Re: Covid-19: what treatments are being investigated? Vitamin D3 may reduce severity of COVID-19 respiratory viral infection
Vitamin D3 may reduce severity of COVID-19 respiratory viral infection
It is well established that the ubiquitously expressed master immune response transcription factor NF-κB is centrally involved in the pathogenesis of respiratory viral infections.  Indeed, COVID-19 is known to activate the NF-κB pathway that results in the upregulation of many inflammatory gene promoters.  It is postulated that this results from multiple catalytic interactions that occurs between the viral nucelocapsid proteins and NF-κB mediated immunomodulation. [3,4,5] This signaling dynamic is similar to the manner in which other highly fatal coronaviruses, such as MERS and SARS-COV, are known to take control of the NF-κB pathway. [6-8] The activation of the NF-kB pathway leads to the release of inflammatory mediators often linked to the systemic inflammatory response syndrome. 
Vitamin D3 (VD3) also is a regulator of NF-kB mediated cellular responses, It is known to inhibit the production of the proinflammatory cytokines TNFα, interleukins, and other key activators of the cellular immune defense. [9,10] VD3 promotes phenotypic shifting of lymphocytes towards an anti-inflammatory subsets.  Furthermore, data from clinical studies indicate that VD3 deficiency is clinically associated with increased susceptibility to respiratory viral infections and increased severity once infected.  In the case of respiratory syncytial virus, vitamin D3 increases synthesis of the NF-κB inhibitor, IκBα, resulting in decreased expression of pro-inflammatory genes. [13,14]
Regarding the existing COVID-19 pandemic, recent epidemiological data has shown that African-Americans currently exhibit both increased incidence and mortality. For example, in Chicago, Illinois, the Department of Public health has recently published data which shows African-Americans comprise 68% of coronavirus deaths and approximately 52% of the confirmed cases, whilst only accounting for 30% of the city’s population. While the decades of structural inequities and healthcare disparities that likely contribute to these findings should not be ignored, it is also important to realize that African Americans tend to have lower total VD3 levels. [15-17]
Given what is known about central role of NF-κB signaling in COVID pathogenesis and the inhibitory effect of Vitamin D on NF-κB mediated inflammatory responses we postulate that VD3 deficiency may be associated with the severe clinical responses to COVID-19 and Vitamin D3 therapy be tested for therapeutic efficacy in the fight against COVID-19.
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Paige-Ashley Campbell, M.S.
Mimi Wu-Young, MD
Raphael C. Lee, MD, ScD, FACS
Competing interests: No competing interests