The Role of Folic Acid in SARS-CoV-2 Infection


The COVID-19 pandemic caused by the SARS-CoV-2 virus has resulted in significant morbidity and mortality worldwide. While vaccines and therapeutic interventions have been developed and implemented, there is still a need for better understanding of the pathogenesis of the disease and potential targets for intervention. Recent studies have suggested a potential role for folic acid in SARS-CoV-2 infection.

Folic acid, also known as vitamin B9, is an essential nutrient that plays a critical role in various biological processes, including DNA synthesis, repair, and methylation. It is particularly important during periods of rapid cell division and growth, such as pregnancy and infancy. Folic acid deficiency can lead to a range of health problems, including anemia, birth defects, and cardiovascular disease.

Several studies have reported an association between folic acid status and the severity of COVID-19. For example, a study of 47 patients with COVID-19 found that those with lower levels of folic acid had a higher risk of severe disease and mortality. Another study of 414 patients with COVID-19 found that those with lower levels of folic acid had higher levels of inflammatory markers and a greater risk of developing acute respiratory distress syndrome (ARDS).

The mechanisms underlying the potential protective effect of folic acid in COVID-19 are not yet fully understood. However, several hypotheses have been proposed.

First, folic acid deficiency can lead to DNA damage and impaired immune function, both of which may increase susceptibility to viral infections.

Second, folic acid plays a role in the methylation of DNA and RNA, which may affect the expression of genes involved in the immune response to viral infections. Third, folic acid has anti-inflammatory properties and may help to regulate the immune response to viral infections.

In addition to its potential role in the prevention and treatment of COVID-19, folic acid may also have broader implications for viral infections and related diseases. For example, a recent study found that folic acid supplementation reduced the risk of cytomegalovirus infection in pregnant women. Folic acid has also been shown to improve outcomes in patients with hepatitis B and C virus infections.

Overall, the evidence suggests a potential role for folic acid in SARS-CoV-2 infection and related diseases. Further research is needed to fully understand the mechanisms underlying this association and to explore the potential for folic acid supplementation as a preventive or therapeutic intervention for COVID-19 and other viral infections.

In conclusion, folic acid is an essential nutrient with a critical role in various biological processes. Recent studies have suggested a potential role for folic acid in the prevention and treatment of COVID-19 and other viral infections. While further research is needed to fully understand the mechanisms underlying this association, these findings highlight the importance of adequate folic acid intake for overall health and disease prevention.

A new study review by researchers from the University of Thessaly, Biopolis-Greece poses the warning that folic acid levels in an individual can determine the direction of the disease progression of a SARS-CoV-2 infection and even the risk of mortality

The study findings were published in the peer reviewed Journal of Personalized Medicine.

This study investigated the potential interplay between FA and the SARS-CoV-2 viral infection. We used studies based on molecular docking, in silico models, and real-world studies. Data from in silico studies and molecular docking supported that FA inhibits SARS-CoV-2 entry into the host and viral replication, binding at essential residues.

On the other hand, real-world data showed contradictory results. A protective role of FA supplementation against SARS-CoV-2 infection has been indicated. However, observational studies indicate that dispensed FA supplementations due to deficits during systemic inflammation from SARS-CoV-2 increase the risk of mortality after the infection.

Studies based on in silico models have the advantage that they can lead to fast predictions concerning a large set of compounds in a high-throughput mode. At the same time, they combine the advantages of both in vivo and in vitro experimentation without subjecting themselves to ethical considerations and lack of control associated with in vivo experiments [38].

In addition, in silico models allow scientists to include a virtually unlimited parameter, rendering the outcomes more applicable to the organism, and they mainly are used in pharmacokinetic experimentation [38].

To the contrary, this kind of model has certain disadvantages. In in silico models and molecular docking studies, the most significant limitation is associated with the lack of confidence in scoring functions’ ability [39].

According to patients’ studies [35,36], it is possible that both inadequate and/or excessive amounts of folate may be detrimental to host resistance to SARS-CoV-2 infection and that there may be an optimal range of physiological folate status related to host resistance to COVID-19 infection and severity.

Data support that folate supplementation increases viral replication in host cells and increases infection, hospitalization, and mortality. However, folate deficiency may also be harmful due to its effects on immune function and other important physiological pathways that protect against SARS-CoV-2 infection and progression [35,36].

Therefore, a major conundrum must be resolved regarding the optimal range of folate levels that are protective against SARS-CoV-2 infection, hospitalization, and mortality. Furthermore, according to Acosta-Elias et al., it is also critical to account for race/ethnicity, given the increased risk for infection, hospitalization, and mortality among black women compared to white women [35].

Although impressive progress has been achieved in the last years within the folate pathway, many questions remain to be answered. Why can the normal concentration of FA not inhibit the entry of SARS-CoV-2 into target cells? Additionally, what concentrations of FA would have to be given above what is already in the blood to be effective? Folate is especially and mainly carried in the blood in red blood cells.

It has multiple mechanisms of uptake into cells that complicate thinking about what blood concentrations would be required to inhibit SARS-CoV-2 entry into target cells effectively. In that context, we should also take into account that a high intake of FA may have adverse effects, such as masking a vitamin B12 deficiency. High ingestion has also been related to carcinogenesis or cancer recurrence in certain groups [13].

There is also emerging knowledge that FA supplements impact other viral infections, including the human immunodeficiency virus (HIV), the hepatitis B virus, and the Zika virus infection, which are all included [40,41,42].

In that context, it has been elucidated that FA deficiency has been associated with HPV-associated atypical squamous cells of undetermined significance [43]. HPV infection persists and progresses to cervical dysplasia in females, given that folate deficiency is linked to insufficient cellular immunity [38]. Moreover, folate receptor alpha (FRalpha) has been described as a factor involved in mediating Ebola virus entry into cells [43], resulting in internalization and subsequent viral ingress into the cytoplasm via caveolae [44].

Furthermore, Vilaceka et al. hypothesized that low folate values are associated with hyperhomocysteinemia related to the risk of a sudden stroke in a group of HIV-infected children, as FA is required for the remethylation of homocysteine to methionine [45]. Besides, folate plays a key role in DNA synthesis, repair, and methylation, forming the basis of mechanistic explanations for the putative role of folate in cancer prevention [46].

Since the discovery of sulfa drugs and trimethoprim, the folate pathway has been a critical target for developing new drugs against infectious diseases [47]. Recently, it has been suggested that folate-conjugated HSV G207 presents a folate receptor-targeted oncolytic virus with an increased anti-tumor efficiency and tumor targeting specificity compared to the naked HSV, with a potential therapeutic value via retargeting to tumor cells [48,49,50].

Authors should discuss the results and how they can be interpreted from the perspective of previous studies and the working hypotheses. The findings and their implications should be discussed in the broadest context possible. Future research directions may also be highlighted.

A major limitation of our study is associated with the fact that the number of patient studies is quite a few. In addition, the studies included in our review article are mainly observational studies, which are prone to bias and cannot show causality. As a result, even though their outcomes might provide us with valuable medical data, more extensive studies are imperative to validate the demonstrated findings.

Moreover, it is essential to raise the awareness of scientists and physicians regarding FA and its potential impact on SARS-CoV-2 infection. One aspect that could provide significant information could be the profound investigation of FA’s role in conditions such as the long COVID period and/or variants.

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