Molecular Neurobiology

, Volume 53, Issue 4, pp 2550–2571 | Cite as

The Putative Role of Viruses, Bacteria, and Chronic Fungal Biotoxin Exposure in the Genesis of Intractable Fatigue Accompanied by Cognitive and Physical Disability

  • Gerwyn Morris
  • Michael Berk
  • Ken Walder
  • Michael Maes
Article

Abstract

Patients who present with severe intractable apparently idiopathic fatigue accompanied by profound physical and or cognitive disability present a significant therapeutic challenge. The effect of psychological counseling is limited, with significant but very slight improvements in psychometric measures of fatigue and disability but no improvement on scientific measures of physical impairment compared to controls. Similarly, exercise regimes either produce significant, but practically unimportant, benefit or provoke symptom exacerbation. Many such patients are afforded the exclusionary, non-specific diagnosis of chronic fatigue syndrome if rudimentary testing fails to discover the cause of their symptoms. More sophisticated investigations often reveal the presence of a range of pathogens capable of establishing life-long infections with sophisticated immune evasion strategies, including Parvoviruses, HHV6, variants of Epstein-Barr, Cytomegalovirus, Mycoplasma, and Borrelia burgdorferi. Other patients have a history of chronic fungal or other biotoxin exposure. Herein, we explain the epigenetic factors that may render such individuals susceptible to the chronic pathology induced by such agents, how such agents induce pathology, and, indeed, how such pathology can persist and even amplify even when infections have cleared or when biotoxin exposure has ceased. The presence of active, reactivated, or even latent Herpes virus could be a potential source of intractable fatigue accompanied by profound physical and or cognitive disability in some patients, and the same may be true of persistent Parvovirus B12 and mycoplasma infection. A history of chronic mold exposure is a feasible explanation for such symptoms, as is the presence of B. burgdorferi. The complex tropism, life cycles, genetic variability, and low titer of many of these pathogens makes their detection in blood a challenge. Examination of lymphoid tissue or CSF in such circumstances may be warranted.

Keywords

Immune Inflammation Oxidative stress Toll-like receptor Cognition Depression Chronic fatigue syndrome Neurology Psychiatry 

