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2021, vol. 78, br. 1, str. 35-39
Mogući uticaj sniženih nivoa folne kiseline i vitamina B12 na reaktivaciju herpes simpleks virusnog keratitisa
aKlinički centar Srbije, Klinika za očne bolesti, Beograd
bKlinički centar Srbije, Klinika za očne bolesti, Beograd + Univerzitet u Beogradu, Medicinski fakultet
cCollege for Specialized Studies, Belgrade
dNaučni institut za veterinarstvo Srbije, Beograd
eUniverzitet u Beogradu, Medicinski fakultet, GAK 'Narodni front'

e-adresasb.bora@gmail.com
Ključne reči: herpesvirus 1, humani; folna kiselina; keratitis; recidiv; faktori rizika; vitamin b12
Sažetak
Uvod/Cilj. Herpetični keratitis u većini slučajeva je rekurentna bolest, a nastaje kao rezultat reaktivacije herpes simpleks virusa tipa 1 iz latentnosti u najbližoj senzornoj gangliji. Zbog toga je razumevanje mehanizma latentnosti i reaktivacije latentnog virusa važna karika u razumevanju nastanka recidivne bolesti oka. Sve više studija potvrđuje epigenetsku regulaciju reaktivacije virusa kao posledicu prisustva transkripciono aktivnog transkripta vezanog za latenciju (LAT) regiona u latentnom virusnom genomu. Aktivnost LAT regiona usmerena je na hromatinsko uređenje. Epigenetska modulacija metilacije DNA je povezana sa unosom folata i vitamina B12 ili njihovim koncentracijama u serumu. Prema našim saznanjima, ne postoji izveštaj o potencijalnoj ulozi vitamina B12 i folne kiseline u reaktivaciji HSV keratitisa. Cilj rada bio je analiza moguće uloge folne kiseline i vitamina B12 u kontroli reaktivacije okularnog herpetičnog keratitisa. Metode. Studijom je bilo obuhvaćeno 50 bolesnika starijih od 18 godina sa različitim formama herpetičnog keratitisa, kao posledicom reaktivacije herpes simpleks virusa tipa 1. Nivoi vitamina B12 i folne kiseline mereni su u akutnoj fazi bolesti. Svi bolesnici su praćeni najmanje godinu dana, a beležen je broj recidiva virusne infekcije. Rezultati. Stopa recidiva herpetičnog keratitisa bila je statistički značajno niža kod bolesnika sa višim nivoom vitamina B12 u krvi. Pored toga, stopa recidiva herpetičnog keratitisa je bila niža i kod bolesnika sa višim nivoom folne kiseline u krvi, ali sa nižom statističkom značajnošću u poređenju sa onom za vitamin B12. Zaključak. Sniženi nivoi vitamina B12 i folne kiseline mogu imati važnu ulogu u reaktivaciji herpetičnog keratitisa.

Introduction

The results of recent studies have shown that 50%-90% of adult humans have serum antibodies to herpes simplex virus (HSV) type 1 (HSV-1) [1][2].

The annual incidence of all types of new ocular HSV infections has recently been estimated at 11.8 to 31.5 per 100,000 persons a year [3][4]. The epithelial dendritic lesion is the most frequent type of recurrent keratitis, with prevalence as high as 56.3%, followed by stromal keratitis, 29.5% 4. The clinical manifestations of primary HSV ocular infection are rare [5]. Reactivation of the latent virus in the ophthalmic branch of trigeminal ganglion can result in its shedding with subsequent infection of the overlying corneal epithelium [6][7]. Herpetic keratitis occurs in various forms, and this largely depends on the depth of virus penetration into a corneal tissue. The direct effect of the virus and potent immune response to the viral proteins trigger corneal inflammation and neovascularisation leading to corneal thinning and scarring [8].

