The ongoing pandemic: Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 has
become one of the most important epidemiological events within the last 100 years,
causing devastating consequences for the public health systems and the socioeconomical
tissue around the world (1–3). Infection with SARS-CoV-2 can lead to a mild or highly
acute respiratory syndrome fueled by altered secretion of inflammatory cytokines (cytokine
storm) that can be fatal within children, elderly populations, patients with chronic
pulmonary or hypertension diseases, and people living in cities with poor air quality
(3, 4). While viral spreading and severity indexes are growing as the virus reaches
new geographic areas, clinical trials for several vaccine prospects are being performed
with the caveat that it may take more than 6 months to provide data of their efficiency
and sero-protection levels (2, 5–7). Consequently, the remaining alternatives to counteract
COVID-19 disease and pandemics are currently based on (i) the implementation of a
broad-spectrum of antivirals that could attenuate the virus infection, (ii) clinical
relief of acute inflammatory symptoms, and (iii) social isolation of at risk populations
to avoid propagation (5, 8). However, given the uncertainty for specific treatment
and the economic consequences of social isolation, especially in developing countries,
repurposing of current drugs it is imperative to develop quick, and cost-effective
therapeutic strategies to protect vulnerable populations (9).
A potential alternative is vitamin D, a natural immunoregulator that has been demonstrated
to enhance antimicrobial activity against several pathogens including respiratory
viruses (10, 11). Indeed, both in vitro observations and supplementation trials have
extensively shown the restrictive features of vitamin D against respiratory viruses
including: syncytial virus, influenza, and coronaviruses (8, 10–19) and other non-respiratory
viruses, such as human immunodeficiency virus 1, hepatitis c virus, and dengue virus
(20–22). Classically, the mechanisms reported to support these antiviral effects are
based on the ability of vitamin D to upregulate antimicrobial peptides and induce
antiviral cytokines to interfere the viral replicative cycle (10, 12, 23–31). Interestingly,
we have recently reported a novel molecular vitamin D-derived mechanism that can also
target early stages of the viral cycle via downregulating the expression of host cell
receptors for viral attachment. This novel mechanism is responsible for impairing
binding and entry of dengue virus, thus, restricting in vitro infection (22) and likely,
further dissemination to other primary host cells.
SARS-CoV-2 can target both upper and lower epithelial lung cells and gain access to,
via anchoring of its spike (S) protein to angiotensin-converting enzyme 2 (ACE2) receptor
(32–36). This receptor is an important enzyme for the regulation of the Renin-Angiotensin
System (RAS) which regulates blood pressure and vascular balance. Notably, ACE2 is
highly expressed in patients with hypertension, diabetes mellitus, coronary heart
diseases, and cerebrovascular disease, which could explain the higher risk of severe
and fatal COVID-19 within these patients (37, 38). In fact, recently it has been demonstrated
that SARS-CoV-2 can also bind and infect central nervous system cells through targeting
the ACE2 receptor, implicating participation of this neurotropic mechanism into the
disease severity and mortality (39).
As concerning inferences may arise from all these observations, it is important to
note that ACE2 receptor has been broadly known to be downregulated by vitamin D activity
(40). Mechanistically, vitamin D works as a potent negative endocrine regulator of
the RAS via the canonical vitamin D receptor pathway which can suppress RAS and downregulates
the expression of ACE2 both in vitro and in vivo (37, 41). Indeed, it has been documented
that vitamin D-derived suppression of RAS can be elicited via vitamin D inhibition
of CREB (cAMP response element-binding protein), a transcription factor key for the
renin gene regulation (42). Moreover, these experimental observations have been corroborated
by mounting clinical and epidemiologic evidence, where decreased serum levels of vitamin
D have been correlated with increased activity of RAS, higher plasma renin activity,
and high blood pressure levels (43–46). For instance, improved vitamin D serum concentrations
due to oral supplementation within hypertensive patients that were previously vitamin
D insufficient, were associated with improvement in the control of blood pressure
(47).
In light of these observations, we anticipate in this comment that the regulating
effects of vitamin D on the renin-angiotensin system, specifically, on ACE2 receptor
downregulation could contribute with restriction of SARS-CoV-2, similarly to what
we have reported with dengue virus (22). Accordingly, an increasing number of studies
are postulating blockade of this receptor as a likely therapeutic strategy for COVID-19
(2, 48–50). Furthermore, besides infection, severity of COVID-19 is strongly associated
with altered and prolonged pro-inflammatory responses in the lung, that ultimately
lead to abnormal respiratory events and further organ failure (3). In line with literature,
our experimental model has shown that beyond the vitamin D-derived downregulation
of relevant receptors for viral attachment, this hormone can also contribute with
fine tuning of the altered pro-inflammatory responses induced by the virus (22, 51).
In fact, others have reported that vitamin D-derived alleviation of pulmonary damage,
caused by inflammation, in a model of acute lung injury, and respiratory distress
was related to modulation of several members of RAS, including ACE2 receptor (37,
40, 41, 52).
In line with findings from other reports (10), our observations that vitamin D-derived
antiviral mechanisms can restrict viral infection and attenuate the pro-inflammatory
response (22) have been corroborated ex vivo in two different vitamin D supplementation
exploratory studies. We demonstrated that a daily oral supplement of 4000 IU of vitamin
D during 10 days represented an adequate dose to enhance dengue virus control and
reduce the cytokine response, in vitro, suggesting that vitamin D status can, in fact,
restrict the viral assault (53, 54). Accordingly, several studies have highlighted
the beneficial role of vitamin D sufficiency levels and supplementation for viral
respiratory infections (55–57). Indeed, outbreaks and higher incidence of respiratory
viruses such as influenza and coronavirus are common beyond subtropical areas with
low sunlight exposure levels and prevalence of vitamin D deficiency/insufficiency
such as Europe and Northern United States, which have been highly affected by COVID-19
(10, 11, 58).
While several drugs targeting the ACE2-dependet entry pathway for SARS-CoV-2 still
await for validation and assessment of their side effects (6, 7, 49, 59), at least
three clinical trials aimed to elucidate the protective role of vitamin D role on
COVID-19 disease severity are currently progressing in Spain, France and United States
(60–62). Moreover, a mounting number of observations worldwide, are consistently suggesting
the preventive and prophylactic features vitamin D status for COVID-19 mortality (63–66).
Our hypothesis provides a call for research pathways to unravel the role of vitamin
D on the pathogenesis of COVID-19, but beyond that, it also opens a hope window for
a more immediate, accessible, natural, and cost-effective strategy to prevent, treat
and ameliorate propagation of SARS-CoV-2. In summary, we postulate that conventional
oral vitamin D supplementation can be a readily strategy to aim: (i) restriction of
SARS-CoV-2 infection via downregulation of ACE2 receptor, and (ii) attenuation of
disease severity by down-tuning the pulmonary pro-inflammatory response or cytokine
storm that fuels COVID-19 severity. Therefore, verifying its beneficial role by means
of epidemiologic, clinical and experimental in vivo and in vitro evidence may turn
Vitamin D into a new “at hand tool” to protect vulnerable populations and mitigate
the impact of the current pandemic events, especially in countries with reduced capability
of their public health systems.
Author Contributions
All authors listed have made a substantial, direct and intellectual contribution to
the work, and approved it for publication.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial
or financial relationships that could be construed as a potential conflict of interest.