Abbreviations

CFS

Chronic fatigue syndrome

TNFα

Tumor necrosis factor

IL

Interleukin

NF-ΚB

Nuclear factor-ΚB

IFN

Interferons

TLR

Toll-like receptors

PAMPs

Pathogen-associated molecular patterns

DAMPs

Damage-associated molecular patterns

MAPK

Mitogen-activated protein kinase

ROS

Reactive oxygen species

RNS

Reactive nitrogen species

4-HNE

4-Hydroxynonenal

MDA

Malondialdehyde

EBV

Epstein-Barr virus

CAEBV

Chronic activated Epstein-Barr virus syndrome

ME

Myalgic encephalomyelitis

CEBVS

Chronic EBV syndrome

MS

Multiple sclerosis

MSRV

MS retrovirus

HHV

Human herpes virus

Th2

T helper 2

DCs

Dendritic cells

Bcl2

B cell lymphoma 2

BAX

Bcl-2-associated X protein

PCR

Polymerase chain reaction

NS1

Nonstructural protein

CNS

Central nervous system

CSF

Cerebrospinal fluid

TGF-β1

Transforming growth factor β1

MRI

Magnetic resonance imaging

HCMV

Human cytomegalovirus

Nrf2

Nuclear factor erythroid 2 [NF-E2]-related factor 2

mTOR

Mammalian target of rapamycin protein

Bf

Borrelia burgdorferi

PG

Prostaglandin

ERK

Extracellular signal-regulated kinase

COX-2

Cyclooxygenase 2

SC

Stachybotrys chartarum

NADH

Reduced nicotinamide adenine dinucleotide

JNK

c-Jun N-terminal kinase

FoxP3

Forkhead box P3

DON

Vomitoxin or deoxynivalenol

STAT3

Signal transducer and activator of transcription 3

iNOS

Inducible nitric oxide synthase

References

  1. 1.
    White PD, Goldsmith KA, Johnson AL, Potts L, Walwyn R, DeCesare JC, Baber HL, Burgess M, Clark LV, Cox DL, Bavinton J, Angus BJ, Murphy G, Murphy M, O’Dowd H, Wilks D, McCrone P, Chalder T, Sharpe M, PACE trial management group (2011) Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomized trial. Lancet 377:823–836PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Núñez M, Fernández-Solà J, Nuñez E, Fernández-Huerta JM, Godás-Sieso T, Gomez-Gil E (2011) Health-related quality of life in patients with chronic fatigue syndrome: group cognitive behavioural therapy and graded exercise versus usual treatment. A randomised controlled trial with 1year of follow-up. Clin Rheumatol 30:381–389PubMedCrossRefGoogle Scholar
  3. 3.
    Morris G, Maes M (2013) Case definitions and diagnostic criteria for Myalgic Encephalomyelitis and Chronic fatigue Syndrome: from clinical-consensus to evidence-based case definitions. Neuro Endocrinol Lett 34:185–199PubMedGoogle Scholar
  4. 4.
    Morris G, Maes M (2013) Myalgic encephalomyelitis/chronic fatigue syndrome and encephalomyelitis disseminata/multiple sclerosis show remarkable levels of similarity in phenomenology and neuroimmune characteristics. BMC Med 11:205PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Morris G, Maes M (2013) A neuro-immune model of myalgic encephalomyelitis/chronic fatigue syndrome. Metab Brain Dis 28:523–540PubMedCrossRefGoogle Scholar
  6. 6.
    Hilgers A, Frank J (1994) Chronic fatigue syndrome: immune dysfunction, role of pathogens and toxic agents and neurological and cardial changes. Wien Med Wochenschr 144:399–406PubMedGoogle Scholar
  7. 7.
    Hilgers A, Krueger GR, Lembke U, Ramon A (1991) Postinfectious chronic fatigue syndrome: case history of thirty-five patients in Germany. In Vivo 5:201–205PubMedGoogle Scholar
  8. 8.
    Gow JW, Hagan S, Herzyk P, Cannon C, Behan PO, Chaudhuri A (2009) A gene signature for post-infectious chronic fatigue syndrome. BMC Med Genet 2:38Google Scholar
  9. 9.
    Carlo-Stella N, Badulli C, De Silvestri A, Bazzichi L, Martinetti M, Lorusso L, Bombardieri S, Salvaneschi L, Cuccia M (2006) A first study of cytokine genomic polymorphisms in CFS: positive association of TNF-857 and IFNgamma 874 rare alleles. Clin Exp Rheumatol 24:179–182PubMedGoogle Scholar
  10. 10.
    Shimosako N, Kerr JR (2014) Use of single-nucleotide polymorphisms (SNPs) to distinguish gene expression subtypes of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). J Clin Pathol 67(12):1078–1083PubMedCrossRefGoogle Scholar
  11. 11.
    Lee KA, Gay CL, Lerdal A, Pullinger CR, Aouizerat BE (2014) Cytokine polymorphisms are associated with fatigue in adults living with HIV/AIDS. Brain Behav Immun 40:95–103PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Turvey SE, Hawn TR (2006) Towards subtlety: understanding the role of Toll-like receptor signaling in susceptibility to human infections. Clin Immunol 120:1–9PubMedCrossRefGoogle Scholar
  13. 13.
    Misch EA, Hawn TR (2008) Toll-like receptor polymorphisms and susceptibility to human disease. Clin Sci (Lond) 114:347–360CrossRefGoogle Scholar
  14. 14.
    Vollmer-Conna U, Piraino B, Cameron B, Davenport T, Hickie I, Wakefield D, Lloyd AE, Dubbo Infection Outcomes Study Group (2008) Cytokine polymorphisms have a synergistic effect on severity of the acute sickness response to infection. Clin Infect Dis 47:1418–1425PubMedCrossRefGoogle Scholar
  15. 15.
    Helbig K, Harris R, Ayres J, Dunckley H, Lloyd A, Robson J, Marmion B (2005) Immune response genes in the post-Q-fever fatigue syndrome, Q fever endocarditis and uncomplicated acute primary Q fever. QJM 98:565–574PubMedCrossRefGoogle Scholar
  16. 16.
    Helbig K, Heatley S, Harris R, Mullighan C, Bardy P, Marmion B (2003) Variation in immune response genes and chronic Q fever. Concepts: preliminary test with post-Q fever fatigue syndrome. Genes Immun 4:82–85PubMedCrossRefGoogle Scholar
  17. 17.
    Hickie I, Davenport T, Wakefield D, Vollmer-Conna U, Cameron B, Vernon S, Reeves WC, Lloyd A, Dubbo Infection Outcomes Study Group (2006) Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study. BMJ 333:575PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Vollmer-Conna U, Fazou C, Cameron B, Li H, Brennan C, Luck L, Davenport T, Wakefield D, Hickie I, Lloyd A (2004) Production of pro-inflammatory cytokines correlates with the symptoms of acute sickness behaviour in humans. Psychol Med 34:1289–1297PubMedCrossRefGoogle Scholar
  19. 19.
    Honstettre A, Imbert G, Ghigo E, Gouriet F, Capo C, Raoult D, Mege J (2003) Dysregulation of cytokines in acute Q fever: role of interleukin-10 and tumor necrosis factor in chronic evolution of Q fever. J Infect Dis 187:956–962PubMedCrossRefGoogle Scholar
  20. 20.
    Morris G, Maes M (2014) Mitochondrial dysfunctions in myalgic encephalomyelitis/chronic fatigue syndrome explained by activated immuno-inflammatory, oxidative and nitrosative stress pathways. Metab Brain Dis 29:19–36PubMedCrossRefGoogle Scholar
  21. 21.
    Cunningham C (2013) Microglia and neurodegeneration: the role of systemic inflammation. Glia 61:71–90PubMedCrossRefGoogle Scholar
  22. 22.
    Lucas K, Maes M (2013) Role of the Toll Like receptor (TLR) radical cycle in chronic inflammation: possible treatments targeting the TLR4 pathway. Mol Neurobiol 48:190–204PubMedCrossRefGoogle Scholar
  23. 23.
    Guijarro-Muñoz I, Compte M, Álvarez-Cienfuegos A, Álvarez-Vallina L, Sanz L (2014) Lipopolysaccharide activates Toll-like receptor 4 (TLR4)-mediated NF-κB signalingpathway and proinflammatory response in human pericytes. J Biol Chem 289:2457–2468PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Yang Y, Kim SC, Yu T, Yi YS, Rhee MH, Sung GH, Yoo BC, Cho JY (2014) Functional roles of p38 mitogen-activated protein kinase in macrophage-mediated inflammatory responses. Mediat Inflamm 2014:352371Google Scholar
  25. 25.
    Uchida K (2013) Redox-derived damage-associated molecular patterns: ligand function of lipid peroxidation adducts. Redox Biol 1:94–96PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Moghaddam AE, Gartlan KH, Kong L, Sattentau QJ (2011) Reactive carbonyls are a major Th2-inducing damage-associated molecular pattern generated by oxidative stress. J Immunol 187:1626–1633PubMedCrossRefGoogle Scholar
  27. 27.
    Simmons JD, Lee YL, Mulekar S, Kuck JL, Brevard SB, Gonzalez RP, Gillespie MN, Richards WO (2013) Elevated levels of plasma mitochondrial DNA DAMPs are linked to clinical outcome in severely injured human subjects. Ann Surg 258:591–596, discussion 596–8 PubMedGoogle Scholar
  28. 28.
    Mathew A, Lindsley TA, Sheridan A, Bhoiwala DL, Hushmendy SF, Yager EJ, Ruggiero EA, Crawford DR (2012) Degraded mitochondrial DNA is a newly identified subtype of the damage associated molecular pattern (DAMP) family and possible trigger of neurodegeneration. J Alzheimers Dis 30:617–627PubMedGoogle Scholar
  29. 29.
    Maes M, Twisk FN (2010) Chronic fatigue syndrome: Harvey and Wessely’s (bio)psychosocial model versus a bio(psychosocial) model based on inflammatory and oxidative and nitrosative stress pathways. BMC Med 8:35PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Liang Y, Liu J, Feng Z (2013) The regulation of cellular metabolism by tumor suppressor p53. Cell Biosci 3:9PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Morris G, Maes M (2012) Increased nuclear factor-κB and loss of p53 are key mechanisms in Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS). Med Hypotheses 79:607–613PubMedCrossRefGoogle Scholar
  32. 32.
    Straus SE, Tosato G, Armstrong G, Lawley T, Preble OT, Henle W, Davey R, Pearson G, Epstein J, Brus I, Blaese RM (1985) Persisting illness and fatigue in adults with evidence of Epstein-Barr virus infection. Ann Intern Med 102:7–16PubMedCrossRefGoogle Scholar
  33. 33.
    Tobi M, Morag A, Ravid Z, Chowers I, Feldman-Weiss V, Michaeli Y, Ben-Chetrit E, Shalit M, Knobler H (1982) Prolonged atypical illness associated with serological evidence of persistent Epstein-Barr virus infection. Lancet 1:61–64PubMedCrossRefGoogle Scholar
  34. 34.
    Okano M, Matsumoto S, Osato T, Sakiyama Y, Thiele GM, Purtilo DT (1991) Severe chronic active Epstein-Barr virus infection syndrome. Clin Microbiol Rev 4:129–135PubMedPubMedCentralGoogle Scholar
  35. 35.
    Okano M, Kawa K, Kimura H, Yachie A, Wakiguchi H, Maeda A, Imai S, Ohga S, Kanegane H, Tsuchiya S, Morio T, Mori M, Yokota S, Imashuku S (2005) Proposed guidelines for diagnosing chronic active Epstein-Barr virus infection. Am J Hematol 80:64–69PubMedCrossRefGoogle Scholar
  36. 36.
    Kimura H, Hoshino Y, Hara S, Sugaya N, Kawada J, Shibata Y, Kojima S, Nagasaka T, Kuzushima K, Morishima T (2005) Differences between T cell-type and natural killer cell-type chronic active Epstein-Barr virus infection. J Infect Dis 191:531–539PubMedCrossRefGoogle Scholar
  37. 37.
    Okano M (2000) Haematological associations of Epstein-Barr virus infection. Baillieres Best Pract Res Clin Haematol 13:199–214PubMedCrossRefGoogle Scholar
  38. 38.
    Okano M (2011) Features of chronic active Epstein-Barr virus infection and related human diseases. Open Hematol J 5:1–3CrossRefGoogle Scholar
  39. 39.
    Thiele GM, Purtilo DT, Okano M (1991) Differential diagnosis of chronic fatigue syndrome: an update. Infect Med 8:45–51Google Scholar
  40. 40.
    Holmes GP, Kaplan JE, Gantz NM, Komaroff AL, Schonberger LB, Straus SE, Jones JF, Dubois RE, Cunningham-Rundles C, Pahwa S et al (1988) Chronic fatigue syndrome: a working case definition. Ann Intern Med 108:387–389PubMedCrossRefGoogle Scholar
  41. 41.
    Buchwald D, Goldenberg DL, Sullivan JL, Komaroff AL (1987) The “chronic, active Epstein-Barr virus infection” syndrome and primary fibromyalgia. Arthritis Rheum 30:1132–1136PubMedCrossRefGoogle Scholar
  42. 42.