Most cases of herpetic keratitis represent a recurrent disease that occurs as a result of HSV-1 reactivation from latency. Due to its recurrent nature, after cataract, herpes virus keratitis is the second leading cause of corneal blindness in the developed world. Therefore, understanding the mechanism and causes of HSV-1 reactivation from the latent state has long been the holy grail of herpes virologists. In animal models and later humans, the latency of the virus may have an epigenetic regulation, primarily because the latent viral genome has a transcriptionally active Latency-Associated Transcript (LAT) region. The activity of the LAT region is directed to chromatin arrangement without the encoding of known proteins [9]. Although viral mutants lacking LATs are still able to establish and maintain reactivation from latency, recent findings indicate that the LAT-region increases the reactivation efficiency and, in some way, controls the latency of the virus itself [10][11].

The aim of this study was to analyze the potential role of folic acid and B12 vitamin in the control of ocular HSV-1 reactivation. To our knowledge, there is no report on the potential role of vitamin B12 and folic acid in keratitis reactivation.

Methods

This study was conducted in compliance with the institutional review board regulations, the informed consent regulation, and it adhered to the tenets of the Declaration of Helsinki. It included 50 patients older than 18 years of age, regardless of gender, with recurrent ocular HSV-1 disease. Recurrent herpetic keratitis was confirmed by slit lamp examination based on clinical findings. The recurrences were classified as epithelial keratitis, stromal keratitis, endothelitis, iridocyclitis, or as combinations of these conditions. Exclusion criteria were as follows: existing history of associated ophthalmic comorbidities, previous ocular surgery, some form of anemia, or systemic and neurological diseases.

All patients received at least a one-year follow-up between January 2017 and January 2018 at the Clinic for Eye Diseases, Clinical Center of Serbia in Belgrade. In all patients, levels of vitamin B12 and folic acid were measured during the acute phase of the recurrent ocular HSV disease.

All patients were fasting for 8 hours before having their blood samples taken. In addition, none of the included patients took any form of vitamin B complex supplementation for at least 12 months prior to the blood sample harvesting. Two milliliters of venous blood was collected in a standard biochemical tube. Vitamin B12 level was measured on the "Roche Cobas 6000" analyzer, (ECLIA Method) and folate level on the "Roche Cobas E411" analyzer, (ECLIA Method). Blood samples were analyzed in the same laboratory, certified by the Total Quality Management (TQM) quality system. Reference values for serum levels of vitamin B12 and folic acid were 6.9-44.4 ng/mL and 4.6-18.7 ng mL, respectively. Statistical analysis was performed using SPSS Statistics 17.

Results

The analysis of our results showed that in all patients, blood levels of vitamin B12 and folic acid were in the lower reference range. According to the scatter diagrams (Figure 1 and Figure 2), there was a drop in the number of relapses (as dependent variable) depending on both the blood level of vitamin B12 and folic acid (independent variable).

Figure 1 Scatter plot for vitamin B12 levels vs. number of herpetic keratitis recurrences

Figure 2 Scatter plot for folic acid levels vs. number of herpetic keratitis recurrences

Analysis of Variance (ANOVA) and F-test (F= 5.031) (Table 1) showed that there were highly statistically significant difference between dependent (number of recurrences) and independent variables (B12 level in the blood); thus, the model had a statistical significance.

Table 1. Differences between number of herpetic keratitis recurrences and vitamin B12 level in blood

Model Sum of squares df Mean square F Sig.
1 Regression 3.265 1 3.265 5.031 0.030
Residual 31.155 48 0.649
Total 34.420 49

Dependent variable: number of recurrences; Predictors: (constant), vitamin B12 level in blood.

Pearsonʼs correlation coefficient (Table 2) showed a statistically significant correlation between the level of vitamin B12 in the acute phase of the disease recurrence and the number of HSV keratitis recurrences.

Table 2. Correlation between the levels of vitamin B12 and folic acid and the number of herpetic keratitis recurrences

Variable B12 in blood Folic acid in blood Number of recurrences
B12 in blood
 correlation coefficient 1 0.587 -0.308
 sig. (2-tailed) 0.000 0.030
Folic acid in blood
 correlation coefficient 1 -0.200
 sig. (2-tailed) 0.164
Number of recurrences
 correlation coefficient 1
 sig. (2-tailed)

sig. – significance.

A higher level of vitamin B12 was associated with a reduced rate of disease recurrences. A higher folate level also had an impact on the decrease of the number of HSV keratitis recurrences; however, it was not as significant as vitamin B12 impact.

