How Do Viruses Really Cause Neuropathology?: Is There More to the Story

¹Department of Psychiatry and Pediatrics, University of Florida College of Medicine, USA

²Dartmouth Hitchcock Medical Center, USA

*Corresponding Author:

Jacqueline A Hobbs
Department of Psychiatry
University of Florida College of Medicine
Gainesville, Florida, USA
Tel: 352294-4945
Fax: 3525941818
E-mail: jahobbs@ufl.edu

Received date: September 19, 2016; Accepted date: September 27, 2016; Published date: September 29, 2016

Citation: Hobbs JA, Waseem H (2016) How Do Viruses Really Cause Neuropathology?: Is There More to the Story. J Neuroinfect Dis 7: 228. doi:10.4172/2314-7326.1000228

Copyright: © 2016 Hobbs JA, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Abstract

Our work has focused over the years on Primate Erythroparvovirus 1 [more commonly known as parvovirus B19 (B19)]. B19 is a human pathogen that is the causative agent of erythema infectiosum, the common rash disease of childhood. In addition to several other human diseases, B19 has also been associated with multiple brain diseases. Those brain diseases include, but are not limited to, encephalitis, encephalopathy, meningitis, meningoencephalitis, ataxia, seizures, and stroke. To date, the association has grown, but causation has not been determined. Several possible mechanisms of pathogenesis including direct infection, indirect/epigenetic, reactivation, and autoimmune/ inflammatory cytotoxicity, as well as effects due to infection of other organs have been suggested. We will also offer other hypotheses.

Keywords

Parvovirus B19; Brain; Autoimmunity; Inflammation; Reactivation; Epigenetic

Introduction

Primate Erythroparvovirus 1 [more commonly known as parvovirus B19 (B19)] is a small, non-enveloped, single-stranded DNA virus [1]. Particle sizes are approximately 23 nm in diameter. The viral genome is 5,596 nucleotides in length. The genome encodes 2 major protein types: the nonstructural (replication) protein (NS1) and the viral capsid proteins (VP1/2), as well as some other more minor proteins. B19 is a human pathogen that is a known cause of several human diseases [1,2] including, but not limited to, aplastic crisis, erythema infectiosum (fifth disease), arthritis, thrombocytopenia, hydrops fetalis, and myocarditis. B19 infection has been associated with multiple brain diseases [1-3] such as encephalitis, encephalopathy, meningitis, meningoencephalitis, ataxia, seizures, and stroke. Herein we discuss possible mechanisms by which B19 and possibly other viruses may cause brain disease.

Direct Infection/Persistence

We have shown in large-scale (N>100 subjects) studies that B19 DNA can be detected in two different regions of the brain: dorosolateral prefrontal cortex [4] and cerebellum [5]. In a smallerscale (N<30 subjects) study, Manning et al. also detected B19 in frontal and occipital lobes [6]. Therefore, B19 infection and persistence in the brain are strongly supported.

Replication of B19 in general leads to expression of its NS1 protein. B19 NS1 has been shown to induce apoptosis in permissive and nonpermissive cell types [7-10]. NS1-induced cytotoxicity was suspected as early as 1994 to play a role in neuropathology [11]. NS1-induced cytotoxicity is likely a major mechanism by which B19 could cause neuropathology.

Indirect/Epigenetic

Another possible mechanism is that B19 may exert epigenetic effects by modifying cellular gene expression. Though there have been no studies linking B19 to brain disease via epigenetic effects, there has been one report of B19 association with a DNA methylation pattern in B cells of subjects with acute lymphoblastic leukemia [12]. Thus there is the potential for B19 to cause neuropathology by indirect effects on cells.

It has been reported that many virally encoded proteins are able to interact with and affect the function of host DNA methyltransferases (DNMTs). An example is the Kaposi's sarcoma-associated virus (KSHV)-encoded latency associated nuclear antigen (LANA) [12,13]. In addition, virus infection can also alter the expression levels of DNMTs. For instance, in HBV-infected cells it has been demonstrated that all levels of DNMTs are elevated [14]. In mammals, DNMTs play a major role in the establishment and maintenance of DNA methylation at non-imprinted loci [15]. Furthermore, recent observation has revealed that DNMTs physically interact with histone methyltransferase G9a and maintain imprinted DNA methylation at imprinted control regions (ICRs) [16]. As normal expression of imprinted genes is controlled by the DNA methylation that is present at the ICRs [17] and aberrant expression of imprinted genes leads to severe human mental disorders [18], viral infection might indirectly lead to human neurological disorders via alteration of DNA methylation that exists at imprinted ICRs.

