A recent study published on the bioRxiv* preprint server reports that vitamin D deficiency enhances disease severity, while adequate vitamin D supplementation reduces inflammation, after H1N1 and severe acute respiratory syndrome coronavirus (SARS-CoV-2) infections in mice.
Study: Vitamin D and the ability to produce 1,25(OH)2D are critical for protection from viral infection of the lungs. Image Credit: Festa / Shutterstock.com
Sommaire
Background
Low vitamin D status is associated with a poor prognosis in patients with acute respiratory diseases, such as influenza and the coronavirus disease 2019 (COVID-19). In fact, recent evidence has indicated that low circulating vitamin D (serum 25(OH)D, 25D) levels were associated with severe disease and higher mortality rates in COVID-19 patients. As a result, high-dose vitamin D supplementation has been recommended to reduce the severity of these infections.
The relationship between vitamin D levels and respiratory disease severity appears to be due to the antiviral activity of vitamin D that may be specific to each virus. For example, vitamin D, as well as its analogs, appear to induce the production of cathelicidin, which is an antimicrobial peptide that is released in response to viral infections. Conversely, vitamin D may also limit inflammatory responses by reducing interferon γ (IFN- γ), interleukin 6 (IL-6), and tumor necrosis factor α (TNF-α) levels.
Lung epithelial cells express the vitamin D receptor (VDR) and are regulated by 1,25D supplementation. Thus, vitamin D treatment has been shown to directly affect the lung epithelium and reduce the inflammatory response within the lungs.
Vitamin D supplementation and H1N1 infection
The researchers in the current study sought to further evaluate the lung response of vitamin D supplementation in treating both H1N1 and SARS-CoV-2 infection in vivo. For the H1N1 studies, the researchers utilized two different strains of mice, of which included wildtype (WT) and CYP27B1 knockout (Cyp KO) mice. Taken together, age and sex-matched mice were fed chow diets, which contained vitamin D (D+) or purified diets with (D+) and without (D-) vitamin D.
The CYP27B1 gene ensures the production of 1-alpha hydroxylase, which initiates the production of 1,25D, the active form of vitamin D. Because Cyp KO mice are unable to produce 1,25D, the researchers were able to assess the effects of both H1N1 and SARS-CoV-2 infection in the presence of a severe vitamin D deficiency, as well as how vitamin D supplementation might improve the inflammatory response in this environment.
Irrespective of the genotype, serum 25hydroxy vitamin D (25D) levels markedly varied amongst mice fed a D+ or D- diet. Nevertheless, 25D levels in D+Cyp KO mice were greater than those of D+WT mice.
Although all mice infected with H1N1 experienced respiratory distress seven days after infection, D+WT mice experienced the least amount of respiratory distress. All symptoms of respiratory distress in both WT and Cyp KO mice receiving vitamin D supplementation were resolved by day 10. Comparatively, both D-WT and D-Cyp KO continued to experience greater symptoms of respiratory distress that did not completely resolve by day 14.
In addition to symptom resolution, vitamin D supplementation provided the greatest benefit to WT mice in terms of their survival, as well as lung pathologies. Despite vitamin D supplementation in Cyp KO mice, their baseline level of damage within the lungs, combined with the respiratory effects of H1N1 infection, could not be recovered with vitamin D supplementation.
Taken together, vitamin D deficiency and the lack of 1,25D synthesis increased the vulnerability of mice to H1N1 infection.
Vitamin D deficiency and Cyp27B1 KO increases susceptibility to H1N1 infection. D+ and D- WT and D+ and D- Cyp KO littermates were infected with H1N1 influenza (n=13-18 per group). A) Serum 25D, B)respiratory distress symptoms and C) survival of D+ WT (n=18), D+ Cyp KO (n=13), D- WT (n=13) and D- Cyp KO (n=12) mice at d14 post-infection. D) lung alveolar hemorrhage, perivascular infiltration and lymphocyte infiltration in D+ WT (n=4) and D- WT (n=4-5) and D- Cyp KO (n=2-3) mice at d0 and d4 post-infection. E) Representative histology of the lung of D+ WT (score = 3), D+ Cyp KO (score = 4), D- WT (score = 5.5) and D- Cyp KO (score = 6) at d14 post-infection. Values are the mean ± SEM. Statistical significance was assessed using one-way ANOVA with Bonferroni multiple comparison test for (A), two-way ANOVA with Bonferroni multiple comparison test for (B & D) and Log rank (Mankel-Cox) survival analysis for (C). **P < 0.01, ***P < 0.001 and ****P < 0.0001.
Vitamin D supplementation and SARS-CoV-2
SARS-CoV-2 infection and the effects of vitamin D supplementation were assessed in mice expressing the human angiotensin-converting enzyme 2 (ACE2) receptor, which is the receptor utilized by SARS-CoV-2 to gain entry into cells. Since Cyp27B1 remained present in this mouse strain, some mice were given a vitamin D deficient chow for eight weeks prior to infection to induce a state of vitamin D deficiency.
Vitamin D supplementation both before and after infection with SARS-CoV-2 led to significantly higher serum 25D levels as compared to vitamin D deficient mice. Meanwhile, vitamin D supplementation did not appear to impact survival rates following SARS-CoV-2 infection.
Mice consuming a vitamin D supplemented diet both before and after SARS-CoV-2 infection exhibited improved lung pathologies in terms of reduced expression of IFN-β, alveolar remodeling, type II hyperplasia, and total histopathology scores.
Les chercheurs ont également évalué les effets de la supplémentation en vitamine D après une infection par le SRAS-CoV-2 chez des hamsters dorés syriens. Semblable aux études sur la souris, les chercheurs ont également établi un état de carence en vitamine D chez les hamsters pour mieux comprendre comment la supplémentation en vitamine D pourrait améliorer les résultats de l’infection par le SRAS-CoV-2 dans cet environnement.
À cette fin, les taux sériques de 25D étaient comparables entre les hamsters nourris avec un régime alimentaire (D+) et ceux nourris avec un régime D- pendant quatre semaines. De plus, l’expression du gène de la nucléocapside (N) du SRAS-CoV-2 ne différait pas entre les poumons ou le côlon D+ et D-.
conclusion
Un état déficient en vitamine D semble être vulnérable aux infections virales en raison de la présence d’une inflammation pulmonaire préexistante.
Pris ensemble, l’étude actuelle démontre que la supplémentation en vitamine D réduit l’inflammation pulmonaire chez les souris infectées par le H1N1 et le SRAS-CoV-2. Notamment, les effets bénéfiques de la supplémentation en vitamine D chez les hamsters infectés par le SRAS-CoV-2 n’étaient pas remarquables. Cette absence d’effet chez les hamsters peut être due à l’incapacité des aliments disponibles dans le commerce à augmenter les niveaux de 25D.
D’autres études sont nécessaires pour décrire le mécanisme antiviral de la vitamine D dans la prévention des maladies respiratoires aiguës et les variations d’effet, le cas échéant, que sa supplémentation a dans la prévention de la grippe H1N1 et de l’infection par le SRAS-CoV-2.
*Avis important
medRxiv publie des rapports scientifiques préliminaires qui ne sont pas évalués par des pairs et, par conséquent, ne doivent pas être considérés comme concluants, guider la pratique clinique/les comportements liés à la santé, ou traités comme des informations établies.
