sv-

Pathogenesis and Host Immune Response to SARS ... - NUS

sph.nus.edu.sg › wp-content › uploads › 2020/03 › CO...

PDFMar 23, 2020 -

I reviewed the physiopathological mechanisms by which COVID-19 infect us and can cause a cytokine storm and ARDS. I also reviewed some aspect of the ARDS causing a downward spiral.

Finally, I suggested some potential treatments using already tested drugs used for other indications which action mechanism could interfere with COVID-19 ability to cause severe diseases.

Here's my manuscript

Preprint New therapeutic approaches against COVID-19: an approach tha...

The host-response to SARS-CoV-2 in mammals have been demonstrated to be sex related and so is the pathogenicity. At least it is know that SARS-CoV-2 enters human cell by binding to angiotensin-converting enzyme 2 using its viral spike (S) proteins, and the S protein priming by transmembrane serine protease 2 (TMPRSS2). However, TMPRSS2 is an androgen-regulated gene. Thus, if a male and a female are exposed to relatively the same viral load, male’s genome is more likely to be overwhelmed with the viral DNA since men produce more androgens than females. Secondly, as the viral load in males becomes higher with time, the body stimulates its inflammatory defense mechanism without any inherent regulatory mechanism. In females on the other hand, while viral load is inhibited by limited expression of TMPRSS2, high expression of estradiol and estriol offer an inflammation-regulatory effect putting the expression of inflammatory cytokines in check and preventing a possible cytokines storm. This is why men and older menopausal women are predisposed to severe COVID-19.

Please find détails in our attached review

If not contained by the immune system, particularly in elderly people, and individuals with comorbidities and other existing ailments, it will result in an exaggerated immune response, which leads to a cytokine storm that is capable of damaging organs and blood vessels.

I hope you will find this paper relevant to the pathological effects of SARS-CoV-2 infection.

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