A protective erythropoietin evolutionary landscape, NLRP3 inflammasome regulation, and multisystem inflammatory syndrome in children

Abstract

The low incidence of pediatric severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection and the associated multisystem inflammatory syndrome (MIS-C) lack a unifying pathophysiological explanation, impeding effective prevention and therapy. Activation of the NACHT, LRR, and PYD domains-containing protein (NLRP) 3 inflammasome in SARS-CoV-2 with perturbed regulation in MIS-C, has been reported. We posit that, early age physiological states and genetic determinants, such as certain polymorphisms of renin-angiotensin aldosterone system (RAAS) molecules, promote a controlled RAAS hyperactive state, and form an evolutionary landscape involving an age-dependent erythropoietin (EPO) elevation, mediating ancestral innate immune defenses that, through appropriate NLRP3 regulation, mitigate tissue injury and pathogen invasion. SARS-CoV-2-induced downregulation of angiotensin-converting enzyme (ACE)2 expression in endothelial cells (EC), impairment of endothelial nitric oxide (NO) synthase (eNOS) activity and downstream NO bioavailability, may promote a hyperactive RAAS with elevated angiotensin II and aldosterone that, can trigger, and accelerate NLRP3 inflammasome activation, while EPO-eNOS/NO abrogate it. Young age and a protective EPO evolutionary landscape may successfully inhibit SARS-CoV-2 and contain NLRP3 inflammasome activation. By contrast, increasing age and falling EPO levels, in genetically susceptible children with adverse genetic variants and co-morbidities, may lead to unopposed RAAS hyperactivity, NLRP3 inflammasome dysregulation, severe endotheliitis with pyroptotic cytokine storm, and development of autoantibodies, as already described in MIS-C. Our haplotype estimates, predicted from allele frequencies in population databases, are in concordance with MIS-C incidence reports in Europeans but indicate lower risks for Asians and African Americans. Targeted Mendelian approaches dissecting the influence of relevant genetic variants are needed.

Beauty and the beast: host microRNA-155 versus SARS-CoV-2

“…MiR-155-mediated translational repression of AGTR1, ARG2 and ETS-1 (Table 1), purposefully tames this SARS-CoV-2-induced RAAS hyperactivity into a balanced, tolerable, and defensive RAAS state, that through AT2R, promotes a protective EPO evolutionary landscape and NLRP3 inflammasome regulation (Fig. 1, 2) [30,106]. MiR-155 engendered AT1R downregulation and reduced membrane availability coaxes a RAAS cardioprotective state [73], avails increased eNOS/ NO pathway activation [47,157], the latter further potentiated by Arg2 repression [80,119,158], leading to increased NO-bioavailability and impaired AT1R-mediated endocytosis, SARS-CoV-2 replication, and cell entry (Fig.…”

“…We have put forward an evolutionary congruent, mechanistical explanation accounting for the interaction between host and SARS-CoV-2, that involves an early age, erythropoietin (EPO)-dependent, protective evolutionary landscape [2,4,5,30]. Such an ancestral, protective EPO evolutionary landscape provides the host with a fitness advantage, forming constraints against pathogen adaptation and invasion [31,32].…”

“…All molecules in this early age protective evolutionary landscape, involving RAAS-EPO-eNOS interactions, are under significant genetic control aiming to support, augment, and extend EPO elevation and eNOS activity upon pathogen insult, as witnessed by the thalassemias, and protective RAAS and eNOS single nucleotide polymorphisms (SNPs) in malaria and Dengue virus (DENV) infection [27,31,32,[38][39][40]. The resulting elevated EPO levels and the consequently enhanced EPO-eNOS/NO pathway responsiveness, are associated with a better outcome in children with cerebral malaria and may reasonably also promote an early age protection against SARS-CoV-2; indeed, children below the age of 5, when EPO response is maximal, generally experience asymptomatic or mild SARS-CoV-2 infections [4,[30][31][32][41][42][43][44][45]. EPO's non-erythropoietic, extensive tissue protective action is mediated through its immunological effects [30], and enhancement of eNOS/NO pathway activity and subsequently increased vaso-protective NO generation and bioavailability [46][47][48][49].…”

“…The resulting elevated EPO levels and the consequently enhanced EPO-eNOS/NO pathway responsiveness, are associated with a better outcome in children with cerebral malaria and may reasonably also promote an early age protection against SARS-CoV-2; indeed, children below the age of 5, when EPO response is maximal, generally experience asymptomatic or mild SARS-CoV-2 infections [4,[30][31][32][41][42][43][44][45]. EPO's non-erythropoietic, extensive tissue protective action is mediated through its immunological effects [30], and enhancement of eNOS/NO pathway activity and subsequently increased vaso-protective NO generation and bioavailability [46][47][48][49]. EPO and eNOS together are known to abrogate the NACHT, LRR, and PYD domains-containing protein (NLRP) 3 inflammasome, centrally involved in the development of SARS-CoV-2 endotheliitis, as well as effectively inhibit SARS-CoV-2 early replication and cell entry [16,44,[47][48][49][50][51][52].…”

“…EPO and eNOS together are known to abrogate the NACHT, LRR, and PYD domains-containing protein (NLRP) 3 inflammasome, centrally involved in the development of SARS-CoV-2 endotheliitis, as well as effectively inhibit SARS-CoV-2 early replication and cell entry [16,44,[47][48][49][50][51][52]. It is thus, evident, that the host intends, with this physiological, and genetically imprinted, RAAS hyperactivity, to ensure adequate EPO levels to support this EPO-mediated, agedependent protective evolutionary landscape, plausibly explaining the first question regarding the uncomplicated and rare SARS-CoV-2 infections in the young [30]. While this physiological RAAS hyperactivity, enhanced by RAAS molecule SNPs, engenders beneficial evolutionary effects in the form of protection against malaria and SARS-CoV-2 at an early age, SNP effects can be pleiotropic, and may turn into a detrimental disadvantage in older individuals, as suggested by the malaria-hypertension hypothesis and their association with severe adult COVID-19 outcomes [28,[53][54][55][56][57][58].…”