    Hotchin NA, Read R, Smith DG, Crawford DH (1989) Active Epstein-Barr virus infection in post-viral fatigue syndrome. J Infect 18:143–150PubMedCrossRefGoogle Scholar
  43. 43.
    Soto NE, Straus SE (2000) Chronic fatigue syndrome and herpesviruses: the fading evidence. Herpes 7:46–50PubMedGoogle Scholar
  44. 44.
    Swanink CM, van der Meer JW, Vercoulen JH, Bleijenberg G, Fennis JF, Galama JM (1995) Epstein-Barr virus (EBV) and the chronic fatigue syndrome: normal virus load in blood and normal immunologic reactivity in the EBV regression assay. Clin Infect Dis 20:1390–1392PubMedCrossRefGoogle Scholar
  45. 45.
    Aydin GB, Akyuz C, Talim B, Evans SE, Sahin S, Sari N, Tabanlioglu D, Ozen S, Cağlar M, Büyükpamukçu M (2007) Extranodal type T/NK-cell lymphoma with an atypical clinical presentation. Pediatr Hematol Oncol 24(4):291–299PubMedCrossRefGoogle Scholar
  46. 46.
    Sonke GS, Ludwig I, van Oosten H, Baars JW, Meijer E, Kater AP, de Jong D (2008) Poor outcomes of chronic active Epstein-Barr virus infection and hemophagocytic lymphohistiocytosis in non-Japanese adult patients. Clin Infect Dis 47:105–108PubMedCrossRefGoogle Scholar
  47. 47.
    Straus SE (1988) The chronic mononucleosis syndrome. J Infect Dis 157:405–412PubMedCrossRefGoogle Scholar
  48. 48.
    Fujieda M, Wakiguchi H, Hisakawa H, Kubota H, Kurashige T (1991) Defective activity of Epstein-Barr virus (EBV) specific cytotoxic T lymphocytes in children with chronic active EBV infection and in their parents. Acta Paediatr Jpn 35:394–399CrossRefGoogle Scholar
  49. 49.
    Sugaya N, Kimura H, Hara S, Hoshino Y, Kojima S, Morishima T, Tsurumi T, Kuzushima K (2004) Quantitative analysis of Epstein-Barr virus (EBV)-specific CD8+ T cells in patients with chronic active EBV infection. J Infect Dis 190:985–988PubMedCrossRefGoogle Scholar
  50. 50.
    Cohen JI, Jaffe ES, Dale JK, Pittaluga S, Heslop HE, Rooney CM, Gottschalk S, Bollard CM, Rao VK, Marques A, Burbelo PD, Turk SP, Fulton R, Wayne AS, Little RF, Cairo MS, El-Mallawany NK, Fowler D, Sportes C, Bishop MR, Wilson W, Straus SE (2011) Characterization and treatment of chronic active Epstein-Barr virus disease: a 28-year experience in the United States. Blood 117:5835–5849PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Macsween KF, Crawford DH (2003) Epstein-Barr virus-recent advances. Lancet Infect Dis 3:131–140PubMedCrossRefGoogle Scholar
  52. 52.
    Kimura H, Morita M, Yabuta Y, Kuzushima K, Kato K, Kojima S, Matsuyama T, Morishima T (1999) Quantitative analysis of Epstein-Barr virus load by using a real-time PCR assay. J Clin Microbiol 37:132–136PubMedPubMedCentralGoogle Scholar
  53. 53.
    Maeda A, Wakiguchi H, Yokoyama W, Hisakawa H, Tomoda T, Kurashige T (1999) Persistently high Epstein-Barr virus (EBV) loads in peripheral blood lymphocytes from patients with chronic active EBV infection. J Infect Dis 179:1012–1015PubMedCrossRefGoogle Scholar
  54. 54.
    Patel S, Zuckerman M, Smith M (2003) Real-time quantitative PCR of Epstein-Barr virus BZLF1 DNA using the Light Cycler. J Virol Methods 109:227–233PubMedCrossRefGoogle Scholar
  55. 55.
    Kamranvar SA, Masucci MG (2011) The Epstein-Barr virus nuclear antigen-1 promotes telomere dysfunction via induction of oxidative stress. Leukemia 25:1017–1025PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Gruhne B, Sompallae R, Marescotti D, Kamranvar SA, Gastaldello S, Masucci MG (2009) The Epstein-Barr virus nuclear antigen-1 promotes genomic instability via induction of reactive oxygen species. Proc Natl Acad Sci U S A 106:2313–2318PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Wiedmer A, Wang P, Zhou J, Rennekamp AJ, Tiranti V, Zeviani M, Lieberman PM (2008) Epstein-Barr virus immediate-early protein Zta co-opts mitochondrial single-stranded DNA binding protein to promote viral and inhibit mitochondrial DNA replication. J Virol 82:4647–4655PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    LaJeunesse DR, Brooks K, Adamson AL (2005) Epstein-Barr virus immediate-early proteins BZLF1 and BRLF1 alter mitochondrial morphology during lytic replication. Biochem Biophys Res Commun 333:438–442PubMedCrossRefGoogle Scholar
  59. 59.
    Sato Y, Kamura T, Shirata N, Murata T, Kudoh A, Iwahori S, Nakayama S, Isomura H, Nishiyama Y, Tsurumi T (2009) Degradation of phosphorylated p53 by viral protein-ECS E3 ligase complex. PLoS Pathog 5, e1000530PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Liu MT, Chang YT, Chen SC, Chuang YC, Chen YR, Lin CS, Chen JY (2005) Epstein-Barr virus latent membrane protein 1 represses p53-mediated DNA repair and transcriptional activity. Oncogene 24:2635–2646PubMedCrossRefGoogle Scholar
  61. 61.
    Mauser A, Saito S, Appella E, Anderson CW, Seaman WT, Kenney S (2002) The Epstein-Barr virus immediate-early protein BZLF1 regulates p53 function through multiple mechanisms. J Virol 76:12503–12512PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Volpi A (2004) Epstein-Barr virus and human herpesvirus type 8 infections of the central nervous system. Herpes Suppl 2:120A–127AGoogle Scholar
  63. 63.
    Fujimoto H, Asaoka K, Imaizumi T, Ayabe M, Shoji H, Kaji M (2003) Epstein-Barr virus infections of the central nervous system. Intern Med 42:33–40PubMedCrossRefGoogle Scholar
  64. 64.
    Tzartos JS, Khan G, Vossenkamper A, Cruz-Sadaba M, Lonardi S, Sefia E, Meager A, Elia A, Middeldorp JM, Clemens M, Farrell PJ, Giovannoni G, Meier UC (2012) Association of innate immune activation with latent Epstein-Barr virus in active MS lesions. Neurology 78:15–23PubMedCrossRefGoogle Scholar
  65. 65.
    García-Montojo M, de la Hera B, Varadé J, de la Encarnación A, Camacho I, Domínguez-Mozo M, Árias-Leal A, García-Martínez A, Casanova I, Izquierdo G, Lucas M, Fedetz M, Alcina A, Arroyo R, Matesanz F, Urcelay E, Alvarez-Lafuente R (2014) HERV-W polymorphism in chromosome X is associated with multiple sclerosis risk and with differential expression of MSRV. Retrovirology 11:2PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Kremer D, Schichel T, Förster M, Tzekova N, Bernard C, van der Valk P, van Horssen J, Hartung HP, Perron H, Küry P (2013) Human endogenous retrovirus type W envelope protein inhibits oligodendroglial precursor cell differentiation. Ann Neurol 74:721–732PubMedCrossRefGoogle Scholar
  67. 67.
    Mameli G, Poddighe L, Mei A, Uleri E, Sotgiu S, Serra C, Manetti R, Dolei A (2012) Expression and activation by Epstein Barr virus of human endogenous retroviruses-W in blood cells and astrocytes: inference for multiple sclerosis. PLoS One 7, e44991PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Kasztelewicz B, Jankowska I, Pawłowska J, Teisseyre J, Dzierżanowska-Fangrat K (2012) The impact of cytokine gene polymorphisms on Epstein-Barr virus infection outcome in pediatric liver transplant recipients. J Clin Virol 55:226–232PubMedCrossRefGoogle Scholar
  69. 69.
    Hurme M, Helminen M (1998) Polymorphism of the IL-1 gene complex in Epstein-Barr virus seronegative and seropositive adult blood donors. Scand J Immunol 48:219–222PubMedCrossRefGoogle Scholar
  70. 70.
    Binkley PF, Cooke GE, Lesinski A, Taylor M, Chen M, Laskowski B, Waldman WJ, Ariza ME, Williams MV Jr, Knight DA, Glaser R (2013) Evidence for the role of Epstein Barr Virus infections in the pathogenesis of acute coronary events. PLoS One 8, e54008PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Agut H (2011) Deciphering the clinical impact of acute human herpesvirus 6 (HHV-6) infections. J Clin Virol 52:164–171PubMedCrossRefGoogle Scholar
  72. 72.
    Yao K, Crawford JR, Komaroff AL, Ablashi DV, Jacobson S (2010) Review part 2: human herpesvirus-6 in central nervous system diseases. J Med Virol 82:1669–1678PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Birnbaum TCS, Padovan B, Sporer B, Rupprecht TA, Ausserer H, Jaeger G, Pfister HW (2005) Severe meningoencephalitis caused by human herpesvirus 6 type B in an immunocompetent woman treated with ganciclovir. Clin Infect Dis 40:887–889PubMedCrossRefGoogle Scholar
  74. 74.
    Isaacson E, Glaser CA, Forghani B, Amad Z, Wallace M, Armstrong RW, Exner MM, Schmid S (2005) Evidence of human herpesvirus 6 infection in 4 immunocompetent patients with encephalitis. Clin Infect Dis 40:890–893PubMedCrossRefGoogle Scholar
  75. 75.
    Tavakoli NP, Nattanmai S, Hull R, Fusco H, Dzigua L, Wang H, Dupuis M (2007) Detection and typing of human herpesvirus 6 by molecular methods in specimens from patients diagnosed with encephalitis or meningitis. J Clin Microbiol 45:3972–3978PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Fox RI, Saito I, Chan EK, Josephs S, Salahuddin SZ, Ahlashi DV, Staal FW, Gallo R, Pei-Ping H, Le CS (1989) Viral genomes in lymphomas of patients with Sjögren’s syndrome. J Autoimmun 2:449–455PubMedCrossRefGoogle Scholar
  77. 77.
    Ranger-Rogez S, Vidal E, Liozon F, Denis F (1994) Primary Sjögren’s syndrome and antibodies to human herpesvirus type 6. Clin Infect Dis 19:1159–1160PubMedCrossRefGoogle Scholar
  78. 78.
    Alvarez-Lafuente R, Fernández-Gutiérrez B, de Miguel S, Jover JA, Rollin R, Loza E, Clemente D, Lamas JR (2005) Potential relationship between herpes viruses and rheumatoid arthritis: analysis with quantitative real time polymerase chain reaction. Ann Rheum Dis 64:1357–1359PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Broccolo F, Drago F, Paolino S, Cassina G, Gatto F, Fusetti L, Matteoli B, Zaccaria E, Parodi A, Lusso P, Ceccherini-Nelli L, Malnati MS (2009) Reactivation of human herpesvirus 6 (HHV-6) infection in patients with connective tissue diseases. J Clin Virol 46:43–46PubMedCrossRefGoogle Scholar
  80. 80.
    Goodman AD, Mock DJ, Powers JM, Baker JV, Blumberg BM (2003) Human herpesvirus 6 genome and antigen in acute multiple sclerosis lesions. J Infect Dis 187:1365–1376PubMedCrossRefGoogle Scholar
  81. 81.
    Akhyani N, Berti R, Brennan MB, Soldan SS, Eaton JM, McFarland HF, Jacobson S (2000) Tissue distribution and variant characterization of human herpesvirus (HHV)-6: increased prevalence of HHV-6A in patients with multiple sclerosis. J Infect Dis 182:1321–1325PubMedCrossRefGoogle Scholar
  82. 82.
    Alvarez-Lafuente R, De las Heras V, Bartolomé M, Picazo JJ, Arroyo R (2004) Relapsing-remitting multiple sclerosis and human herpesvirus 6 active infection. Arch Neurol 61:1523–1527PubMedCrossRefGoogle Scholar
  83. 83.
    Watt T, Oberfoell S, Balise R, Lunn MR, Kar AK, Merrihew L, Bhangoo MS, Montoya JG (2012) Response to valganciclovir in chronic fatigue syndrome patients with human herpesvirus 6 and Epstein-Barr virus IgG antibody titers. J Med Virol 84:1967–1974PubMedCrossRefGoogle Scholar
  84. 84.
    Komaroff AL (2006) Is human herpesvirus-6 a trigger for chronic fatigue syndrome? J Clin Virol 37:S39–S46PubMedCrossRefGoogle Scholar
  85. 85.
    Nicolson GL, Gan R, Haier J (2003) Multiple co-infections (Mycoplasma, Chlamydia, human herpes virus-6) in blood of chronic fatigue syndrome patients: association with signs and symptoms. APMIS 111:557–566PubMedCrossRefGoogle Scholar
  86. 86.
    Ablashi DV, Josephs SF, Buchbinder A, Hellman K, Nakamura S, Llana T, Lusso P, Kaplan M, Dahlberg J, Memon S et al (1988) Human B-lymphotropic virus (human herpesvirus-6). J Virol Methods 21:29–48PubMedCrossRefGoogle Scholar