Discussion

Both vitamin B12 and folic acid are involved in the methylation process of DNA molecules. Methylation of DNA molecules is associated with folate intake and serum folate concentrations in the body [12]. A better insight into the epigenetic nature of the virus itself might help control HSV reactivation by using additional supplements in patients at higher risk of the disease recurrence. Interestingly, a case study from 1956 did not consider the epigenetic nature of virus reactivation. However, additional vitamin B12 supplementation significantly improved the clinical course of herpetic keratitis. Those patients experienced a milder clinical picture of recurrent herpetic eye disease [13][14].

Reactivation of the virus from a latent phase of the disease into active HSV-1 keratitis may depend on the minimal deficiency of vitamin B12 or folic acids.

In our study, all patients had lower reference values of these vitamins in the acute phase of the disease. Therefore, this may be a potential trigger for virus reactivation and more severe clinical manifestations of herpetic keratitis.

Several studies have also found similar results with other viruses. Interestingly, Piyathilake et al. [15] evaluated the influence of plasma folate and vitamin B12 concentrations on cervical cancer risk. Folate and vitamin B12 may play a critical role in lowering the human papillomavirus (HPV) 16 methylation-associated risk of developing higher grades of cervical intraepithelial neoplasia. Likewise, Lopes et al. [16] revealed that vitamin B12 intake was inversely associated with nononcogenic HPV persistence. Recently, it has been observed that recurrent aphthous stomatitis, including herpetic etiology, was also related to iron and vitamin B12 deficiency [17].

HSV establishes a latent infection in sensory neurons. The fact that the latent viral genome has a transcriptionally active LAT region that encodes the protein and transcriptionally inactive lytic gene regions suggests epigenetic regulation. The LAT region itself records various forms of histone arrangement [9][18][19].

Immunological control of virus reactivation should also be considered. The environmental and physiologic factors that induce HSV-1 reactivation from latency include exposure to UV light, stress, and immune suppression, suggesting a possible role for T cells in preventing viral reactivation [20][21][22]. Studies in rabbits and mice also demonstrated that T cells infiltrate sensory neurons of the eye region around 8-10 days after corneal infection and remain there [23][24].

The virus does not produce proteins in the latency period, and in that way, it ʽhidesʼ from the immune system. Therefore, what maintained the attraction of CD8+ T cells for latently infected neurons was unclear. At this juncture, a definition of the terms latency and reactivation is important. The virus is able to hide from the host immune system during latency since the immune system can only respond to viral protein synthesis.

As recently postulated, asymptomatic virus latency may also be related to the epigenetic nature of the virus. In our study, higher blood levels of both folic acid and vitamin B12 were associated with a reduced rate of recurrent herpetic keratitis. Future clinical and molecular epigenetic studies are necessary to clarify this further.

Conclusion

Our study showed that all patients in the acute phase of the disease had lower reference values of vitamin B12 and folic acid. Moreover, the recurrence rate of herpetic keratitis was lower in patients with higher blood levels of vitamin B12 and folic acid during the follow-up period.

Here, it is assumed that the reactivation of the HSV virus may be related to the minimal deficiency of vitamin B12 and folic acid during the latent phase of the disease.

Therefore, additional supplementation with vitamin B12 and folic acid may be helpful in preventing the reactivation of herpetic keratitis, potentially due to the epigenetic nature of virus reactivation. Further molecular epigenetic research and clinical studies may contribute to understanding and applying epigenetic therapy in herpetic eye disease.

