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      Vitamin D Supplementation: A Potential Approach for Coronavirus/COVID-19 Therapeutics?

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          Abstract

          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.

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          Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding

          Summary Background In late December, 2019, patients presenting with viral pneumonia due to an unidentified microbial agent were reported in Wuhan, China. A novel coronavirus was subsequently identified as the causative pathogen, provisionally named 2019 novel coronavirus (2019-nCoV). As of Jan 26, 2020, more than 2000 cases of 2019-nCoV infection have been confirmed, most of which involved people living in or visiting Wuhan, and human-to-human transmission has been confirmed. Methods We did next-generation sequencing of samples from bronchoalveolar lavage fluid and cultured isolates from nine inpatients, eight of whom had visited the Huanan seafood market in Wuhan. Complete and partial 2019-nCoV genome sequences were obtained from these individuals. Viral contigs were connected using Sanger sequencing to obtain the full-length genomes, with the terminal regions determined by rapid amplification of cDNA ends. Phylogenetic analysis of these 2019-nCoV genomes and those of other coronaviruses was used to determine the evolutionary history of the virus and help infer its likely origin. Homology modelling was done to explore the likely receptor-binding properties of the virus. Findings The ten genome sequences of 2019-nCoV obtained from the nine patients were extremely similar, exhibiting more than 99·98% sequence identity. Notably, 2019-nCoV was closely related (with 88% identity) to two bat-derived severe acute respiratory syndrome (SARS)-like coronaviruses, bat-SL-CoVZC45 and bat-SL-CoVZXC21, collected in 2018 in Zhoushan, eastern China, but were more distant from SARS-CoV (about 79%) and MERS-CoV (about 50%). Phylogenetic analysis revealed that 2019-nCoV fell within the subgenus Sarbecovirus of the genus Betacoronavirus, with a relatively long branch length to its closest relatives bat-SL-CoVZC45 and bat-SL-CoVZXC21, and was genetically distinct from SARS-CoV. Notably, homology modelling revealed that 2019-nCoV had a similar receptor-binding domain structure to that of SARS-CoV, despite amino acid variation at some key residues. Interpretation 2019-nCoV is sufficiently divergent from SARS-CoV to be considered a new human-infecting betacoronavirus. Although our phylogenetic analysis suggests that bats might be the original host of this virus, an animal sold at the seafood market in Wuhan might represent an intermediate host facilitating the emergence of the virus in humans. Importantly, structural analysis suggests that 2019-nCoV might be able to bind to the angiotensin-converting enzyme 2 receptor in humans. The future evolution, adaptation, and spread of this virus warrant urgent investigation. Funding National Key Research and Development Program of China, National Major Project for Control and Prevention of Infectious Disease in China, Chinese Academy of Sciences, Shandong First Medical University.
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            The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak

            Coronavirus disease (COVID-19) is caused by SARS-COV2 and represents the causative agent of a potentially fatal disease that is of great global public health concern. Based on the large number of infected people that were exposed to the wet animal market in Wuhan City, China, it is suggested that this is likely the zoonotic origin of COVID-19. Person-to-person transmission of COVID-19 infection led to the isolation of patients that were subsequently administered a variety of treatments. Extensive measures to reduce person-to-person transmission of COVID-19 have been implemented to control the current outbreak. Special attention and efforts to protect or reduce transmission should be applied in susceptible populations including children, health care providers, and elderly people. In this review, we highlights the symptoms, epidemiology, transmission, pathogenesis, phylogenetic analysis and future directions to control the spread of this fatal disease.
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              Is Open Access

              The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak – an update on the status

              An acute respiratory disease, caused by a novel coronavirus (SARS-CoV-2, previously known as 2019-nCoV), the coronavirus disease 2019 (COVID-19) has spread throughout China and received worldwide attention. On 30 January 2020, World Health Organization (WHO) officially declared the COVID-19 epidemic as a public health emergency of international concern. The emergence of SARS-CoV-2, since the severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002 and Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012, marked the third introduction of a highly pathogenic and large-scale epidemic coronavirus into the human population in the twenty-first century. As of 1 March 2020, a total of 87,137 confirmed cases globally, 79,968 confirmed in China and 7169 outside of China, with 2977 deaths (3.4%) had been reported by WHO. Meanwhile, several independent research groups have identified that SARS-CoV-2 belongs to β-coronavirus, with highly identical genome to bat coronavirus, pointing to bat as the natural host. The novel coronavirus uses the same receptor, angiotensin-converting enzyme 2 (ACE2) as that for SARS-CoV, and mainly spreads through the respiratory tract. Importantly, increasingly evidence showed sustained human-to-human transmission, along with many exported cases across the globe. The clinical symptoms of COVID-19 patients include fever, cough, fatigue and a small population of patients appeared gastrointestinal infection symptoms. The elderly and people with underlying diseases are susceptible to infection and prone to serious outcomes, which may be associated with acute respiratory distress syndrome (ARDS) and cytokine storm. Currently, there are few specific antiviral strategies, but several potent candidates of antivirals and repurposed drugs are under urgent investigation. In this review, we summarized the latest research progress of the epidemiology, pathogenesis, and clinical characteristics of COVID-19, and discussed the current treatment and scientific advancements to combat the epidemic novel coronavirus.
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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                23 June 2020
                2020
                23 June 2020
                : 11
                : 1523
                Affiliations
                [1] 1Group of Immunovirology, Faculty of Medicine, University of Antioquia , Medellin, Colombia
                [2] 2Behavioural Science and Health Care Habits Unit, Comfama , Medellin, Colombia
                Author notes

                Edited by: Susu M. Zughaier, Qatar University, Qatar

                Reviewed by: William B. Grant, Sunlight Nutrition and Health Research Center, United States

                *Correspondence: John F. Arboleda guanojf@ 123456gmail.com

                This article was submitted to Viral Immunology, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2020.01523
                7324720
                32655583
                e505dd6c-d685-47fa-b453-71c58c818159
                Copyright © 2020 Arboleda and Urcuqui-Inchima.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 31 March 2020
                : 09 June 2020
                Page count
                Figures: 0, Tables: 0, Equations: 0, References: 66, Pages: 4, Words: 3335
                Categories
                Immunology
                Opinion

                Immunology
                sars-cov-2,covid-19,vitamin d,antiviral,anti-inflammatory
                Immunology
                sars-cov-2, covid-19, vitamin d, antiviral, anti-inflammatory

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