  87. 87.
    Patnaik M, Komaroff AL, Conley E, Ojo-Amaize EA, Peter JB (1995) Prevalence of IgM antibodies to human herpesvirus 6 early antigen (p41/38) in patients with chronic fatigue syndrome. J Infect Dis 172:1364–1367PubMedCrossRefGoogle Scholar
  88. 88.
    Arena A, Liberto MC, Iannello D, Capozza AB, Focà A (1999) Altered cytokine production after human herpes virus type 6 infection. New Microbiol 22:293–300PubMedGoogle Scholar
  89. 89.
    Flamand L, Gosselin J, D’Addario M, Hiscott J, Ablashi DV, Gallo RC, Menezes J (1991) Human herpesvirus 6 induces interleukin-1 beta and tumor necrosis factor alpha, but not interleukin-6, in peripheral blood mononuclear cell cultures. J Virol 65:5105–5110PubMedPubMedCentralGoogle Scholar
  90. 90.
    Kikuta H, Nakane A, Lu H, Taguchi Y, Minagawa T, Matsumoto S (1990) Interferon induction by human herpesvirus 6 in human mononuclear cells. J Infect Dis 162:35–38PubMedCrossRefGoogle Scholar
  91. 91.
    Prusty BK, Böhme L, Bergmann B, Siegl C, Krause E, Mehlitz A, Rudel T (2012) Imbalanced oxidative stress causes chlamydial persistence during non-productive human herpes virus co-infection. PLoS One 7, e47427PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Yeo WM, Isegawa Y, Chow VT (2008) The U95 protein of human herpesvirus 6B interacts with human GRIM-19: silencing of U95 expression reduces viral load and abrogates loss of mitochondrial membrane potential. J Virol 82:1011–1020PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Li L, Chi J, Zhou F, Guo D, Wang F, Liu G, Zhang C, Yao K (2010) Human herpesvirus 6A induces apoptosis of HSB-2 cells via a mitochondrion-related caspase pathway. J Biomed Res 24:444–451PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Kofod-Olsen E, Møller JM, Schleimann MH, Bundgaard B, Bak RO, Øster B, Mikkelsen JG, Hupp T, Höllsberg P (2013) Inhibition of p53-dependent, but not p53-independent, cell death by U19 protein from human herpesvirus 6B. PLoS One 8, e59223PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Schleimann MH, Møller JM, Kofod-Olsen E, Höllsberg P (2009) Direct Repeat 6 from human herpesvirus-6B encodes a nuclear protein that forms a complex with the viral DNA processivity factor p41. PLoS One 4, e7457PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Reynaud JM, Horvat B (2013) Human herpesvirus 6 and neuroinflammation. ISRN Virol 2013:834890Google Scholar
  97. 97.
    Opsahl ML, Kennedy PG (2005) Early and late HHV-6 gene transcripts in multiple sclerosis lesions and normal appearing white matter. Brain 128:516–527PubMedCrossRefGoogle Scholar
  98. 98.
    Donati D, Akhyani N, Fogdell-Hahn A, Cermelli C, Cassiani-Ingoni R, Vortmeyer A, Heiss JD, Cogen P, Gaillard WD, Sato S, Theodore WH, Jacobson S (2003) Detection of human herpesvirus-6 in mesial temporal lobe epilepsy surgical brain resections. Neurology 61:1405–1411PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Nordström I, Eriksson K (2012) HHV-6B induces IFN-lambda1 responses in cord plasmacytoid dendritic cells through TLR9. PLoS ONE 7, e38683PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Frémont M, Metzger K, Rady H, Hulstaert J, De Meirleir K (2009) Detection of herpesviruses and parvovirus B19 in gastric and intestinal mucosa of chronic fatigue syndrome patients. In Vivo 23:209–213PubMedGoogle Scholar
  101. 101.
    Dominguez-Mozo MI, Garcia-Montojo M, López-Cavanillas M, De Las Heras V, Garcia-Martinez A, Arias-Leal AM, Casanova I, Urcelay E, Arroyo R, Alvarez-Lafuente R (2014) Toll-like receptor-9 in Spanish multiple sclerosis patients: an association with the gender. Eur J Neurol 21:537–540PubMedCrossRefGoogle Scholar
  102. 102.
    Chapenko S, Krumina A, Logina I, Rasa S, Chistjakovs M, Sultanova A, Viksna L, Murovska M (2012) Association of active human herpesvirus-6, -7 and parvovirus b19 infection with clinical outcomes in patients with myalgic encephalomyelitis/chronic fatigue syndrome. Adv Virol 2012:205085PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Vinnard C, Barton T, Jerud E, Blumberg E (2009) A report of human herpesvirus 6-associated encephalitis in a solid organ transplant recipient and a review of previously published cases. Liver Transpl 15:1242–1246PubMedCrossRefGoogle Scholar
  104. 104.
    Norja P, Hokynar K, Aaltonen LM, Chen R, Ranki A, Partio EK, Kiviluoto O, Davidkin I, Leivo T, Eis-Hübinger AM, Schneider B, Fischer HP, Tolba R, Vapalahti O, Vaheri A, Söderlund-Venermo M, Hedman K (2006) Bioportfolio: lifelong persistence of variant and prototypic erythrovirus DNA genomes in human tissue. Proc Natl Acad Sci U S A 103:7450–7453PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Norja P, Eis-Hübinger AM, Söderlund-Venermo M, Hedman K, Simmonds P (2008) Rapid sequence change and geographical spread of human parvovirus B19: comparison of B19 virus evolution in acute and persistent infections. J Virol 82:6427–6433PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    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 195:1345–1352PubMedCrossRefGoogle Scholar
  107. 107.
    Servant A, Laperche S, Lallemand F, Marinho V, De Saint Maur G, Meritet JF, Garbarg-Chenon A (2002) Genetic diversity within human erythroviruses: identification of three genotypes. J Virol 76:9124–9134PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Shackelton LA, Holmes EC (2006) Phylogenetic evidence for the rapid evolution of human B19 erythrovirus. J Virol 80:3666–3669PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Corcioli F, Zakrzewska K, Fanci R, De Giorgi V, Innocenti M, Rotellini M, Di Lollo S, Azzi A (2010) Human parvovirus PARV4 DNA in tissues from adult individuals: a comparison with human parvovirus B19 (B19V). Virol J 7:272PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Schneider B, Fryer JF, Reber U, Fischer HP, Tolba RH, Baylis SA, Eis-Hübinger AM (2008) Persistence of novel human parvovirus PARV4 in liver tissue of adults. J Med Virol 80:345–351PubMedCrossRefGoogle Scholar
  111. 111.
    Matano S, Kinoshita H, Tanigawa K, Terahata S, Sugimoto T (2003) Acute parvovirus B19 infection mimicking chronic fatigue syndrome. Intern Med 42:903–905PubMedCrossRefGoogle Scholar
  112. 112.
    Seishima M, Mizutani Y, Shibuya Y, Arakawa C (2008) Chronic fatigue syndrome after human parvovirus B19 infection without persistent viremia. Dermatology 2164:341–346CrossRefGoogle Scholar
  113. 113.
    Kerr JR, Tyrrell DA (2003) Cytokines in parvovirus B19 infection as an aid to understanding chronic fatigue syndrome. Curr Pain Headache Rep 7:333–341PubMedCrossRefGoogle Scholar
  114. 114.
    Kerr JR (2005) Pathogenesis of parvovirus B19 infection: host gene variability, and possible means and effects of virus persistence. J Vet Med B Infect Dis Vet Public Health 52:335–339PubMedCrossRefGoogle Scholar
  115. 115.
    Sieben M, Schäfer P, Dinsart C, Galle PR, Moehler M (2013) Activation of the human immune system via toll-like receptors by the oncolytic parvovirus H-1. Int J Cancer 132:2548–2556PubMedCrossRefGoogle Scholar
  116. 116.
    Hsu GJ, Tzang BS, Tsai CC, Chiu CC, Huang CY, Hsu TC (2011) Effects of human parvovirus B19 on expression of defensins and Toll-like receptors. Chin J Physiol 54:367–376PubMedCrossRefGoogle Scholar
  117. 117.
    Raykov Z, Grekova SP, Hörlein R, Leuchs B, Giese T, Giese NA, Rommelaere J, Zawatzky R, Daeffler L (2013) TLR-9 contributes to the antiviral innate immune sensing of rodent parvoviruses MVMp and H-1PV by normal human immune cells. PLoS One 8, e55086PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Duechting A, Tschöpe C, Kaiser H, Lamkemeyer T, Tanaka N, Aberle S, Lang F, Torresi J, Kandolf R, Bock CT (2012) Human parvovirus B19 NS1 protein modulates inflammatory signaling by activation of STAT3/PIAS3 in human endothelial cells. J Virol 82(16):7942–7952CrossRefGoogle Scholar
  119. 119.
    Nykky J, Vuento M, Gilbert L (2014) Role of mitochondria in parvovirus pathology. PLoS One 9, e86124PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Nykky J, Tuusa JE, Kirjavainen S, Vuento M, Gilbert L (2010) Mechanisms of cell death in canine parvovirus-infected cells provide intuitive insights to developing nanotools for medicine. Int J Nanomedicine 5:417–428PubMedPubMedCentralGoogle Scholar
  121. 121.
    Chia JK, Jackson B (1996) Myopericarditis due to parvovirus B19 in an adult. Clin Infect Dis 23:200–201PubMedCrossRefGoogle Scholar
  122. 122.
    Nakashima A, Tanaka N, Tamai K, Kyuuma M, Ishikawa Y, Sato H, Yoshimori T, Saito S, Sugamura K (2006) Survival of parvovirus B19-infected cells by cellular autophagy. Virology 349:254–263PubMedCrossRefGoogle Scholar
  123. 123.
    Bucher Praz C, Dessimoz C, Bally F, Reymond S, Troillet N (2012) Guillain-Barré syndrome associated with primary parvovirus B19 infection in an HIV-1-infected patient. Case Rep Med 2012:140780PubMedPubMedCentralGoogle Scholar
  124. 124.
    Hobbs JA (2007) Parvovirus B19-brain interactions: infection, autoimmunity, or both? J Clin Virol 38:364–365PubMedCrossRefGoogle Scholar
  125. 125.
    Douvoyiannis M, Litman N, Goldman DL (2009) Neurologic manifestations associated with parvovirus B19 infection. Clin Infect Dis 48:1713–1723PubMedCrossRefGoogle Scholar
  126. 126.
    Endresen GK (2003) Mycoplasma blood infection in chronic fatigue and fibromyalgia syndromes. Rheumatol Int 23:211–215PubMedCrossRefGoogle Scholar
  127. 127.
    Nijs J, Nicolson GL, De Becker P, Coomans D, De Meirleir K (2022) High prevalence of Mycoplasma infections among European chronic fatigue syndrome patients. Examination of four Mycoplasma species in blood of chronic fatigue syndrome patients. FEMS Immunol Med Microbiol 34:209–214CrossRefGoogle Scholar
  128. 128.
    Zuo LL, Wu YM, You XX (2009) Mycoplasma lipoproteins and Toll-like receptors. J Zhejiang Univ Sci B 10:67–76PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Shimizu T, Kida Y, Kuwano K (2008) Mycoplasma pneumoniae-derived lipopeptides induce acute inflammatory responses in the lungs of mice. Infect Immun 76:270–277PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Into T, Kiura K, Yasuda M, Kataoka H, Inoue N, Hasebe A, Takeda K, Akira S, Shibata K (2004) Stimulation of human Toll-like receptor (TLR) 2 and TLR6 with membrane lipoproteins of Mycoplasma fermentans induces apoptotic cell death after NF-kappa B activation. Cell Microbiol 6:187–199PubMedCrossRefGoogle Scholar
  131. 131.
    He J, You X, Zeng Y, Yu M, Zuo L, Wu Y (2009) Mycoplasma genitalium-derived lipid-associated membrane proteins activate NF-kappaB through toll-like receptors 1, 2, and 6 and CD14 in a MyD88-dependent pathway. Clin Vaccine Immunol 16:1750–1757PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Rawadi G, Roman-Roman S (1996) Mycoplasma membrane lipoproteins induced proinflammatory cytokines by a mechanism distinct from that of lipopolysaccharide. Infect Immun 64:637–643PubMedPubMedCentralGoogle Scholar
  133. 133.