References

1.Rabenau HF, Buxbaum S, Preiser W, Weber B, Doerr HW. Seroprevalence of herpes simplex virus types 1 and type 2 in the Frankfurt am Main area, Germany. Med Microbiol Immunol. 2002;190(4):153-160. [Crossref]
2.Xu F, Sternberg MR, Kottiri BJ, Mcquillan GM, Lee FK, Nahmias AJ, et al. Trends in herpes simplex virus type 1 and type 2 seroprevalence in the United States. JAMA. 2006;296(8):964-73. [Crossref]
3.Young RC, Hodge DO, Liesegang TJ, Baratz KH. Incidence, recurrence, and outcomes of herpes simplex virus eye disease in Olmsted County, Minnesota, 1976-2007: The effect of oral antiviral prophylaxis. Arch Ophthalmol. 2010;128(9):1178-83. [Crossref] [PubMed] [PMC]
4.Labetoulle M, Auquier P, Conrad H, Crochard A, Daniloski M, Bouee S, et al. Incidence of herpes simplex virus keratitis in France. Ophthalmology. 2005;112(5):888-895. [Crossref]
5.Darougar S, Wishart MS, Viswalingam ND. Epidemiological and clinical features of primary herpes simplex virus ocular infection. Br J Ophthalmol. 1985;69(1):2-6. [Crossref] [PubMed] [PMC]
6.Shimeld C, Hill TJ, Blyth WA, Easty DL. Passive immunization protects the mouse eye from damage after herpes simplex virus infection by limiting spread of virus in the nervous system. J Gen Virol. 1990;71(Pt 3):681-7. [Crossref]
7.Shimeld C, Hill TJ, Blyth WA, Easty DL. Reactivation of latent infection and induction of recurrent herpetic eye disease in mice. J Gen Virol. 1990;71(Pt 2):397-404. [Crossref]
8.Jones BR. The clinical features of viral keratitis and a concept of their pathogenesis. Proc R Soc Med. 1958;51(11):917-924. [Crossref]
9.Umbach JL, Kramer MF, Jurak I, Karnowski HW, Coen DM, Cullen BR, et al. MicroRNAs expressed by herpes simplex virus 1 during latent infection regulate viral mRNAs. Nature. 2008;454(7205):780-783. [Crossref] [PubMed] [PMC]
10.Bertke AS, Swanson SM, Chen J, Imai Y, Kinchington PR, Margolis TP, et al. A5-positive primary sensory neurons are nonpermissive for productive infection with herpes simplex virus 1 in vitro. J Virol. 2011;85(13):6669-6677. [Crossref] [PubMed] [PMC]
11.Yang L, Voytek CC, Margolis TP. Immunohistochemical analysis of primary sensory neurons latently infected with herpes simplex virus type 1. J Virol. 2000;74(1):209-217. [Crossref] [PubMed] [PMC]
12.Anderson OS, Sant KE, Dolinoy DC. Nutrition and epigenetics: An interplay of dietary methyl donors, one-carbon metabolism and DNA methylation. J Nutr Biochem. 2012;23(8):853-859. [Crossref] [PubMed] [PMC]
13.Maclatchy RS. Herpes ophthalmicus. Br J Ophthalmol. 1956;40(12):762-764. [Crossref] [PubMed] [PMC]
14.Rossler H. Zur Behandlung des Herpes zoster ophthalmicus. Klin Mbl Augenheilk. 1956;128.
15.Piyathilake CJ, Macaluso M, Chambers MM, Badiga S, Siddiqui NR, Bell WC, et al. Folate and vitamin B12 may play a critical role in lowering the HPV 16 methylation-associated risk of developing higher grades of CIN. Cancer Prev Res (Phila). 2014;7(11):1128-1137. [Crossref] [PubMed] [PMC]
16.Lopes RDVC, Teixeira JA, Marchioni D, Villa LL, Giuliano AR, Luiza BM, et al. Dietary intake of selected nutrients and persistence of HPV infection in men. Int J Cancer. 2017;141(4):757-765. [Crossref] [PubMed] [PMC]
17.Ślebioda Z, Krawiecka E, Szponar E, Dorocka-Bobkowska B. Haematinic deficiencies and patient clinical profiles in Polish patients with recurrent aphthous stomatitis (RAS). J Oral Pathol Med. 2018;47(5):531-537. [Crossref]
