Coronavirus disease 2019 (COVID-19) is caused by Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. SARS-CoV-2 enters the host cell by binding its spike protein with the angiotensin-converting enzyme 2 (ACE2) receptor. Cluster of differentiation 147 (CD147) also known as Basigin or extracellular matrix metalloproteinase inducer (EMMPRIN), has been proposed as another host cell receptor that might be involved in SARS-CoV-2 cellular entry . Any other host cell receptors that exist for SARS-CoV-2 is not known at present. I suggest that the Beta adrenergic receptor might be involved in the SARS-CoV-2 cell entry, and act as a co-receptor by its interaction via surface vimentin to the ACE2 receptor and by forming a complex with CD147.

Even though high NO via iNOS was involved in most of the pathologies including sepsis, any 56 substance that inhibits or uncouples the mitochondrial respiration can initiate this Warburg effect 57 and irreversible dedifferentiation. A mild and reversible Warburg differentiation dedifferentiation 58 effect may be necessary for normal functioning and the same effect in exaggerated and irreversible 59 way leading to irreversible dedifferentiation states may be the underlying mechanism in most of the 60 diseases including septic shock. 61 62 Keywords: Septic shock, Warburg effect, dedifferentiation, differentiation therapy, ascorbic acid, 63 adrenergic blockers, glycolysis. 64Abbreviations : systemic hypertension(SHT), pulmonary arterial hypertension (PAH),congestive 65 heart failure (CHF), acute kidney injury(AKI),acute respiratory distress syndrome(ARDS),diabetes 66 mellitus(DM),inducible nitric oxide synthase (iNOS) . 67 68 69 70 INTRODUCTION: 71This review article tries to show the fundamental role played by Warburg effect in most of the 72 pathologies. Warburg common pathogenesis model is proposed to show the common underlying 73 mechanism in most of the pathologies and septic shock was used as the base model. 74Sepsis is the harmful systemic response of the host to the infection (1). According to Lewis Thomas 75 the host's response to pathogen is more detrimental than the pathogen itself (2). Septic shock and 76 severe sepsis associated multi-organ dysfunction carries high mortality rate ~ 40 -70% (3,4). 77Septic shock is refractory to the vasopressors in most of the cases; this includes norepinephrine, the 78 primary drug used in reviving blood pressure in septic shock. Vascular hypo reactivity to various 79 vasopressors in septic shock has been studied extensively, many reviews are available (5,86). 80Irrespective of advances in this field, exact underlying mechanism behind septic shock is still a 81 mystery. Post mortem studies couldn't find the underlying cause in most of the cases, surprisingly 82 most of the organs looked normal (6).Lot of treatment options which were successful in animal 83 models were failed to show benefit in human studies, ranging from Nitric oxide Synthase (NOS) 84Inhibitors, Cyclooxygenase (COX) Inhibitors, endotoxin neutralizing proteins, TNF alpha 85 antagonists etc.., (3). Some of the recent promising directions include, counterintuitive use of 86 antihypertensive in septic shock -alpha2 adrenergic receptor agonists -clonidine (7-9), beta 87 blockers reviewed in (10, 11) -aimed to reduce the sympathetic hyper activation and hyper 88 metabolism associated with sepsis. Alpha2 AR antagonist also has been shown to improve survival 89 in sepsis animal model (12). Vitamin C has been used in sepsis reviewed in (13), Glycolysis 90 inhibitor shikonin (14), cytochrome C (15) and Caffeine (16). 91 Warburg common pathogenesis model has been proposed in this review article to explain the role of 92Warburg effect in most of the pathologies using septic shock as the base model. The model was 9...

At present, there is no specific treatment available for COVID-19 patients. I propose that re-purposing the beta-adrenergic blockers for treating COVID-19 patients may be beneficial. This drug may decrease the ACE2 receptors which are used by the SARS-COV-2 Virus to enter the cell. Also 1 to 3% of the COVID-19 patients develop complications like ARDS and Septic shock. Beta-adrenergic blockers has been already shown to decrease mortality rate in these conditions. In a nutshell, beta-adrenergic blockers will decrease the SARS-COV-2 virus entry in to the cell and also decrease the mortality in the severely affected patients.A retrospective study has been proposed to check the validity of the hypothesis. This idea has the potential to save millions of lives.

: 31Septic shock is a major problem in medicine and carries high mortality rate. 32Irrespective of the advances in this field the underlying mechanism behind septic shock still 33 remains a mystery. To understand septic shock we need to understand the evolution of 34 eukaryotic cell and the billion year war between archaeal/nuclear genome and the 35 bacterial/mitochondrial genome. The ancient infection of archaeal host by the bacteria 36 (α-proteobacteria) resulted in the formation of eukaryotes and mitochondrial endosymbiont 37 occurred >1.5 billion years ago and this extraordinary event is occurring from then on all the 38 time till now resulted in formation of complex life forms. In this article I propose 'Warburg 39 common pathogenesis evolutionary model', which has the potential to explain septic shock 40 and most of the pathophysiological processes. I hypothesize that the bacterial/mitochondrial 41 invasion of the eukaryote cell is supported by the mitochondrial system of the host 42 eukaryotic cell and resisted by the innate immune system which is the archaeal part of the 43 host eukaryotic cell, as archaea is the real host before it became eukaryote.Three major 44 outcomes may result because of the bacterial /mitochondrial invasion related event, 45 1) PAMP/DAMP via PRR eg.TLR4 over activates innate immune system which in turn 46 inhibits the mitochondrial respiration and decreases the mitochondrial genome. Nuclear 47 genome overpowers mitochondrial genome which results in the loss of the endosymbiotic 48 relation between them, produces Warburg effect and the bacterial /mitochondrial invasion is 49 successfully defeated. By Warburg effect, the eukaryotic host cell now returned to its original 50 billion year old primitive form i.e. it became archaea like. This dedifferentiated state switching 51 can be seen as the cells local survival strategy in response to injuries as the cells are now 52 archaea like which has the ability to live in harsh environments. But returning to their 53 primitive forms leads to disorder and ends in global collapse of the organ systems and 54 organism which requires order in terms of differentiation which is maintained by the 55 mitochondrial system in the eukaryotic cell and across the cells by intercellular mitochondrial 56 transfer. Death of the organism may be due to the immortality pathway chosen by the cells 57 locally. 2) Successful bacterial /mitochondrial invasion of the eukaryotic host will increase the 58 mitochondrial genome and overpower the nuclear genome which may trigger apoptosis by 59 degrading the nuclear genome and expelling it. 3) Partially successful invasion may result in 60 the formation of cellular memory by increase in both OXPHOS and glycolysis. 61 I propose that the treatment in septic shock should aim at activation of mitochondrial 62 respiration thereby decreasing the aerobic glycolysis and changing the cell to its normal 63 adult dynamic differentiation phenotype i.e all the drugs should be used as differentiation 64 therapy. Adrenergic b...