    Li S, Li X, Wang Y, Yang J, Chen Z, Shan S (2014) Global secretome characterization of A549 human alveolar epithelial carcinoma cells during Mycoplasma pneumoniae infection. BMC Microbiol 14:27PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Xu Y, Li H, Chen W, Yao X, Xing Y, Wang X, Zhong J (2013) Mycoplasma hyorhinis activates the NLRP3 inflammasome and promotes migration and invasion of gastric cancer cells. PLoS ONE 8, e77955PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Yang J, Hooper WC, Phillips DJ, Talkington DF (2003) Interleukin-1beta responses to Mycoplasma pneumoniae infection are cell-type specific. Microb Pathog 34:17–25PubMedCrossRefGoogle Scholar
  136. 136.
    Lee GS, Subramanian N, Kim AI, Aksentijevich I, Goldbach-Mansky R, Sacks DB, Germain RN, Kastner DL, Chae JJ (2012) The calcium-sensing receptor regulates the NLRP3 inflammasome through Ca2+ and cAMP. Nature 492:123–127PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    Murakami T, Ockinger J, Yu J, Byles V, McColl A, Hofer AM, Horng T (2012) Critical role for calcium mobilization in activation of the NLRP3 inflammasome. Proc Natl Acad Sci U S A 109:11282–11287PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Zhou R, Yazdi AS, Menu P, Tschopp J (2011) A role for mitochondria in NLRP3 inflammasome activation. Nature 469:221–225PubMedCrossRefGoogle Scholar
  139. 139.
    Sun G, Xu X, Wang Y, Shen X, Chen Z, Yang J (2008) Mycoplasma pneumoniae infection induces reactive oxygen species and DNA damage in A549 human lung carcinoma cells. Infect Immun 76:4405–44413PubMedPubMedCentralCrossRefGoogle Scholar
  140. 140.
    Citti C, Nouvel L, Baranowski E (2010) Phase and antigenic variation in mycoplasmas. Future Microbiol 5:1073–1085PubMedCrossRefGoogle Scholar
  141. 141.
    van der Merwe J, Prysliak T, Perez-Casal J (2010) Invasion of bovine peripheral blood mononuclear cells and erythrocytes by Mycoplasma bovis. Infect Immun 78:4570–5478PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Grover R, Zhu X, Nieusma T, Jones T, Boero I, MacLeod A, Mark A, Niessen S, Kim HJ, Kong L, Assad-Garcia N, Kwon K, Chesi M, Smider VV, Salomon DR, Jelinek DF, Kyle RA, Pyles RB, Glass JI, Ward AB, Wilson IA, Lerner RA (2014) A structurally distinct human mycoplasma protein that generically blocks antigen-antibody union. Science 343:656–661PubMedPubMedCentralCrossRefGoogle Scholar
  143. 143.
    Hopfe M, Deenen R, Degrandi D, Kohrer K, Henrich B (2013) Host cell responses to persistent mycoplasmas-different stages in infection of HeLa cells with Mycoplasma hominis. Plos One 8:54219CrossRefGoogle Scholar
  144. 144.
    Vancini R, Benchimol M (2008) Entry and intracellular location of Mycoplasma hominis in Trichomonas vaginalis. Arch Microbiol 1891:7–18Google Scholar
  145. 145.
    McGowin C, Annan R, Quayle A, Greene S, Ma L, Mancuso MM, Adegboye D, Martin DH (2012) Persistent Mycoplasma genitalium infection of human endocervical epithelial cells elicits chronic inflammatory cytokine secretion. Infect Immun 80:3842–3849PubMedPubMedCentralCrossRefGoogle Scholar
  146. 146.
    Nicolson G, Nasralla M, Haier J, Nicolson N (1998) Diagnosis and treatment of chronic mycoplasmal infections in fibromyalgia and chronic fatigue syndromes: relationship to Gulf War Illness. Biomed Ther 16:266–271Google Scholar
  147. 147.
    Rogers M (2011) Mycoplasma and cancer: in search of the link. Oncotarget 2:271PubMedPubMedCentralCrossRefGoogle Scholar
  148. 148.
    Logunov D, Scheblyakov D, Zubkova O, Shmarov M, Rakovskaya I, Gurova K, Tararova ND, Burdelya LG, Naroditsky BS, Ginzburg AL, Gudkov AV (2008) Mycoplasma infection suppresses p53, activates NF-kappaB and cooperates with oncogenic Ras in rodent fibroblast transformation. Oncogene 27:4521–4531PubMedPubMedCentralCrossRefGoogle Scholar
  149. 149.
    Christo PP, Silva JS, Werneck IV, Dias SL (2010) Rhombencephalitis possibly caused by Mycoplasma pneumoniae. Arq Neuropsiquiatr 68:656–658PubMedCrossRefGoogle Scholar
  150. 150.
    Pellegrini M, O’Brien TJ, Hoy J, Sedal L (1996) Mycoplasma pneumoniae infection associated with an acute brainstem syndrome. Acta Neurol Scand 90:203–206Google Scholar
  151. 151.
    Urbanek C, Goodison S, Chang M, Porvasnik S, Sakamoto N, Li CZ, Boehlein SK, Rosser CJ (2011) Detection of antibodies directed at M. hyorhinis p37 in the serum of men with newly diagnosed prostate cancer. BMC Cancer 11:233PubMedPubMedCentralCrossRefGoogle Scholar
  152. 152.
    Bahar M, Ashtari F, Aghaei M, Akbari M, Salari M, Ghalamkari S (2012) Mycoplasma pneumonia seroposivity in Iranian patients with relapsing-remitting multipl sclerosis: a randomized case–control study. J Pak Med Assoc 62:6–8Google Scholar
  153. 153.
    Witkin S, Bierhals K, Linhares I, Normand N, Dieterle S, Neuer A (2010) Genetic polymorphism in an inflammasome component, cervical mycoplasma detection and female infertility in women undergoing in vitro fertilization. J Reprod Immunol 84:171–175PubMedCrossRefGoogle Scholar
  154. 154.
    Griffiths P, Whitley R, Snydman DR, Singh N, Boeckh M (2008) International Herpes Management Forum. Contemporary management of cytomegalovirus infection in transplant recipients: guidelines from an IHMF workshop, 2007. Herpes 15:4–12PubMedGoogle Scholar
  155. 155.
    Griffiths P (1993) Current management of cytomegalovirus disease. J Med Virol 41:106–111CrossRefGoogle Scholar
  156. 156.
    Kano Y, Shiohara T (2000) Current understanding of cytomegalovirus infection in immunocompetent individuals. J Dermatol Sci 22:196–204PubMedCrossRefGoogle Scholar
  157. 157.
    Eddleston M, Peacock S, Juniper M, Warrell D (1997) Severe cytomegalovirus infection in immunocompetent patients. Clin Infect Dis 24:52–56PubMedCrossRefGoogle Scholar
  158. 158.
    Wreghitt T, Teare E, Sule O, Devi R, Rice P (2003) Cytomegalovirus infection in immunocompetent patients. Clin Infect Dis 37:1603–1606PubMedCrossRefGoogle Scholar
  159. 159.
    Frascaroli G, Varani S, Mastroianni A, Britton S, Gibellini D, Rossini G, Landini MP, Söderberg-Nauclér C (2006) Dendritic cell function in cytomegalovirus-infected patients with mononucleosis. J Leukoc Biol 79:932–940PubMedCrossRefGoogle Scholar
  160. 160.
    Yew K, Carpenter C, Duncan R, Harrison C (2012) Human cytomegalovirus induces TLR4 signaling components in monocytes altering TIRAP, TRAM and downstream interferon-beta and TNF-alpha expression. Plos One 7:44500CrossRefGoogle Scholar
  161. 161.
    Compton T, Kurt-Jones E, Boehme K, Belko J, Latz E, Golenbock D, Finberg R (2003) Human cytomegalovirus activates inflammatory cytokine responses via CD14 and Toll-like receptor 2. J Virol 77:4588–4596PubMedPubMedCentralCrossRefGoogle Scholar
  162. 162.
    Kijpittayarit S, Eid A, Brown R, Paya C, Razonable R (2007) Relationship between Toll-like receptor 2 polymorphism and cytomegalovirus disease after liver transplantation. Clin Infect Dis 44:1315–1320PubMedCrossRefGoogle Scholar
  163. 163.
    Wujcicka W, Wilczy’nski J, Nowakowska D (2014) Alterations in TLRs as new molecular markers of congenital infections with Human cytomegalovirus? Pathog Dis 70:3–16PubMedCrossRefGoogle Scholar
  164. 164.
    Jablo’nska A, Paradowska E, Studzi’nska M, Suski P, Nowakowska D, Wiśniewska-Ligier M, Woźniakowska-Gęsicka T, Wilczyński J, Leśnikowski ZJ (2014) Relationship between toll-like receptor 2 Arg677Trp and Arg753Gln and toll-like receptor 4 Asp299Gly polymorphisms and cytomegalovirus infection. Int J Infect Dis 25:11–15CrossRefGoogle Scholar
  165. 165.
    Lee G, Kim B (2013) Mitochondria-targeted apoptosis in human cytomegalovirus-infected cells. J Microbiol Biotechnol 23:1627–1635PubMedCrossRefGoogle Scholar
  166. 166.
    Andoniou C, Degli-Esposti M (2006) Insights into the mechanisms of CMV-mediated interference with cellular apoptosis. Immunol Cell Biol 84:99–106PubMedCrossRefGoogle Scholar
  167. 167.
    Brune W (2011) Inhibition of programmed cell death by cytomegaloviruses. Virus Res 157:144–150PubMedCrossRefGoogle Scholar
  168. 168.
    Tanaka K, Zou J, Takeda K, Ferrans V, Sandford G, Johnson T, Finkel T, Epstein SE (1999) Effects of human cytomegalovirus immediate-early proteins on p53-mediated apoptosis in coronary artery smooth muscle cells. Circulation 99:1656–1659PubMedCrossRefGoogle Scholar
  169. 169.
    Goldmacher V, Bartle L, Skaletskaya A, Dionne C, Kedersha N, Vater CA, Han JW, Lutz RJ, Watanabe S, Cahir McFarland ED, Kieff ED, Mocarski ES, Chittenden T (1999) A cytomegalovirus-encoded mitochondria-localized inhibitor of apoptosis structurally unrelated to Bcl-2. Proc Natl Acad Sci U S A 96:12536–12541PubMedPubMedCentralCrossRefGoogle Scholar
  170. 170.
    O’Brien V (1998) Viruses and apoptosis. J Gen Virol 79:1833–1845PubMedCrossRefGoogle Scholar
  171. 171.
    Roulston A, Marcellus R, Branton P (1999) Viruses and apoptosis. Annu Rev Microbiol 53:577–628PubMedCrossRefGoogle Scholar
  172. 172.
    Pleskoff O, Casarosa P, Verneuil L, Ainoun F, Beisser P, Smit M, Leurs R, Schneider P, Michelson S, Ameisen JC (2005) The human cytomegalovirus-encoded chemokine receptor US28 induces caspase-dependent apoptosis. FEBS J 272:4163–4177PubMedCrossRefGoogle Scholar
  173. 173.
    Rinaldo C, Carney W, Richter B, Black P, Hirsch MS (1980) Mechanisms of immunosuppression in cytomegaloviral mononucleosis. J Infect Dis 141:488–495PubMedCrossRefGoogle Scholar
  174. 174.
    Schrier R, Rice G, Oldstone M (1986) Suppression of natural killer cell activity and T cell proliferation by fresh isolates of human cytomegalovirus. J Infect Dis 153:1084–1091PubMedCrossRefGoogle Scholar
  175. 175.
    Michelson S (2004) Consequences of human cytomegalovirus mimicry. Hum Immunol 65:465–475PubMedCrossRefGoogle Scholar
  176. 176.
    Spencer J, Lockridge K, Barry P, Lin G, Tsang M, Penfold M, Schall T (2002) Potent immunosuppressive activities of cytomegalovirus-encoded interleukin-10. J Virol 76:1285–1292PubMedPubMedCentralCrossRefGoogle Scholar
  177. 177.
    Beck K, Meyer-Konig U, Weidmann M, Nern C, Hufert F (2003) Human cytomegalovirus impairs dendritic cell function: a novel mechanism of human cytomegalovirus immune escape. Eur J Immunol 33:1528–1538PubMedCrossRefGoogle Scholar
  178. 178.
    Varani S, Frascaroli G, Homman-Loudiyi M, Feld S, Landini M, Soderberg-Naucler C (2005) Human cytomegalovirus inhibits the migration of immature dendritic cells by down-regulating cell-surface CCR1 and CCR5. J Leukoc Biol 77:219–228PubMedCrossRefGoogle Scholar
  179. 179.
    Moutaftsi M, Brennan P, Spector S, Tabi Z (2004) Impaired lymphoid chemokine-mediated migration due to a block on the chemokine receptor switch in human cytomegalovirus-infected dendritic cells. J Virol 78:3046–3054PubMedPubMedCentralCrossRefGoogle Scholar
  180. 180.
    Kaarbo M, Ager-Wick E, Osenbroch P, Kilander A, Skinnes R, Muller F, Eide L (2011) Human cytomegalovirus infection increases mitochondrial biogenesis. Mitochondrion 11:935–945PubMedCrossRefGoogle Scholar
  181. 181.
    Zhang A, Williamson C, Wong D, Bullough M, Brown K, Hathout Y, Colberg-Poley A (2011) Quantitative proteomic analyses of human cytomegalovirus-induced restructuring of endoplasmic reticulum-mitochondrial contacts at late times of infection. Mol Cell Proteomics 10:M111.009936PubMedPubMedCentralCrossRefGoogle Scholar
  182. 182.
    Roumier T, Szabadkai G, Simoni AM, Perfettini JL, Paulau AL, Castedo M, Métivier D, Badley A, Rizzuto R, Kroemer G (2006) HIV-1 protease inhibitors and cytomegalovirus vMIA induce mitochondrial fragmentation without triggering apoptosis. Cell Death Differ 13:348–351PubMedCrossRefGoogle Scholar
