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

Severe acute respiratory coronavirus 2 (SARS-CoV-2) infection in the young and healthy usually results in an asymptomatic or mild viral syndrome, possibly through an erythropoietin (EPO)-dependent, protective evolutionary landscape. In the old and in the presence of co-morbidities, however, a potentially lethal coronavirus disease 2019 (COVID-19) cytokine storm, through unrestrained renin-angiotensin aldosterone system (RAAS) hyperactivity, has been described. Multifunctional microRNA-155 (miR-155) elevation in malaria, dengue virus (DENV), the thalassemias, and SARS-CoV-1/2, plays critical antiviral and cardiovascular roles through its targeted translational repression of over 140 genes. In the present review, we propose a plausible miR-155-dependent mechanism whereby the translational repression of AGRT1, Arginase-2 and Ets-1, reshapes RAAS towards Angiotensin II (Ang II) type 2 (AT2R)-mediated balanced, tolerable, and SARS-CoV-2-protective cardiovascular phenotypes. In addition, it enhances EPO secretion and endothelial nitric oxide synthase activation and substrate availability, and negates proinflammatory Ang II effects. Disrupted miR-155 repression of AT1R + 1166C-allele, significantly associated with adverse cardiovascular and COVID-19 outcomes, manifests its decisive role in RAAS modulation. BACH1 and SOCS1 repression creates an anti-inflammatory and cytoprotective milieu, robustly inducing antiviral interferons. MiR-155 dysregulation in the elderly, and in comorbidities, allows unimpeded RAAS hyperactivity to progress towards a particularly aggressive COVID-19 course. Elevated miR-155 in thalassemia plausibly engenders a favorable cardiovascular profile and protection against malaria, DENV, and SARS-CoV-2. MiR-155 modulating pharmaceutical approaches could offer novel therapeutic options in COVID-19.

Automated summary

Severe acute respiratory coronavirus 2 (SARS-CoV-2) infection causes mild symptoms or is asymptomatic in young and healthy individuals, possibly due to the protective effects of erythropoietin (EPO). However, in older individuals with comorbidities, a potentially lethal cytokine storm can occur as a result of hyperactive renin-angiotensin aldosterone system (RAAS). MicroRNA-155 (miR-155) plays a critical role in antiviral and cardiovascular functions and its dysregulation may contribute to the severe course of COVID-19.