Reactivation and Interaction with Other Viruses

B19 has been proven to actively replicate in erythroid progenitors [1-2]. Although the virus has been detected (via DNA) in different areas of the CNS [4-6], it has not yet been shown to fully replicate in any other cells, including the brain. Our group, as well as others, has shown that B19 gene expression, albeit at a low level, occurs in several other organs including bone marrow, heart, liver, skin, and thyroid [19,20]. We speculate that this persistent virus may be reactivated within the brain, and when this replication process is stimulated it may lead to neurological symptoms via direct cytotoxicity, due to NS1 expression, as described above. In addition, the possibility of interactions with other latent/reactivating viruses is also intriguing.

In our studies [4,5], B19 was not the only virus detected in the brain. Up to 21% of our study cohort was double-positive for B19 and adeno-associated virus (AAV). In the Manning et al. study [6], some of the subjects were also infected with the human immunodeficiency virus (HIV), also known to infect the brain. Many viruses, such as the herpes simplex virus and retroviruses, can infect and persist in the brain. The question is whether we really understand how all of these viruses interact, especially at the cellular level in the brain.

Autoimmunity/Inflammation

Suspicion of an immunological mechanism for B19 infection that may lead to neurological disorders was proposed as early as 1994 [21]. There have been numerous reports documenting B19 DNA within the brain, but some have proposed a theory suggesting that the brain may be an incomplete host for the virus and therefore stimulates an autoimmune response as opposed to direct NS1 cytotoxicity causing brain cell death [22].

The other most often discussed theory is the stimulation of the immune system by NS1. During the acute and convalescent phase of B19 infection, NS1upregulates expression of cytokines TNF-alpha and IL-6 leading to an auto-inflammatory process [23,24]. TNF-alpha is known to play an important role in cell apoptosis associated with B19 infection [25]. This could lead to a host immune response with the release of NS1 protein during cell death [26]. Also auto-antibodies such as antinuclear antibody (ANA) and rheumatoid factor (RF) have been found during and after a B19 infection [27,28]. This autoimmune response via NS1 protein may lead to brain damage, due to cell death, which in turn could manifest in specific neurological symptoms and disorders.

Infection of Other Organs and its Resulting Effect on Brain

B19 is known to cause diseases in other organs. These disease states could potentially affect brain pathology. A study found that B19 grew better under hypoxic conditions [29,30]. During a B19-induced anemia, the decreased oxygen circulation and delivery to the brain could lead to neurological manifestations. In myocarditis, fluctuating blood volumes delivered to the brain could lead to similar neurological disorders. Rheumatic disease caused by B19 can lead to vascular disorders that could cause stroke as well as hypoxia within the brain [31]. An infection of the liver with B19 can cause hyperammonemia and jaundice [32]. Bilirubin deposition in the brain and high levels of ammonia may lead to encephalopathy as well as other brain abnormalities.

The thyroid has also been implicated. There have been 3 case studies and a fourth group study linking thyroid diseases with B19 [33-36]. Our laboratory and others have shown that B19 infects the thyroid [37-39]. The thyroid’s critical role in early neurological development may be altered by B19 infections [40].

Closing Remarks

There are likely many possible mechanisms, both direct and indirect, by which viruses such as B19 may contribute to neuropathology. It is very likely that there are multiple mechanisms at play, not just one. Another thing to keep in mind is that there are many emerging or undiscovered viruses that either already have or will infect and persist in the brain. Zika virus is a prime and more recent example. How these viruses affect the brain is still not completely understood. The full extent of their contribution to neuropathology is not known. We do not fully understand how they interact with known viruses. There is also so much we do not understand about the brain.

We have a great deal to learn about virus contribution to brain disease. It is important to keep studying individual viruses and their interactions with the brain. However, we must broaden our hypotheses to incorporate an awareness of how to take into account the effects of multiple viruses on the brain.

