Age and genotype dependent erythropoietin protection in COVID-19

Abstract

Erythropoietin (EPO) is the main mediator of erythropoiesis and an important tissue protective hormone that appears to mediate an ancestral neuroprotective innate immune response mechanism at an early age. When the young brain is threatened-prematurity, neonatal hyperbilirubinemia, malaria- EPO is hyper-secreted disproportionately to any concurrent anemic stimuli. Under eons of severe malarial selection pressure, neuroprotective EPO augmenting genetic determinants such as the various hemoglobinopathies, and the angiotensin converting enzyme (ACE) I/D polymorphism, have been positively selected. When malarial and other cerebral threats abate and the young child survives to adulthood, EPO subsides. Sustained high ACE and angiotensin II (Ang II) levels through the ACE D allele in adulthood may then become detrimental as witnessed by epidemiological studies. The ubiquitous renin angiotensin system (RAS) influences the α-klotho/fibroblast growth factor 23 (FGF23) circuitry, and both are interconnected with EPO. Here we propose that at a young age, EPO augmenting genetic determinants through ACE D allele elevated Ang II levels in some or HbE/beta thalassemia in others would increase EPO levels and shield against coronavirus disease 2019, akin to protection from malaria and dengue fever. Human evolution may use ACE2 as a “bait” for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) to gain cellular entry in order to trigger an ACE/ACE2 imbalance and stimulate EPO hypersecretion using tissue RAS, uncoupled from hemoglobin levels. In subjects without EPO augmenting genetic determinants at any age, ACE2 binding and internalization upon SARS-CoV-2 entry would trigger an ACE/ACE2 imbalance, and Ang II oversecretion leading to protective EPO stimulation. In children, low nasal ACE2 Levels would beneficially augment this imbalance, especially for those without protective genetic determinants. On the other hand, in predisposed adults with the ACE D allele, ACE/ACE2 imbalance, may lead to uncontrolled RAS overactivity and an Ang II induced proinflammatory state and immune dysregulation, with interleukin 6 (IL-6), plasminogen activator inhibitor, and FGF23 elevations. IL-6 induced EPO suppression, aggravated through co-morbidities such as hypertension, diabetes, obesity, and RAS pharmacological interventions may potentially lead to acute respiratory distress syndrome, cytokine storm and/or autoimmunity. HbE/beta thalassemia carriers would enjoy protection at any age as their EPO stimulation is uncoupled from the RAS system. The timely use of rhEPO, EPO analogs, acetylsalicylic acid, bioactive lipids, or FGF23 antagonists in genetically predisposed individuals may counteract those detrimental effects.

Genetic polymorphisms affecting nitric oxide and β-cytokine pathways may contribute to increased COVID-19 mortality in schizophrenia

“…1 ) and associated with greater disease severity, continuous progression, worse outcomes, and adverse antipsychotic medication results ( Nadalin et al, 2021 ). ACE polymorphisms are also implicated in increased disease severity and mortality in COVID-19 and engender an adverse predisposition in SCZ ( Papadopoulos et al, 2021 ). Co-inherited eNOS and RAAS polymorphisms synergistically potentiate CVD, nicotine dependence, and modulate pharmacological interventions including the effects of pharmacological RAAS inhibition, with known angiotensin II type 1 receptor blocker (ARB)-induced eNOS upregulation especially of the mutant alleles ( Fig.…”

“…Increased NO-generation and bioavailability through eNOS activation may counteract SARS-CoV-2 spike (S) protein-induced endotheliitis and inhibit SARS-CoV-1/2 infection at an early stage, as shown to inhibit i) fusion of the SARS-CoV (S) protein to ACE2 by decreasing its palmitoylation, and ii) early production of viral RNA, processes critical in controlling membrane fusion and virion infectivity ( Fig. 1 ) ( Papadopoulos et al, 2021 ). Downregulated eNOS have been reported in adults with severe COVID-19 and related acute respiratory distress syndrome (ARDS) ( Vassiliou et al, 2021 ).…”

“…An extra level of complexity in NO regulation is added as CSF2RB polymorphisms in SCZ potentially impact βcR function. Apart from canonical βc-cytokine effects, βcR demonstrates non-canonical interactions with erythropoietin (EPO) by forming its effector, the tissue protective receptor (TPR), a heterodimer between βcR and EPO receptor (EPOR) ( Papadopoulos et al, 2021 ). βcR is essential in the formation of a βcR-EPOR-eNOS complex, integral in mediating EPO’s non-erythropoietic, neuro-, cardio-, reno-, and potentially SARS-CoV-2 protective effects.…”

“…CSF2RB polymorphisms could thus lead to decreased EPO-mediated NO-generation by inhibiting βcR-dependent EPO-induced eNOS activation, hence abolishing EPO-engendered SARS-Cov-2 protection ( Fig. 1 ) ( Chen et al, 2008 ; Papadopoulos et al, 2021 ).…”

Too hard to die: Exercise training mediates specific and immediate SARS-CoV-2 protection

“…Evolutionary evidence supports the survival of the fittest through natural selection for pathogen resistance, with effects mediated through younger age, lifestyle choices and importantly, genetics[ 2 ]. Epidemiological data support a lower COVID-19 incidence and severity in children and adolescents[ 3 ], individuals with high cardiorespiratory fitness (CRF) and muscle strength[ 4 ] as well as certain protective erythropoietin (EPO) augmenting genetic variants[ 3 ]. At the other end of the spectrum, inactivity, obesity, insulin resistance, diabetes, and hypertension, are associated with worse SARS-CoV-2 infection course and disproportionate COVID-19 mortality risk[ 5 , 6 ].…”