  183. 183.
    Lee Y, Liu C, Cho W, Kuo C, Cheng W, Huang C, Liu C (2014) Presence of cytomegalovirus DNA in leucocytes is associated with increased oxidative stress and subclinical atherosclerosis in healthy adults. Biomarkers 19(2):109–113PubMedCrossRefGoogle Scholar
  184. 184.
    Scholz M, Cinatl J, Gross V, Vogel JU, Blaheta RA, Freisleben HJ, Markus BH, Doerr HW (1996) Impact of oxidative stress on human cytomegalovirus replication and on cytokine-mediated stimulation of endothelial cells. Transplantation 61:1763–1770PubMedCrossRefGoogle Scholar
  185. 185.
    Jaganjac M, Matijevic T, Cindric M, Cipak A, Mrakovcic L, Gubisch W, Zarkovic N (2010) Induction of CMV-1 promoter by 4-hydroxy-2-nonenal in human embryonic kidney cells. Acta Biochim Pol 57:179–183PubMedGoogle Scholar
  186. 186.
    Lee J, Koh K, Kim Y, Ahn J, Kim S (2013) Upregulation of Nrf2 expression by human cytomegalovirus infection protects host cells from oxidative stress. J Gen Virol 94:1658–1668PubMedCrossRefGoogle Scholar
  187. 187.
    Tilton C, Clippinger A, Maguire T, Alwine J (2011) Human cytomegalovirus induces multiple means to combat reactive oxygen species. J Virol 85:12585–12593PubMedPubMedCentralCrossRefGoogle Scholar
  188. 188.
    Savaryn JP, Reitsma JM, Bigley TM, Halligan BD, Qian Z, Yu D, Terhune SS (2013) Human cytomegalovirus pUL29/28 and pUL38 repression of p53-regulated p21CIP1 and caspase 1 promoters during infection. J Virol 87:2463–2474PubMedPubMedCentralCrossRefGoogle Scholar
  189. 189.
    Chen Z, Knutson E, Wang S, Martinez L, Albrecht T (2007) Stabilization of p53 in human cytomegalovirus-initiated cells is associated with sequestration of HDM2 and decreased p53 ubiquitination. J Biol Chem 282:29284–29295PubMedCrossRefGoogle Scholar
  190. 190.
    Alcendor DJ, Charest AM, Zhu WQ, Vigil HE, Knobel SM (2012) Infection and upregulation of proinflammatory cytokines in human brain vascular pericytes by human cytomegalovirus. J Neuroinflammation 9:95PubMedPubMedCentralCrossRefGoogle Scholar
  191. 191.
    Kossmann T, Morganti-Kossmann MC, Orenstein JM, Britt WJ, Wahl SM, Smith PD (2003) Cytomegalovirus production by infected astrocytes correlates with transforming growth factor-beta release. J Infect Dis 187:534–541PubMedCrossRefGoogle Scholar
  192. 192.
    Cheeran M, Hu S, Yager S, Gekker G, Peterson P, Lokensgard J (2001) Cytomegalovirus induces cytokine and chemokine production differentially in microglia and astrocytes: antiviral implications. J Neurovirol 7:135–147PubMedCrossRefGoogle Scholar
  193. 193.
    Orlikowski D, Porcher R, Sivadon-Tardy V, Quincampoix J, Raphaël JC, Durand Raphaël JC, Durand Gaillard JL, Gault E (2011) Guillain–Barr’e syndrome following primary cytomegalovirus infection: a prospective cohort study. Clin Infect Dis 52:837–844PubMedCrossRefGoogle Scholar
  194. 194.
    Steininger C, Seiser A, Gueler N, Puchhammer-Stöckl E, Aberle S, Stanek G, Popow-Kraupp T (2007) Primary cytomegalovirus infection in patients with Guillain-Barr’e syndrome. J Neuroimmunol 183:214–219PubMedCrossRefGoogle Scholar
  195. 195.
    Cook C (2007) Cytomegalovirus reactivation in“ immunocompetent” patients: a call for scientific prophylaxis. J Infect Dis 196:1273–1275PubMedCrossRefGoogle Scholar
  196. 196.
    Ogawa-Goto K, Ueno T, Oshima K, Yamamoto H, Sasaki J, Fujita K, Sata T, Taniguchi S, Kanda Y, Katano H (2012) Detection of active human cytomegalovirus by the promyelocytic leukemia body assay in cultures of PBMCs from patients undergoing hematopoietic stem cell transplantation. J Med Virol 84:479–486PubMedCrossRefGoogle Scholar
  197. 197.
    Chandra A, Keilp J, Fallon B (2013) Correlates of perceived health-related quality of life in post-treatment Lyme Encephalopathy. Psychosomatics 54:552–559PubMedCrossRefGoogle Scholar
  198. 198.
    Johnson L, Wilcox S, Mankoff J, Stricker R (2014) Severity of chronic Lyme disease compared to other chronic conditions: a quality of life survey. Peer J 2, e322PubMedPubMedCentralCrossRefGoogle Scholar
  199. 199.
    Eikeland R, Mygland Å, Herlofson K, Ljostad U (2013) Risk factors for a non-favorable outcome after treated European neuroborreliosis. Acta Neurol Scand 127:154–160PubMedCrossRefGoogle Scholar
  200. 200.
    Hildenbrand P, Craven D, Jones R, Nemeskal P (2009) Lyme neuroborreliosis: manifestations of a rapidly emerging zoonosis. AJNR Am J Neuroradiol 30:1079–1087PubMedCrossRefGoogle Scholar
  201. 201.
    Rupprecht T, Koedel U, Fingerle V, Pfister H (2008) The pathogenesis of Lyme neuroborreliosis: from infection to inflammation. Mol Med 14:205–212PubMedPubMedCentralGoogle Scholar
  202. 202.
    Kraiczy P, Skerka C, Kirschfink M, Zipfel P, Brade V (2002) Immune evasion of Borrelia burgdorferi: insufficient killing of the pathogens by complement and antibody. Int J Med Microbiol 291:141–146PubMedCrossRefGoogle Scholar
  203. 203.
    Strle K, Drouin E, Shen S, El Khoury J, McHugh G, Ruzic-Sabljic E, Strle F, Steere AC (2009) Borrelia burgdorferi stimulates macrophages to secrete higher levels of cytokines and chemokines than Borrelia afzelii or Borrelia garinii. J Infect Dis 200:1936–1943PubMedPubMedCentralCrossRefGoogle Scholar
  204. 204.
    Sandholm K, Henningsson A, Save S, Bergstrom S, Forsberg P, Jonsson N, Ernerudh J, Ekdahl KN (2014) Early cytokine release in response to live Borrelia burgdorferi Sensu Lato spirochetes is largely complement independent. Plos One 9, e108013PubMedPubMedCentralCrossRefGoogle Scholar
  205. 205.
    Hirschfeld M, Kirschning C, Schwandner R, Wesche H, Weis J, Wooten R, Weis J (1999) Cutting edge: inflammatory signaling by Borrelia burgdorferi lipoproteins is mediated by toll-like receptor 2. J Immunol 163:2382–2386PubMedGoogle Scholar
  206. 206.
    Dennis V, Dixit S, O’Brien S, Alvarez X, Pahar B, Philipp M (2009) Live Borrelia burgdorferi spirochetes elicit inflammatory mediators from human monocytes via the Toll-like receptor signaling pathway. Infect Immun 77:1238–1245PubMedPubMedCentralCrossRefGoogle Scholar
  207. 207.
    Cervantes J, Dunham-Ems S, La Vake C, Petzke M, Sahay B, Sellati TJ, Radolf JD, Salazar JC (2011) Phagosomal signaling by Borrelia burgdorferi in human monocytes involves Toll-like receptor (TLR) 2 and TLR8 cooperativity and TLR8-mediated induction of IFN-beta. Proc Natl Acad Sci U S A 108:3683–3688PubMedPubMedCentralCrossRefGoogle Scholar
  208. 208.
    Love A, Schwartz I, Petzke M (2014) Borrelia burgdorferi RNA induces type I and III interferons via Toll-like receptor 7 and contributes to production of NF-$kappa$B-dependent cytokines. Infect Immun 82:2405–2416PubMedPubMedCentralCrossRefGoogle Scholar
  209. 209.
    Cruz A, Moore M, La Vake C, Eggers C, Salazar J, Radolf J (2008) Phagocytosis of Borrelia burgdorferi, the Lyme disease spirochete, potentiates innate immune activation and induces apoptosis in human monocytes. Infect Immun 76:56–70PubMedPubMedCentralCrossRefGoogle Scholar
  210. 210.
    Cervantes J, Hawley K, Benjamin S, Weinerman B, Luu S, Salazar J (2014) Phagosomal TLR signaling upon Borrelia burgdorferi infection. Front Cell Infect Microbiol 4:55PubMedPubMedCentralGoogle Scholar
  211. 211.
    Ligor M, Olszowy P, Buszewski B (2012) Application of medical and analytical methods in Lyme borreliosis monitoring. Anal Bioanal Chem 402:2233–2248PubMedPubMedCentralCrossRefGoogle Scholar
  212. 212.
    Łuczaj W, Moniuszko A, Rusak M, Pancewicz S, Zajkowska J, Skrzydlewska E (2011) Lipid peroxidation products as potential bioindicators of Lyme arthritis. Eur J Clin Microbiol Infect Dis 30:415–422PubMedCrossRefGoogle Scholar
  213. 213.
    Ratajczak-Wrona W, Jabłońska E, Pancewicz SA, Zajkowska J, Garley M, Iżycka-Herman A, Sawko Ł (2013) Evaluation of serum levels of nitric oxide and its biomarkers in patients with Lyme borreliosis. Prog Health Sci 3:26–32Google Scholar
  214. 214.
    Bhattacharjee A, Oeemig J, Kolodziejczyk R, Meri T, Kajander T, Lehtinen MJ, Iwaï H, Jokiranta TS, Goldman A (2013) Structural basis for complement evasion by Lyme disease pathogen Borrelia burgdorferi. J Biol Chem 288:18685–18695PubMedPubMedCentralCrossRefGoogle Scholar
  215. 215.
    Parthasarathy G, Philipp M (2014) The MEK/ERK pathway is the primary conduit for Borrelia burgdorferi-induced inflammation and P53-mediated apoptosis in oligodendrocytes. Apoptosis 19:76–89PubMedPubMedCentralCrossRefGoogle Scholar
  216. 216.
    Ramesh G, Borda J, Dufour J, Kaushal D, Ramamoorthy R, Lackner A, Philipp M (2008) Interaction of the Lyme disease spirochete Borrelia burgdorferi with brain parenchyma elicits inflammatory mediators from glial cells as well as glial and neuronal apoptosis. Am J Pathol 173:1415–1427PubMedPubMedCentralCrossRefGoogle Scholar
  217. 217.
    Ramesh G, Santana-Gould L, Inglis F, England J, Philipp M (2013) The Lyme disease spirochete Borrelia burgdorferi induces inflammation and apoptosis in cells from dorsal root ganglia. J Neuroinflammation 10:88PubMedPubMedCentralCrossRefGoogle Scholar
  218. 218.
    Myers T, Kaushal D, Philipp M (2009) Microglia are mediators of Borrelia burgdorferi–induced apoptosis in SH-SY5Y neuronal cells. PLoS Pathog 5, e1000659PubMedPubMedCentralCrossRefGoogle Scholar
  219. 219.
    Rasley A, Anguita J, Marriott I (2002) Borrelia burgdorferi induces inflammatory mediator production by murine microglia. J Neuroimmunol 130:22–31PubMedCrossRefGoogle Scholar
  220. 220.
    Miklossy J, Kasas S, Zurn A, McCall S, Yu S, McGeer P (2008) Persisting atypical and cystic forms of Borrelia burgdorferi and local inflammation in Lyme neuroborreliosis. J Neuroinflammation 5:1–18CrossRefGoogle Scholar
  221. 221.
    Henningsson AJ, Christiansson M, Tjernberg I, Löfgren S, Matussek A (2014) Laboratory diagnosis of Lyme neuroborreliosis: a comparison of three CSF anti-Borrelia antibody assays. Eur J Clin Microbiol Infect Dis 33:797–803PubMedPubMedCentralCrossRefGoogle Scholar
  222. 222.
    Eshoo MW, Crowder CC, Rebman AW, Rounds MA, Matthews HE, Picuri JM, Soloski MJ, Ecker DJ, Schutzer SE, Aucott JN (2012) Direct molecular detection and genotyping of Borrelia burgdorferi from whole blood of patients with early Lyme disease. PLoS One 7, e36825PubMedPubMedCentralCrossRefGoogle Scholar
  223. 223.
    Miklossy J (2011) Alzheimer’s disease - a neurospirochetosis. Analysis of the evidence following Koch’s and Hill’s criteria. J Neuroinflammation 8:90PubMedPubMedCentralCrossRefGoogle Scholar
  224. 224.
    Crago BR, Gray MR, Nelson LA, Davis M, Arnold L, Thrasher JD (2003) Psychological, neuropsychological and electrocortical effects of mixed mold exposure. Arch Environ Health 58:452–463PubMedCrossRefGoogle Scholar
  225. 225.
    Baldo J, Ahmad L, Ruff R (2002) Neuropsychological performance of patients following mold exposure. Appl Neuropsychol 9:193–202PubMedCrossRefGoogle Scholar
  226. 226.
    Kilburn KH (2002) Inhalation of molds and mycotoxins. Eur J Oncol 7:197–202Google Scholar
  227. 227.
    Hope J (2013) A review of the mechanism of injury and treatment approaches for illness resulting from exposure to water-damaged buildings, mold, and mycotoxins. Sci World J 2013:767482CrossRefGoogle Scholar
  228. 228.
    Brasel TL, Douglas DR, Wilson SC, Straus DC (2005) Detection of airborne Stachybotrys chartarum macrocyclic trichothecene mycotoxins on particulates smaller than conidia. Appl Environ Microbiol 71:114–122PubMedPubMedCentralCrossRefGoogle Scholar