18.Bloom DC, Giordani NV, Kwiatkowski DL. Epigenetic regulation of latent HSV-1 gene expression. Biochim Biophys Acta Gene Regul Mech. 2010;1799(3-4):246-256. [Crossref] [PubMed] [PMC]
19.Cliffe AR, Garber DA, Knipe DM. Transcription of the herpes simplex virus latency-associated transcript promotes the formation of facultative heterochromatin on lytic promoters. J Virol. 2009;83(16):8182-90.
20.Blyth WA, Hill TJ, Field HJ, Harbour DA. Reactivation of herpes simplex virus infection by ultraviolet light and possible involvement of prostaglandins. J Gen Virol. 1976;33(3):547-550. [Crossref]
21.Bonneau RH, Sheridan JF, Feng N, Glaser R. Stress-induced modulation of the primary cellular immune response to herpes simplex virus infection is mediated by both adrenal-dependent and independent mechanisms. J Neuroimmunol. 1993;42(2):167-176. [Crossref]
22.Sainz B, Loutsch JM, Marquart ME, Hill JM. Stress-associated immunomodulation and herpes simplex virus infections. Med Hypotheses. 2001;56(3):348-356. [Crossref]
23.Vicetti MRD, Sheridan BS, Harvey SAK, Schreiner RS, Hendricks RL, Cherpes TL, et al. 17-beta estradiol promotion of herpes simplex virus type 1 reactivation is estrogen receptor dependent. J Virol. 2010;84(1):565-572. [Crossref] [PubMed] [PMC]
24.Gebhardt BM, Hill JM. T lymphocytes in the trigeminal ganglia of rabbits during corneal HSV infection. Invest Ophthalmol Vis Sci. 1988;29(11):1683-691.
25.Liu T, Tang Q, Hendricks RL. Inflammatory infiltration of the trigeminal ganglion after herpes simplex virus type 1 corneal infection. J Virol. 1996;70(1):264-271. [Crossref]
Reference
Anderson, O.S., Sant, K.E., Dolinoy, D.C. (2012) Nutrition and epigenetics: An interplay of dietary methyl donors, one-carbon metabolism and DNA methylation. J Nutr Biochem, 23(8): 853-859
Bertke, A.S., Swanson, S.M., Chen, J., Imai, Y., Kinchington, P.R., Margolis, T.P. (2011) A5-positive primary sensory neurons are nonpermissive for productive infection with herpes simplex virus 1 in vitro. J Virol, 85(13): 6669-6677
Bloom, D.C., Giordani, N.V., Kwiatkowski, D.L. (2010) Epigenetic regulation of latent HSV-1 gene expression. Biochim Biophys Acta Gene Regul Mech, 1799(3-4): 246-256
Blyth, W.A., Hill, T.J., Field, H.J., Harbour, D.A. (1976) Reactivation of herpes simplex virus infection by ultraviolet light and possible involvement of prostaglandins. J Gen Virol, 33(3): 547-550
Bonneau, R.H., Sheridan, J.F., Feng, N., Glaser, R. (1993) Stress-induced modulation of the primary cellular immune response to herpes simplex virus infection is mediated by both adrenal-dependent and independent mechanisms. J Neuroimmunol, 42(2): 167-176
Cliffe, A.R., Garber, D.A., Knipe, D.M. (2009) Transcription of the herpes simplex virus latency-associated transcript promotes the formation of facultative heterochromatin on lytic promoters. J Virol, 83(16): 8182-90
Darougar, S., Wishart, M.S., Viswalingam, N.D. (1985) Epidemiological and clinical features of primary herpes simplex virus ocular infection. Br J Ophthalmol, 69(1): 2-6
Gebhardt, B.M., Hill, J.M. (1988) T lymphocytes in the trigeminal ganglia of rabbits during corneal HSV infection. Invest Ophthalmol Vis Sci, 29(11): 1683-691
Jones, B.R. (1958) The clinical features of viral keratitis and a concept of their pathogenesis. Proc R Soc Med, 51(11): 917-924
