Re: Covid-19: what treatments are being investigated? Vitamin D3 may reduce severity of COVID-19 respiratory viral infection
Dear Editor
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. [1] Indeed, COVID-19 is known to activate the NF-κB pathway that results in the upregulation of many inflammatory gene promoters. [2] 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. [8]
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. [11] Furthermore, data from clinical studies indicate that VD3 deficiency is clinically associated with increased susceptibility to respiratory viral infections and increased severity once infected. [12] 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.
References:
1. Christman JW, Sadikot RT, Blackwell TS. The role of nuclear factor-κB in pulmonary diseases. Chest (2000) 117: 1482–1487
2. Guo YR, Cao QD, Hong ZS, et al. The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak - an update on the status. Military Medical Research (2020) 7(11): 1-10
3. DeDiego ML, Nieto-Torres JL, Regla-Nava JA, Jimenez-Guardeño JM, Fernandez
4. Delgado R, Fett C, Castaño-Rodriguez C, Perlman S, Enjuanes L. Inhibition of NF-κB-mediated inflammation in severe acute respiratory syndrome coronavirus-infected mice increases survival. J Virol. .(2014) Jan;88(2):913-24.
5. Ziebuhr J.. The coronavirus replicase. Curr. Top. Microbiol. Immunol. (2005)25 287:57–94.
6. Dosch SF, Mahajan SD, Collins AR. SARS coronavirus spike protein-induced innate immune response occurs via activation of the NF-kappaB pathway in human monocyte macrophages in vitro. Virus Res. (2009) 142(1-2):19–27.
7. Law AH, Lee DC, Cheung BK, Yim HC, Lau A . Role for nonstructural protein 1 of severe acute respiratory syndrome coronavirus in chemokine dysregulation. J. Virol. (2007) 81:416-422.
8. Liao QJ, Ye LB, Timani KA, Zeng YC, She YL, Ye L, Wu ZH . Activation of NF-κB by the full-length nucleocapsid protein of the SARS coronavirus. Acta Biochim. Biophys. Sin. (2005). 37:607-612.
9. Wöbke TK, Sorg BL, Steinhilber D. Vitamin D in inflammatory diseases. Front Physiol. (2014) Jul 2;5:244.
10. Zhang Y., Leung D. Y., Richers B. N., Liu Y., Remigio L. K., Riches D. W., et al. Vitamin D inhibits monocyte/macrophage proinflammatory cytokine production by targeting MAPK phosphatase-1. J. Immunol. (2012). 188, 2127–2135
11. Cantorna, M., Zhu, Y., Froicu, M. and Wittke, A.. Vitamin D status, 1,25-dihydroxyvitamin D3, and the immune system. The American Journal of Clinical Nutrition, (2004) 80(6), pp.1717S-1720S.
12. Ginde A. A., J. M. Mansbach, C. A. Camargo Jr... Association between serum 25-hydroxyvitamin D level and upper respiratory tract infection in the Third National Health and Nutrition Examination Survey. Arch. Intern. Med. (2009)169: 384–390.
13. Cohen-Lahav M., Shany S, Tobvin D, Chaimovitz C and Douvdevani A. Vitamin D decreases NFiB activity by increasing IiBa levels. Nephrol Dial Transplant (2006) 21: 889–897
14. Beard JA, Bearden A, Striker R. Vitamin D and the anti-viral state. J Clin Virol. 2011 Mar;50(3):194-200
15. Kritchevsky SB, Tooze JA, Neiberg RH, Schwartz GG, Hausman DB, Johnson MA, Bauer DC, Cauley JA, Shea MK, Cawthon PM, et al. 25-hydroxyvitamin D, parathyroid hormone, and mortality in black and white older adults: the health ABC study. J Clin Endocrinol Metab (2012) ;97:4156–65.
16. Clemens TL, Adams JS, Henderson SL, Holick MF. Increased skin pigment reduces the capacity of skin to synthesise vitamin D3. Lancet (1982);1:74–6
17. Cooke, G.L., Chien, A.., Brodsky, A. and Lee RC “Is the Incidence of Hypertrophic Scars among African-Americans Linked to Vitamin D3 Metabolism?” J Nat’l Med Assoc. (2005) 97(7):1004-9
Paige-Ashley Campbell, M.S.