  229. 229.
    Brasel TL, Martin JM, Carriker CG, Wilson SC, Straus DC (2005) Detection of airborne Stachybotrys chartarum macrocyclic trichothecene mycotoxins in the indoor environment. Appl Environ Microbiol 71:7376–7388PubMedPubMedCentralCrossRefGoogle Scholar
  230. 230.
    Cho S-H, Seo S-C, Schmechel D, Grinshpun SS, Reponen T (2005) Aerodynamic characteristics and respiratory deposition of fungal fragments. Atmos Environ 39:5454–5465CrossRefGoogle Scholar
  231. 231.
    Charpin-Kadouch C, Maurel G, Felipo R, Queralt J, Ramadour M, Dumon H, Garans M, Botta A, Charpin D (2006) Mycotoxin identification in moldy dwellings. J Appl Toxicol 26:475–479PubMedCrossRefGoogle Scholar
  232. 232.
    Górny RL, Reponen T, Willeke K, Schmechel D, Robine E, Boissier M, Grinshpun SA (2002) Fungal fragments as indoor air biocontaminants. Appl Environ Microbiol 68:3522–3531PubMedPubMedCentralCrossRefGoogle Scholar
  233. 233.
    Creasia DA, Thurman JD, Jones LJ 3rd, Nealley ML, York CG, Wannemacher RW Jr, Bunner DL (1987) Acute inhalation toxicity of T-2 mycotoxin in mice. Fundam Appl Toxicol 8:230–235PubMedCrossRefGoogle Scholar
  234. 234.
    Brasel TL, Campbell AW, Demers RE, Ferguson BS, Fink J, Vojdani A, Wilson SC, Straus DC (2004) Detection of trichothecene mycotoxins in sera from individuals exposed to Stachybotrys chartarum in indoor environments. Arch Environ Health 59:317–323PubMedGoogle Scholar
  235. 235.
    Rocha O, Ansari K, Doohan FM (2005) Effects of trichothecene mycotoxins on eukaryotic cells: a review. Food Addit Contam 22:369–378PubMedCrossRefGoogle Scholar
  236. 236.
    Zajtchuk R, Bellamy RF (1997) Textbook of military medicine. Borden Institute, WashingtonGoogle Scholar
  237. 237.
    Karunasena E, Larrañaga MD, Simoni JS, Douglas DR, Straus DC (2010) Building-associated neurological damage modeled in human cells: a mechanism of neurotoxic effects by exposure to mycotoxins in the indoor environment. Mycopathologia 170:377–390PubMedCrossRefGoogle Scholar
  238. 238.
    Chung YJ, Yang GH, Islam Z, Pestka JJ (2003) Up-regulation of macrophage inflammatory protein-2 and complement 3A receptor by the trichothecenes deoxynivalenol and satratoxin G. Toxicology 186:51–65PubMedCrossRefGoogle Scholar
  239. 239.
    Moon Y, Pestka JJ (2003) Deoxynivalenol-induced mitogen-activated protein kinase phosphorylation and IL-6 expression in mice suppressed by fish oil. J Nutr Biochem 14:717–726PubMedCrossRefGoogle Scholar
  240. 240.
    Moon Y, Uzarski R, Pestka JJ (2003) Relationship of trichothecene structure to COX-2 induction in the macrophage: selective action of type B (8-keto) trichothecenes. J Toxicol Environ Health A 66:1967–1983PubMedCrossRefGoogle Scholar
  241. 241.
    Pestka JJ, Zhou HR, Moon Y, Chung YJ (2004) Cellular and molecular mechanisms for immune modulation by deoxynivalenol and other trichothecenes: unraveling a paradox. Toxicol Lett 153:61–73PubMedCrossRefGoogle Scholar
  242. 242.
    Zhou HR, Islam Z, Pestka JJ (2003) Rapid, sequential activation of mitogen-activated protein kinases and transcription factors precedes proinflammatory cytokine mRNA expression in spleens of mice exposed to the trichothecene vomitoxin. Toxicol Sci 72:130–142PubMedCrossRefGoogle Scholar
  243. 243.
    Zhou HR, Jia Q, Pestka JJ (2005) Ribotoxic stress response to the trichothecene deoxynivalenol in the macrophage involves the SRC family kinase Hck. Toxicol Sci 85:916–926PubMedCrossRefGoogle Scholar
  244. 244.
    Edmondson DA, Barrios CS, Brasel TL, Straus DC, Kurup VP, Fink JN (2009) Immune response among patients exposed to molds. Int J Mol Sci 10:5471–5484PubMedPubMedCentralCrossRefGoogle Scholar
  245. 245.
    Gray MR, Thrasher JD, Crago R, Madison RA, Campbell AW, Vojdani A (2003) Mixed mold exposure: immunological changes in humans with exposure in water damaged buildings. Arch Environ Health 58:410–420PubMedGoogle Scholar
  246. 246.
    Campbell AW, Thrasher JD, Madison RA, Vojdani A, Gray MR, Johnson A (2003) Neural antigen autoantibodies and neurophysiology abnormalities in patients exposed to moulds in water-damaged buildings. Arch Environ 58:464–474CrossRefGoogle Scholar
  247. 247.
    Sorensen B, Streib JE, Strand M, Make B, Giclas PC, Fleshner M, Jones JF (2003) Complement activation in a model of chronic fatigue syndrome. J Allergy Clin Immunol 112:397–403PubMedCrossRefGoogle Scholar
  248. 248.
    Thrasher JD, Gray MR, Kilburn KH, Dennis DP, Yu A (2012) A water-damaged home and health of occupants: a case study. J Environ Public Health 2012:312836PubMedPubMedCentralCrossRefGoogle Scholar
  249. 249.
    Liu J, Wang Y, Cui J, Xing L, Shen H, Wu S, Lian H, Wang J, Yan X, Zhang X (2012) Ochratoxin A induces oxidative DNA damage and G1 phase arrest in human peripheral blood mononuclear cells in vitro. Toxicol Lett 211:164–171PubMedCrossRefGoogle Scholar
  250. 250.
    Doi K, Uetsuka K (2011) Mechanisms of mycotoxin-induced neurotoxicity through oxidative stress-associated pathways. Int J Mol Sci 12:5213–5237PubMedPubMedCentralCrossRefGoogle Scholar
  251. 251.
    Bouslimi A, Ouannes Z, Golli EE, Bouaziz C, Hassen W, Bacha H (2008) Cytotoxicity and oxidative damage in kidney cells exposed to the mycotoxins ochratoxin a and citrinin: individual and combined effects. Toxicol Mech Methods 18:341–349PubMedCrossRefGoogle Scholar
  252. 252.
    Islam Z, Amuzie CJ, Harkema JR, Pestka JJ (2007) Neurotoxicity and inflammation in the nasal airways of mice exposed to the macrocyclic trichothecene mycotoxin roridin a: kinetics and potentiation by bacterial lipopolysaccharide coexposure. Toxicol Sci 98:526–541PubMedCrossRefGoogle Scholar
  253. 253.
    Jussila J, Komulainen H, Kosma VM, Nevalainen A, Pelkonen J, Hirvonen MR (2002) Spores of Aspergillus versicolor isolated from indoor air of a moisture-damaged building provoke acute inflammation in mouse lungs. Inhal Toxicol 14:1261–1277PubMedCrossRefGoogle Scholar
  254. 254.
    Cavin C, Delatour T, Marin-Kuan M, Fenaille F, Holzhäuser D, Guignard G, Bezençon C, Piguet D, Parisod V, Richoz-Payot J, Schilter B (2009) Ochratoxin A-mediated DNA and protein damage: roles of nitrosative and oxidative stresses. Toxicol Sci 110:84–94PubMedCrossRefGoogle Scholar
  255. 255.
    Zhang X, Jiang L, Geng C, Cao J, Zhong L (2009) The role of oxidative stress in deoxynivalenol-induced DNA damage in HepG2 cells. Toxicon 54:513–518PubMedCrossRefGoogle Scholar
  256. 256.
    Roberts RA, Laskin DL, Smith CV, Robertson FM, Allen EM, Doorn JA, Slikker W (2009) Nitrative and oxidative stress in toxicology and disease. Toxicol Sci 112:4–16PubMedPubMedCentralCrossRefGoogle Scholar
  257. 257.
    Cremer B, Soja A, Sauer JA, Damm M (2012) Pro-inflammatory effects of ochratoxin A on nasal epithelial cells. Eur Arch Otorhinolaryngol 269:1155–1161PubMedCrossRefGoogle Scholar
  258. 258.
    Hoehler D, Marquardt RR, McIntosh AR, Hatch GM (1997) Induction of free radicals in hepatocytes, mitochondria and microsomes of rats by ochratoxin A and its analogs. Biochim Biophys Acta 1357:225–233PubMedCrossRefGoogle Scholar
  259. 259.
    Sajan MP, Satav JG, Battacharya RK (1997) Effect of aflatoxin B1 in vitro on rat liver mitochondrial respiratory functions. Indian J Exper Biol 35:1187–1190Google Scholar
  260. 260.
    Bin-Umer MA, McLaughlin JE, Basu D, McCormick S, Tumer NE (2011) Trichothecene mycotoxins inhibit mitochondrial translation–implication for the mechanism of toxicity. Toxins (Basel) 3:1484–1501CrossRefGoogle Scholar
  261. 261.
    Domijan AM, Abramov AY (2011) Fumonisin B1 inhibits mitochondrial respiration and deregulates calcium homeostasis–implication to mechanism of cell toxicity. Int J Biochem Cell Biol 43:897–904PubMedCrossRefGoogle Scholar
  262. 262.
    Kim HY, Jung YH, Hong K, Jang GC, Seo JH, Kwon JW, Kim BJ, Kim HB, Lee SY, Song DJ, Kim WK, Shim JY, Kang MJ, Kim YJ, Yu HS, Hong SJ (2013) Gene-environment interaction between Toll-like receptor 4 and mold exposure in the development of atopic dermatitis in preschool children. Allergy Asthma Respir Dis 1:129–137CrossRefGoogle Scholar
  263. 263.
    Lanciotti M, Pigullo S, Lanza T, Dufour C, Caviglia I, Castagnola E (2008) Possible role of toll-like receptor 9 polymorphism in chemotherapy-related invasive mold infections in children with hematological malignancies. Pediatr Blood Cancer 50:944PubMedCrossRefGoogle Scholar
  264. 264.
    Ramirez-Ortiz ZG, Specht CA, Wang JP, Lee CK, Bartholomeu DC, Gazzinelli RT, Levitz SM (2008) Toll-like receptor 9-dependent immune activation by unmethylated CpG motifs in Aspergillus fumigatus DNA. Infect Immun 76:2123–2129PubMedPubMedCentralCrossRefGoogle Scholar
  265. 265.
    Bhan U, Newstead MJ, Zeng X, Podsaid A, Goswami M, Ballinger MN, Kunkel SL, Standiford TJ (2013) TLR9-dependent IL-23/IL-17 is required for the generation of Stachybotrys chartarum-induced hypersensitivity pneumonitis. J Immunol 190:349–356PubMedPubMedCentralCrossRefGoogle Scholar
  266. 266.
    Larypoor M, Bayat M, Zuhair MH, Akhavan Sepahy A, Amanlou M (2013) Evaluation of the number of CD4(+) CD25(+) FoxP3(+) Treg cells in normal mice exposed to AFB1 and treated with aged garlic extract. Cell J 15:37–44PubMedPubMedCentralGoogle Scholar
  267. 267.
    Azcona-Olivera JI, Ouyang Y, Murtha J, Chu FS, Pestka JJ (1995) Induction of cytokine mRNAs in mice after oral exposure to the trichothecene vomitoxin (deoxynivalenol): relationship to toxin distribution and protein synthesis inhibition. Toxicol Appl Pharmacol 133:109–120PubMedCrossRefGoogle Scholar
  268. 268.
    Pinton P, Oswald IP (2014) Effect of deoxynivalenol and other Type B trichothecenes on the intestine: a review. Toxins (Basel) 6:1615–1643CrossRefGoogle Scholar
  269. 269.
    Cano PM, Seeboth J, Meurens F, Cognie J, Abrami R, Oswald IP, Guzylack-Piriou L (2013) Deoxynivalenol as a new factor in the persistence of intestinal inflammatory diseases: an emerging hypothesis through possible modulation of Th17-mediated response. PLoS One 8, e53647PubMedPubMedCentralCrossRefGoogle Scholar
  270. 270.
    Pestka JJ, Amuzie CJ (2008) Tissue distribution and proinflammatory cytokine gene expression following acute oral exposure to deoxynivalenol: comparison of weanling and adult mice. Food Chem Toxicol 46:2826–2831PubMedPubMedCentralCrossRefGoogle Scholar
  271. 271.
    Amuzie CJ, Shinozuka J, Pestka JJ (2009) Induction of suppressors of cytokine signaling by the trichothecene deoxynivalenol in the mouse. Toxicol Sci 111:277–287PubMedPubMedCentralCrossRefGoogle Scholar
  272. 272.
    Maresca M, Yahi N, Younes-Sakr L, Boyron M, Caporiccio B, Fantini J (2008) Both direct and indirect effects account for the pro-inflammatory activity of enteropathogenic mycotoxins on the human intestinal epithelium: stimulation of interleukin-8 secretion, potentiation of interleukin-1beta effect and increase in the transepithelial passage of commensal bacteria. Toxicol Appl Pharmacol 228:84–92PubMedCrossRefGoogle Scholar
  273. 273.
    Maes M, Ringel K, Kubera M, Anderson G, Morris G, Galecki P, Geffard M (2013) In myalgic encephalomyelitis/chronic fatigue syndrome, increased autoimmune activity against 5-HT is associated with immuno-inflammatory pathways and bacterial translocation. J Affect Disord 150:223–230PubMedCrossRefGoogle Scholar