References

1. Heegaard ED, Brown KE (2002) Human parvovirus B19. Clin Microbiol Rev 15: 485-505.
2. Young NS, Brown KE (2004) Parvovirus B19. N Engl J Med 350: 586-597.
3. Douvoyiannis M, Litman N, Goldman DL (2009) Neurologic manifestations associated with parvovirus B19 infection. Clin Infect Dis 48: 1713-1723.
4. Hobbs JA (2006) Detection of adeno-associated virus 2 and parvovirus B19 in the human dorsolateral prefrontal cortex. J Neurovirol 12: 190-199.
5. Grant JK, Yin NC, Zaytoun AM, Waseem H, Hobbs JA (2009) Persistent adeno-associated virus 2 and parvovirus B19 sequences in post-mortem human cerebellum. Cerebellum 8: 490-498.
6. Manning A, Willey SJ, Bell JE, Simmonds P (2007) Comparison of tissue distribution, persistence, and molecular epidemiology of parvovirus B19 and novel human parvoviruses PARV4 and human bocavirus. J Infect Dis 195: 1345-1352.
7. Poole BD, Zhou J, Grote A, Schiffenbauer A, Naides SJ (2006) Apoptosis of liver-derived cells induced by parvovirus B19 nonstructural protein. J Virol 80: 4114-4121.
8. Hsu TC, Wu WJ, Chen MC, Tsay GJ (2004) Human parvovirus B19 non-structural protein (NS1) induces apoptosis through mitochondria cell death pathway in COS-7 cells. Scand. J Infect Dis 36: 570-577.
9. Moffatt S, Yaegashi N, Tada K, Tanaka N, Sugamura K (1998) Human parvovirus B19 nonstructural (NS1) protein induces apoptosis in erythroid lineage cells. J Virol 72: 3018-3028.
10. Ozawa K, Ayub J, Kajigaya S, Shimada T, Young N (1988) The gene encoding the nonstructural protein of B19 (human) parvovirus may be lethal in transfected cells. J Virol 62: 2884-2889.
11. Yoto Y, Kudoh T, Asanuma H, Numazaki K, Tsutsumi Y, et al. (1994) Transient disturbance of consciousness and hepatic dysfunction associated with human parvovirus B19 infection. Lancet 344: 624-625.
12. Vasconcelos GM, Christensen BC, Houseman EA, Xiao J, Marsit CJ, et al (2011) History of parvovirus B19 infection is associated with a DNA methylation signature in childhood acute lymphoblastic leukemia. Epigenetics 6: 1436-1443.
13. Shamay M, Krithivas A, Zhang J, Hayward SD (2006) Recruitment of the de novo DNA methyltransferase Dnmt3a by Kaposi’s sarcoma-associated herpesvirus LANA. Proc Natl Acad Sci USA 103: 14554-14559.
14. Vivekanandan P, Daviel HD, Kannangai R, Martinez-Murillo F, Torbenson M (2010) Hepatitis B virus replication induces methylation of both host and viral DNA. J Virol 84: 4321-4329.
15. Okano M, Bell DW, Haber DA, Li E (1999) DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99: 247-257.
16. Zhang T, Termanis A, Özkan B, Bao XX, Culley J, et al (2016) G9a/GLP complex maintains imprinted DNA methylation in embryonic stem cells. Cell Rep 15: 77-85.
17. Reik W, Walter J (2001) Genomic imprinting: parental influence on the genome. Nat Rev Genet 2: 21-32.
18. Butler MG (2009) Genomic imprinting disorders in humans: a mini-review. J Assist Reprod Genet 26: 477-486.
19. Adamson-Small LA, Ignatovich IV, Laemmerhirt MG, Hobbs JA (2014) Persistent parvovirus B19 infection in non-erythroid tissues: possible role in the inflammatory and disease process. Virus Res 190: 8-16.
20. Adamson LA, Fowler LJ, Ewald AS, Clare-Salzler MJ, Hobbs JA (2014) Infection and persistence of erythrovirus B19 in benign and cancerous thyroid tissues. J Med Virol 86: 1614-1620.
21. Watanabe T, Satoh M, Oda Y (1994) Human parvovirus B19 encephalopathy. Arch Dis Child 70: 71.
