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Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Stem Cells. Oct 26, 2021; 13(10): 1513-1529
Published online Oct 26, 2021. doi: 10.4252/wjsc.v13.i10.1513
Age and genotype dependent erythropoietin protection in COVID-19
Konstantinos I Papadopoulos, Warachaya Sutheesophon, Somjate Manipalviratn, Tar-Choon Aw
Konstantinos I Papadopoulos, Department of Research and Development, THAI StemLife, Bangkok 10310, Thailand
Warachaya Sutheesophon, Laboratory Department, THAI StemLife, Bangkok 10310, Thailand
Somjate Manipalviratn, Department of Reproductive Endocrinology, Jetanin Institute for Assisted Reproduction, Bangkok 10330, Thailand
Tar-Choon Aw, Department of Laboratory Medicine, Changi General Hospital, Singapore 529889, Singapore
Tar-Choon Aw, Department of Medicine, National University of Singapore, Singapore 119228, Singapore
Author contributions: Papadopoulos KI had the original idea on the hypothesis concept and composed the manuscript; Sutheesophon W, Manipalviratn S and Aw TC assisted in literature search, and all have made substantial, direct, and intellectual contributions to the work; all authors critically assessed the manuscript and approved it for publication.
Conflict-of-interest statement: Authors declare no conflict of interests for this article.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Konstantinos I Papadopoulos, MD, PhD, Chairman, Chief Doctor, Director, Department of Research and Development, THAI StemLife, 566/3 Soi Ramkhamhaeng 39 (Thepleela 1), Prachaouthit Road, Wangthonglang, Bangkok 10310, Thailand. kostas@thaistemlife.co.th
Received: May 17, 2021
Peer-review started: May 17, 2021
First decision: June 16, 2021
Revised: June 23, 2021
Accepted: September 19, 2021
Article in press: September 19, 2021
Published online: October 26, 2021
Processing time: 162 Days and 3.3 Hours
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.

Keywords: Erythropoietin; Angiotensin converting enzyme; Angiotensin II; Hemoglobinopathy; Malaria; Coronavirus disease 2019; Fibroblast growth factor 23

Core Tip: Erythropoietin (EPO) appears to mediate an ancestral neuroprotective innate immune response mechanism mitigating tissue injury and pathogen invasion at an early age. Age-dependent but anemia-unrelated EPO elevation has been reported in conditions that threaten the young brain such as prematurity, incipient kernicterus, and malaria. Malaria protective genetic determinants such as the angiotensin converting enzyme (ACE) D allele and the thalassemias can raise EPO and extend their protection against coronavirus disease 2019 in an age-dependent manner but could turn detrimental in genetically predisposed adults. ACE2 could represent a “bait” for severe acute respiratory syndrome coronavirus-2 to induce ACE/ACE2 imbalance and angiotensin II engendered protective EPO increase at a young age irrespective of genetic predisposition.