  274. 274.
    Maes M, Mihaylova I, Leunis JC (2007) Increased serum IgA and IgM against LPS of enterobacteria in chronic fatigue syndrome (CFS): indication for the involvement of gram-negative enterobacteria in the etiology of CFS and for the presence of an increased gut-intestinal permeability. J Affect Disord 99:237–240PubMedCrossRefGoogle Scholar
  275. 275.
    Akbari P, Braber S, Gremmels H, Koelink PJ, Verheijden KA, Garssen J, Fink-Gremmels J (2014) Deoxynivalenol: a trigger for intestinal integrity breakdown. FASEB J 28:2414–2429PubMedCrossRefGoogle Scholar
  276. 276.
    Pinton P, Nougayrede JP, del Rio JC, Moreno C, Marin DE, Ferrier L, Bracarense AP, Kolf-Clauw M, Oswald IP (2009) The food contaminant deoxynivalenol, decreases intestinal barrier permeability and reduces claudin expression. Toxicol Appl Pharmacol 237:41–48PubMedCrossRefGoogle Scholar
  277. 277.
    Van De Walle J, Sergent T, Piront N, Toussaint O, Schneider YJ, Larondelle Y (2010) Deoxynivalenol affects in vitro intestinal epithelial cell barrier integrity through inhibition of protein synthesis. Toxicol Appl Pharmacol 245:291–298PubMedCrossRefGoogle Scholar
  278. 278.
    Pinton P, Braicu C, Nougayrede JP, Laffitte J, Taranu I, Oswald IP (2010) Deoxynivalenol impairs porcine intestinal barrier function and decreases the protein expression of claudin-4 through a mitogen-activated protein kinase-dependent mechanism. J Nutr 140:1956–1962PubMedCrossRefGoogle Scholar
  279. 279.
    Mbandi E, Pestka JJ (2006) Deoxynivalenol and satratoxin G potentiate proinflammatory cytokine and macrophage inhibitory protein 2 induction by Listeria and Salmonella in the macrophage. J Food Prot 69:1334–1339PubMedGoogle Scholar
  280. 280.
    Empting LD (2009) Neurologic and neuropsychiatric syndrome features of mold and mycotoxin exposure. Toxicol Ind Health 25:577–581PubMedCrossRefGoogle Scholar
  281. 281.
    Rea WJ, Didriksen N, Simon TR, Pan Y, Fenyves EJ, Griffiths B (2003) Effects of toxic exposure to molds and mycotoxins in building-related illnesses. Arch Environ Health 58:399–405PubMedGoogle Scholar
  282. 282.
    Kilburn KH (2009) Neurobehavioral and pulmonary impairment in 105 adults with indoor exposure to molds compared to 100 exposed to chemicals. Toxicol Ind Health 25:681–692PubMedCrossRefGoogle Scholar
  283. 283.
    Ross GH, Rea WJ, Johnson AR, Hickey DC, Simon TR (1999) Neurotoxicity in single photon emission computed tomography brain scans of patients reporting chemical sensitivities. Toxicol Ind Health 15:415–420PubMedGoogle Scholar
  284. 284.
    Shifrin VI, Anderson P (1999) Trichothecene mycotoxins trigger a ribotoxic stress response that activates c-Jun N-terminal kinase and p38 mitogen-activated protein kinase and induces apoptosis. J Biol Chem 274:13985–13992PubMedCrossRefGoogle Scholar
  285. 285.
    Eriksen GS, Petterson H, Lund H (2004) Comparative cytotoxicity of deoxynivalenol, nivalenol, triacetylated derivatives and de-epoxy metabolites. Food Chem Toxicol 42:619–624CrossRefGoogle Scholar
  286. 286.
    Boyd KE, Fitzpatrick DW, Wilson JR, Wilson LM (1988) Effect of T-2 toxin on brain biogenic monoamines in rats and chickens. Can J Vet Res 52:181–185PubMedPubMedCentralGoogle Scholar
  287. 287.
    Wang J, Fiztpatrick DW, Wilson JR (1998) Effects of the trichothecene mycotoxin T-2 toxin on the neurotransmitters and metabolites in discrete areas of the rat brain. Food Chem Toxicol 36:947–953PubMedCrossRefGoogle Scholar
  288. 288.
    Galtier P, Paulin F, Eeckhoutte C, Larrieu G (1989) Comparative effects of T-2 toxin and diacetoxyscirpenol on drug metabolizing enzymes in rat tissues. Food Chem Toxicol 27:215–220PubMedCrossRefGoogle Scholar
  289. 289.
    Guerre P, Eeckhoutte C, Burgat V, Galtier P (2000) The effects of T-2 toxin exposure on liver drug metabolizing enzymes in rabbit. Food Addit Contam 17:1019–1026PubMedCrossRefGoogle Scholar
  290. 290.
    Chaudhary M, Rao PV (2010) Brain oxidative stress after dermal and subcutaneous exposure of T-2 toxin in mice. Food Chem Toxicol 48:3436–3442PubMedCrossRefGoogle Scholar
  291. 291.
    Weidner M, Hüwel S, Ebert F, Schwerdtle T, Galla HJ, Humpf HU (2013) Influence of T-2 and HT-2 toxin on the blood–brain barrier in vitro: new experimental hints for neurotoxic effects. PLoS One 8, e60484PubMedPubMedCentralCrossRefGoogle Scholar
  292. 292.
    Ravindran J, Agrawal M, Gupta N, Rao PV (2011) Alteration of blood brain barrier permeability by T-2 toxin: Role of MMP-9 and inflammatory cytokines. Toxicology 280:44–52PubMedCrossRefGoogle Scholar
  293. 293.
    Andersen B, Nielsen KF, Jarvis BB (2002) Characterization of Stachybotrys from water-damaged buildings based on morphology, growth, and metabolite production. Mycologia 94:392–403PubMedCrossRefGoogle Scholar
  294. 294.
    Chung YJ, Zhou HR, Pestka JJ (2003) Transcriptional and posttranscriptional roles for p38 mitogen-activated protein kinase in upregulation of TNF-α expression by deoxynivalenol (vomitoxin). Toxicol Appl Pharmacol 193:188–201PubMedCrossRefGoogle Scholar
  295. 295.
    Hope JH, Hope BE (2012) A review of the diagnosis and treatment of Ochratoxin A inhalational exposure associated with human illness and kidney disease including focal segmental glomerulosclerosis. J Environ Public Health 2012:835059PubMedPubMedCentralCrossRefGoogle Scholar
  296. 296.
    Sava V, Reunova O, Velasquez A, Harbison R, Sanchez-Ramos J (2006) Acute neurotoxic effects of the fungal netabolite ochratoxin-A. Neurotoxicology 27:82–92PubMedCrossRefGoogle Scholar
  297. 297.
    Sava V, Reunova O, Velasquez A, Sanchez-Ramos J (2006) Can low level exposure to ochratoxin-A cause parkinsonism? J Neurol Sci 249:68–75PubMedCrossRefGoogle Scholar
  298. 298.
    Gautier JC, Holzhaeuser D, Markovic J, Gremaud E, Schilter B, Turesky RJ (2001) Oxidative damage and stress response from ochratoxin exposure in rats. Free Radic Biol Med 30:1089–1098PubMedCrossRefGoogle Scholar
  299. 299.
    Aleo MD, Wyatt RD, Schnellmann RG (1991) Mitochondrial dysfunction is an early event in ochratoxin A but not oosporein toxicity to rat renal proximal tubules. Toxicol Appl Pharmacol 107:73–80PubMedCrossRefGoogle Scholar
  300. 300.
    Zhang X, Boesch-Saadatmandi C, Lou Y, Wolffram S, Huebbe P, Rimbach G (2009) Ochratoxin A induces apoptosis in neuronal cells. Genes Nutr 4:41–48PubMedPubMedCentralCrossRefGoogle Scholar
  301. 301.
    Zurich MG, Lengacher S, Braissant O, Monnet-Tschudi F, Pellerin L, Honegger P (2005) Unusual astrocyte reactivity caused by the food mycotoxin ochratoxin A in aggregating rat brain cell cultures. Neuroscience 134:771–782PubMedCrossRefGoogle Scholar
  302. 302.
    Hong JT, Lee MK, Park KS, Jung KM, Lee RD, Jung HK, Park KL, Yang KJ, Chung YS (2002) Inhibitory effect of peroxisome proliferator-activated receptor gamma agonist on ochratoxin A-induced cytotoxicity and activation of transcription factors in cultured rat embryonic midbrain cells. J Toxicol Environ Health A 65:407–418PubMedCrossRefGoogle Scholar
  303. 303.
    Stockmann-Juvala H, Savolainen K (2008) A review of the toxic effects and mechanisms of action of fumonisin B1. Hum Exp Toxicol 27:799–809PubMedCrossRefGoogle Scholar
  304. 304.
    Islam Z, Harkema JR, Pestka JJ (2006) Satratoxin G from the black mold Stachybotrys chartarum evokes olfactory sensory neuron loss and inflammation in the murine nose and brain. Environ Health Perspect 114:1099–1107PubMedPubMedCentralCrossRefGoogle Scholar
  305. 305.
    Islam Z, Pestka JJ (2006) LPS priming potentiates and prolongs proinflammatory cytokine response to the trichothecene deoxynivalenol in the mouse. Toxicol Appl Pharmacol 211:53–63PubMedCrossRefGoogle Scholar
  306. 306.
    Thrasher JD, Crawley S (2009) The biocontaminants and complexity of damp indoor spaces: more than what meets the eyes. Toxicol Ind Health 25:583–615PubMedCrossRefGoogle Scholar
  307. 307.
    Alassane-Kpembi I, Kolf-Clauw M, Gauthier T, Abrami R, Abiola FA, Oswald IP, Puel O (2013) New insights into mycotoxin mixtures: the toxicity of low doses of Type B trichothecenes on intestinal epithelial cells is synergistic. Toxicol Appl Pharmacol 272:191–198PubMedCrossRefGoogle Scholar
  308. 308.
    Tai JH, Pestka JJ (1988) Synergistic interaction between the trichothecene T-2 toxin and Salmonella typhimurium lipopolysaccharide in C3H/HeN and C3H/HeJ mice. Toxicol Lett 44:191–200PubMedCrossRefGoogle Scholar
  309. 309.
    Zhou HR, Harkema JR, Yan D, Pestka JJ (1999) Amplified proinflammatory cytokine expression and toxicity in mice coexposed to lipopolysaccharide and the trichothecene vomitoxin (deoxynivalenol). J Toxicol Environ Health A 57(2):115–136PubMedCrossRefGoogle Scholar
  310. 310.
    Islam Z, Pestka JJ (2003) Role of IL-1(beta) in endotoxin potentiation of deoxynivalenol-induced corticosterone response and leukocyte apoptosis in mice. Toxicol Sci 74:93–102PubMedCrossRefGoogle Scholar
  311. 311.
    Morris G, Berk M, Galecki P, Maes M (2014) The emerging role of autoimmunity in myalgic encephalomyelitis/chronic fatigue syndrome (ME/cfs). Mol Neurobiol 49:741–756PubMedCrossRefGoogle Scholar
  312. 312.
    Morris G, Anderson G, Galecki P, Berk M, Maes M (2013) A narrative review on the similarities and dissimilarities between myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and sickness behavior. BMC Med 11:64PubMedPubMedCentralCrossRefGoogle Scholar
  313. 313.
    Calderón-Garcidueñas L, Azzarelli B, Acuna H, Garcia R, Gambling TM, Osnaya N, Monroy S, DEL Tizapantzi MR, Carson JL, Villarreal-Calderon A, Rewcastle B (2002) Air pollution and brain damage. Toxicol Pathol 30:373–389PubMedCrossRefGoogle Scholar
  314. 314.
    Calderón-Garcidueñas L, Mora-Tiscareño A, Ontiveros E, Gómez-Garza G, Barragán-Mejía G, Broadway J, Chapman S, Valencia-Salazar G, Jewells V, Maronpot RR, Henríquez-Roldán C, Pérez-Guillé B, Torres-Jardón R, Herrit L, Brooks D, Osnaya-Brizuela N, Monroy ME, González-Maciel A, Reynoso-Robles R, Villarreal-Calderon R, Solt AC, Engle RW (2008) Air pollution, cognitive deficits and brain abnormalities: a pilot study with children and dogs. Brain Cogn 68:117–127PubMedCrossRefGoogle Scholar
  315. 315.
    Calderón-Garcidueñas L, Franco-Lira M, Mora-Tiscareño A, Medina-Cortina H, Torres-Jardón R, Kavanaugh M (2013) Early Alzheimer’s and Parkinson’s disease pathology in urban children: friend versus foe responses—it is time to face the evidence. Biomed Res Int 2013:161687PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Gerwyn Morris
    • 1
  • Michael Berk
    • 2
    • 3
  • Ken Walder
    • 4
  • Michael Maes
    • 2
    • 5
  1. 1.Tir Na NogLlanelliUK
  2. 2.IMPACT Strategic Research Centre, School of MedicineDeakin UniversityGeelongAustralia
  3. 3.Orygen, The National Centre of Excellence in Youth Mental Health, Department of Psychiatry and The Florey Institute of Neuroscience and Mental HealthThe University of MelbourneParkvilleAustralia
  4. 4.Centre for Molecular and Medical Research, School of MedicineDeakin UniversityGeelongAustralia
  5. 5.Department of Psychiatry, Faculty of MedicineChulalongkorn UniversityBangkokThailand

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