22. Kerr JR, Barah F, Chiswick ML, McDonnell GV, Smith J, et al. (2002) Evidence for the role of demyelination, HLA-DR alleles, and cytokines in the pathogenesis of parvovirus B19 meningoencephalitis and its sequelae. J Neurol Neurosurg Psychiatr 73: 739-746.
23. Kerr JR, Barah F, Mattey DL, Laing I, Hopkins SJ, et al. (2001) Circulating tumour necrosis factor-alpha and interferon-gamma are detectable during acute and convalescent parvovirus B19 infection and are associated with prolonged and chronic fatigue. J Gen Virol 82: 3011-3019.
24. Tsay GJ, Zouali M (2006) Unscrambling the role of human parvovirus B19 signaling in systemic autoimmunity. Biochem Pharmacol 72: 1453-1459.
25. Sol N, Le Junter J, Vassias I, Freyssinier JM, Thomas A, et al. (1999) Possible interactions between the NS-1 protein and tumor necrosis factor alpha pathways in erythroid cell apoptosis induced by human parvovirus B19. J Virol 73: 8762-8770.
26. Lehmann HW, Kühner L, Beckenlehner K, Müller-Godeffroy E, Heide K-G, et al. (2002) Chronic human parvovirus B19 infection in rheumatic disease of childhood and adolescence. J Clin Virol 25: 135-143.
27. Lunardi C, Tinazzi E, Bason C, Dolcino M, Corrocher R, et al. (2008) Human parvovirus B19 infection and autoimmunity. Autoimmunity Rev 8: 116-120.
28. von Landenberg P, Lehmann HW, Modrow S (2007) Human parvovirus B19 infection and antiphospholipid antibodies. Autoimmun Rev 6: 278-285.
29. Pillet S, Le Guyader N, Hofer T, NguyenKhac F, Koken M, et al. (2004) Hypoxia enhances human B19 erythrovirus gene expression in primary erythroid cells. Virology 327: 1-7.
30. Caillet-Fauquet P, Draps ML, Di Giambattista M, de Launoit Y, Laub R (2004) Hypoxia enables B19 erythrovirus to yield abundant infectious progeny in a pluripotent erythroid cell line. J Virol Methods 121: 145-153.
31. Kerr JR (2000) Pathogenesis of human parvovirus B19 in rheumatic disease. Ann Rheum Dis 59: 672-683.
32. Karetnyi YV, Beck PR, Markin RS, Langnas AN, Naides SJ (1999) Human parvovirus B19 infection in acute fulminant liver failure. Arch Virol 144: 1713-1724.
33. Lehmann HW, Lutterbüse N, Plentz A, Akkurt I, Albers N, et al. (2008) Association of parvovirus B19 infection and Hashimoto’s thyroiditis in children. Viral Immunol 21: 379-383.
34. Mori K, Munakata Y, Saito T, J-ichi T, Nakagawa Y, et al. (2007) Intrathyroidal persistence of human parvovirus B19 DNA in a patient with Hashimoto’s thyroiditis. J Infect 55: e29-31.
35. Munakata Y, Kodera T, Saito T, Sasaki T (2005) Rheumatoid arthritis, type 1 diabetes, and Graves’ disease after acute parvovirus B19 infection. Lancet 366: 780.
36. Vejlgaard TB, Nielsen OB (1994) Subacute thyroiditis in Parvovirus B19 infection. Ugeskr Laeg 156: 6039-6040.
37. Adamson LA, Fowler LJ, Clare-Salzler MJ, Hobbs JA (2011) Parvovirus B19 Infection in Hashimoto’s Thyroiditis, Papillary Thyroid Carcinoma, and Anaplastic Thyroid Carcinoma. Thyroid 21: 411-417.
38. Wang J, Zhang W, Liu H, Wang D, Wang W, et al. (2010) Parvovirus B19 infection associated with Hashimoto’s thyroiditis in adults. J Infection 60: 360-370.
39. Wang JH, Zhang WP, Liu HX, Wang D, Li YF, et al. (2008) Detection of human parvovirus B19 in papillary thyroid carcinoma. Br J Cancer 98: 611-618.
40. Patel J, Landers K, Li H, Mortimer RH, Richard K (2011) Thyroid hormones and fetal neurological development. J Endocrinol 209: 1-8.