Labetoulle, M., Auquier, P., Conrad, H., Crochard, A., Daniloski, M., Bouee, S., Elhasnaoui, A., Colin, J. (2005) Incidence of herpes simplex virus keratitis in France. Ophthalmology, 112(5): 888-895.e1
Liu, T., Tang, Q., Hendricks, R.L. (1996) Inflammatory infiltration of the trigeminal ganglion after herpes simplex virus type 1 corneal infection. J Virol, 70(1): 264-271
Lopes, R.D.V.C., Teixeira, J.A., Marchioni, D., Villa, L.L., Giuliano, A.R., Luiza, B.M., Fisberg, R.M. (2017) Dietary intake of selected nutrients and persistence of HPV infection in men. Int J Cancer, 141(4): 757-765
Maclatchy, R.S. (1956) Herpes ophthalmicus. Br J Ophthalmol, 40(12): 762-764
Piyathilake, C.J., Macaluso, M., Chambers, M.M., Badiga, S., Siddiqui, N.R., Bell, W.C., Edberg, J.C., Partridge, E.E., Alvarez, R.D., Johanning, G.L. (2014) Folate and vitamin B12 may play a critical role in lowering the HPV 16 methylation-associated risk of developing higher grades of CIN. Cancer Prev Res (Phila), 7(11): 1128-1137
Rabenau, H.F., Buxbaum, S., Preiser, W., Weber, B., Doerr, H.W. (2002) Seroprevalence of herpes simplex virus types 1 and type 2 in the Frankfurt am Main area, Germany. Med Microbiol Immunol, 190(4): 153-160
Rossler, H. (1956) Zur Behandlung des Herpes zoster ophthalmicus. Klin Mbl Augenheilk, 128: 727. (German)
Sainz, B., Loutsch, J.M., Marquart, M.E., Hill, J.M. (2001) Stress-associated immunomodulation and herpes simplex virus infections. Med Hypotheses, 56(3): 348-356
Shimeld, C., Hill, T.J., Blyth, W.A., Easty, D.L. (1990) Passive immunization protects the mouse eye from damage after herpes simplex virus infection by limiting spread of virus in the nervous system. J Gen Virol, 71(Pt 3): 681-7
Shimeld, C., Hill, T.J., Blyth, W.A., Easty, D.L. (1990) Reactivation of latent infection and induction of recurrent herpetic eye disease in mice. J Gen Virol, 71(Pt 2): 397-404
Ślebioda, Z., Krawiecka, E., Szponar, E., Dorocka-Bobkowska, B. (2018) Haematinic deficiencies and patient clinical profiles in Polish patients with recurrent aphthous stomatitis (RAS). J Oral Pathol Med, 47(5): 531-537
Umbach, J.L., Kramer, M.F., Jurak, I., Karnowski, H.W., Coen, D.M., Cullen, B.R. (2008) MicroRNAs expressed by herpes simplex virus 1 during latent infection regulate viral mRNAs. Nature, 454(7205): 780-783
Vicetti, M.R.D., Sheridan, B.S., Harvey, S.A.K., Schreiner, R.S., Hendricks, R.L., Cherpes, T.L. (2010) 17-beta estradiol promotion of herpes simplex virus type 1 reactivation is estrogen receptor dependent. J Virol, 84(1): 565-572
Xu, F., Sternberg, M.R., Kottiri, B.J., Mcquillan, G.M., Lee, F.K., Nahmias, A.J., Berman, S.M., Markowitz, L.E. (2006) Trends in herpes simplex virus type 1 and type 2 seroprevalence in the United States. JAMA, 296(8): 964-73
Yang, L., Voytek, C.C., Margolis, T.P. (2000) Immunohistochemical analysis of primary sensory neurons latently infected with herpes simplex virus type 1. J Virol, 74(1): 209-217
Young, R.C., Hodge, D.O., Liesegang, T.J., Baratz, K.H. (2010) Incidence, recurrence, and outcomes of herpes simplex virus eye disease in Olmsted County, Minnesota, 1976-2007: The effect of oral antiviral prophylaxis. Arch Ophthalmol, 128(9): 1178-83
 

O članku

jezik rada: engleski
vrsta rada: izvorni naučni članak
DOI: 10.2298/VSP181001037S
primljen: 01.10.2018.
revidiran: 05.03.2019.
prihvaćen: 11.03.2019.
objavljen onlajn: 15.03.2019.
objavljen u SCIndeksu: 05.02.2021.
metod recenzije: dvostruko anoniman
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