Retinol Depletion in Severe COVID-19

Abstract

Background and PurposeVitamin A is depleted during infections. Vitamin A has been used successfully in measles, RSV and AIDS patients and is an effective vaccine adjuvant. In this study, low retinol levels were found in patients with severe COVID-19. Retinoid signaling impairment in COVID-19 disrupts Type-I interferon synthesis.Material and MethodTwo groups were formed in the study. The patient group consisted of 27 (Group 1) severe COVID-19 patients hospitalized in the intensive care unit with respiratory failure, and the control group consisted of 23 (Group 2) patients without COVID-19 symptoms. Serum retinol levels were analyzed by ELIZA and HPLC in both groups.FindingsRetinol levels were found to be significantly lower in the patient group (P <0.001). There was no difference in retinol between two different age groups in the patient group (P> 0.05). There was no significant difference in retinol between men and women (P> 0.05). Comorbidity did not affect serum retinol levels (P >0.05).ConclusionSerum retinol levels were low in patients with severe COVID-19. Drugs preventing retinol excretion were not stopped in the patient group. Some patients took vitamin A externally. Despite this, retinol was low in COVID-19 patients. Retinol depletion impairs Type-I interferon synthesis by impairing retinoid signaling. Retinoid signaling may be the main pathogenetic disorder in COVID-19. This pathogenesis can serve as a guide for adjuvants, drug targets, and candidate drugs. Retinol, retinoic acid derivatives, and some CYP450 inhibitors may work on COVID-19.

A novel hypothesis for COVID-19 pathogenesis: Retinol depletion and retinoid signaling disorder

“…In the case of COVID-19, Riva et al, have reported that the expression of genes within RAR signaling pathway were significantly decreased in Vero E6 culture cells infected with SARS-CoV-2 [140] . They further found that RA receptor agonists inhibited SARS-CoV-2 replication, and that this inhibition was reversed with RA receptor antagonist molecules indicating the importance of RA receptor signaling in COVID-19 pathogenesis [140] .These data demonstrate that retinol metabolism and retinoid signaling can function as a critical host-pathogen-interaction circuit in controlling SARS-CoV-2 infection, which indicates that VitA supplementation may help fight COVID-19 [41] , [59] , [303] .…”

“…Although the dose-dependent bimodal activity of ATRA in the immune system, especially on inflammatory processes, has been previously studied [192] , [320] , it has not been investigated in the case of COVID-19. We believe that this sudden and unexpected transition between the innate and the adaptive components of the immune system in COVID-19 is ignited by the retinol depletion and consequently impaired retinoid signaling disorder [59] . Depletion of retinol causes a transition from a proper innate immune response to the exacerbated cytokine storm [41] .…”

“…The reason why the regulation mechanism of endogenous RAs in COVID-19 has not been noticed until now may be the assumption that retinol and RAs, which have large reserves, can always be present in the body stores. However, the stored amount of RA in the human body is limited and is sufficient for about three months [41] , [58] , [59] , [60] . The serum retinol level is kept constant as it is supplemented per need from body's retinol depots, mainly liver.…”

“…We believe that this might also be true in the case of COVID19 infection and that the primary triggering role in inflammatory pathogenesis is the impaired RAR signaling while cytokines and dysbiosis are responsible for the aggravation of the inflammatory process. Therefore, VitA supplementation may help turn off the inflammatory response and help decrease the severe immunopathogenesis at initial stage ofCOVID-19 infection [41] , [59] , [141] .…”

“…The first phase is the normal immune response at the beginning of the infection when there is enough retinoic signaling, which activates RIG-I signaling that leads to the high level of Type I IFN synthesis. The second phase is the disruption of Type I IFN synthesis and overactivation of the Th17 arm of the adaptive immune system leading to the release of excessive inflammatory cytokines that causes systemic organ damage [41] , [59] , [124] , [131] , [216] , [313] . The resulting process is the severe COVID-19 picture characterized by SIRS, ARDS, hypoxia, and systemic organ damage leading to mortality [118] , [131] , [225] .…”