Mimi Wu-Young, MD
Raphael C. Lee, MD, ScD, FACS
Competing interests:
No competing interests
08 April 2020
Paige-Ashley Campbell
Medical Student
Mimi Wu-Young, MD, and Raphael C. Lee, MD, ScD
Pritzker School of Medicine, University of Chicago
c/o Raphael C. Lee, MD, ScD, Dsc, University of Chicago Hospitals, Chicago, Illinois 60637
Rapid Response:
Re: Covid-19: what treatments are being investigated? Vitamin D3 may reduce severity of COVID-19 respiratory viral infection
Dear Editor
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. [1] Indeed, COVID-19 is known to activate the NF-κB pathway that results in the upregulation of many inflammatory gene promoters. [2] 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. [8]
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. [11] Furthermore, data from clinical studies indicate that VD3 deficiency is clinically associated with increased susceptibility to respiratory viral infections and increased severity once infected. [12] 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.
References:
1. Christman JW, Sadikot RT, Blackwell TS. The role of nuclear factor-κB in pulmonary diseases. Chest (2000) 117: 1482–1487
2. Guo YR, Cao QD, Hong ZS, et al. The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak - an update on the status. Military Medical Research (2020) 7(11): 1-10
3. DeDiego ML, Nieto-Torres JL, Regla-Nava JA, Jimenez-Guardeño JM, Fernandez
4. Delgado R, Fett C, Castaño-Rodriguez C, Perlman S, Enjuanes L. Inhibition of NF-κB-mediated inflammation in severe acute respiratory syndrome coronavirus-infected mice increases survival. J Virol. .(2014) Jan;88(2):913-24.
5. Ziebuhr J.. The coronavirus replicase. Curr. Top. Microbiol. Immunol. (2005)25 287:57–94.
6. Dosch SF, Mahajan SD, Collins AR. SARS coronavirus spike protein-induced innate immune response occurs via activation of the NF-kappaB pathway in human monocyte macrophages in vitro. Virus Res. (2009) 142(1-2):19–27.
7. Law AH, Lee DC, Cheung BK, Yim HC, Lau A . Role for nonstructural protein 1 of severe acute respiratory syndrome coronavirus in chemokine dysregulation. J. Virol. (2007) 81:416-422.
8. Liao QJ, Ye LB, Timani KA, Zeng YC, She YL, Ye L, Wu ZH . Activation of NF-κB by the full-length nucleocapsid protein of the SARS coronavirus. Acta Biochim. Biophys. Sin. (2005). 37:607-612.
9. Wöbke TK, Sorg BL, Steinhilber D. Vitamin D in inflammatory diseases. Front Physiol. (2014) Jul 2;5:244.
10. Zhang Y., Leung D. Y., Richers B. N., Liu Y., Remigio L. K., Riches D. W., et al. Vitamin D inhibits monocyte/macrophage proinflammatory cytokine production by targeting MAPK phosphatase-1. J. Immunol. (2012). 188, 2127–2135
11. Cantorna, M., Zhu, Y., Froicu, M. and Wittke, A.. Vitamin D status, 1,25-dihydroxyvitamin D3, and the immune system. The American Journal of Clinical Nutrition, (2004) 80(6), pp.1717S-1720S.
12. Ginde A. A., J. M. Mansbach, C. A. Camargo Jr... Association between serum 25-hydroxyvitamin D level and upper respiratory tract infection in the Third National Health and Nutrition Examination Survey. Arch. Intern. Med. (2009)169: 384–390.
13. Cohen-Lahav M., Shany S, Tobvin D, Chaimovitz C and Douvdevani A. Vitamin D decreases NFiB activity by increasing IiBa levels. Nephrol Dial Transplant (2006) 21: 889–897
14. Beard JA, Bearden A, Striker R. Vitamin D and the anti-viral state. J Clin Virol. 2011 Mar;50(3):194-200
15. Kritchevsky SB, Tooze JA, Neiberg RH, Schwartz GG, Hausman DB, Johnson MA, Bauer DC, Cauley JA, Shea MK, Cawthon PM, et al. 25-hydroxyvitamin D, parathyroid hormone, and mortality in black and white older adults: the health ABC study. J Clin Endocrinol Metab (2012) ;97:4156–65.
16. Clemens TL, Adams JS, Henderson SL, Holick MF. Increased skin pigment reduces the capacity of skin to synthesise vitamin D3. Lancet (1982);1:74–6
17. Cooke, G.L., Chien, A.., Brodsky, A. and Lee RC “Is the Incidence of Hypertrophic Scars among African-Americans Linked to Vitamin D3 Metabolism?” J Nat’l Med Assoc. (2005) 97(7):1004-9
Paige-Ashley Campbell, M.S.
Mimi Wu-Young, MD
Raphael C. Lee, MD, ScD, FACS
Competing interests: No competing interests