Murine roseolovirus does not accelerate amyloid-β pathology and human roseoloviruses are not over-represented in Alzheimer disease brains

Springer Science and Business Media LLC - Tập 17 Số 1 - 2022
Tarin M. Bigley1, Monica Xiong2, Muhammad Ali3, Yun Chen2, Chao Wang2, Javier Remolina Serrano2, Abdallah M. Eteleeb3, Oscar Harari2, Liping Yang4, Sanket Patel4, Carlos Cruchaga3, Wayne M. Yokoyama4, David M. Holtzman2
1Division of Rheumatology, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, 63110, USA
2Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, USA
3Department Psychiatry, Washington University School of Medicine (WUSM), 660 S. Euclid Ave. B8134, St. Louis, MO, 63110, USA
4Division of Rheumatology, Department of Medicine, Washington University School of Medicine St. Louis, MO 63110, USA

Tóm tắt

AbstractBackgroundThe role of viral infection in Alzheimer Disease (AD) pathogenesis is an area of great interest in recent years. Several studies have suggested an association between the human roseoloviruses, HHV-6 and HHV-7, and AD. Amyloid-β (Aβ) plaques are a hallmark neuropathological finding of AD and were recently proposed to have an antimicrobial function in response to infection. Identifying a causative and mechanistic role of human roseoloviruses in AD has been confounded by limitations in performing in vivo studies. Recent -omics based approaches have demonstrated conflicting associations between human roseoloviruses and AD. Murine roseolovirus (MRV) is a natural murine pathogen that is highly-related to the human roseoloviruses, providing an opportunity to perform well-controlled studies of the impact of roseolovirus on Aβ deposition.MethodsWe utilized the 5XFAD mouse model to test whether MRV induces Aβ deposition in vivo. We also evaluated viral load and neuropathogenesis of MRV infection. To evaluate Aβ interaction with MRV, we performed electron microscopy. RNA-sequencing of a cohort of AD brains compared to control was used to investigate the association between human roseolovirus and AD.ResultsWe found that 5XFAD mice were susceptible to MRV infection and developed neuroinflammation. Moreover, we demonstrated that Aβ interacts with viral particles in vitro and, subsequent to this interaction, can disrupt infection. Despite this, neither peripheral nor brain infection with MRV increased or accelerated Aβ plaque formation. Moreover, −omics based approaches have demonstrated conflicting associations between human roseoloviruses and AD. Our RNA-sequencing analysis of a cohort of AD brains compared to controls did not show an association between roseolovirus infection and AD.ConclusionAlthough MRV does infect the brain and cause transient neuroinflammation, our data do not support a role for murine or human roseoloviruses in the development of Aβ plaque formation and AD.

Từ khóa


Tài liệu tham khảo

Long JM, Holtzman DM. Alzheimer disease: an update on pathobiology and treatment strategies. Cell. 2019;179(2):312–39. https://doi.org/10.1016/j.cell.2019.09.001.

Soscia SJ, Kirby JE, Washicosky KJ, Tucker SM, Ingelsson M, Hyman B, et al. The Alzheimer’s disease-associated amyloid beta-protein is an antimicrobial peptide. PLoS One. 2010;5(3):e9505. https://doi.org/10.1371/journal.pone.0009505.

Bourgade K, Dupuis G, Frost EH, Fulop T. Anti-viral properties of amyloid-beta peptides. J Alzheimers Dis. 2016;54(3):859–78. https://doi.org/10.3233/JAD-160517.

Kumar DK, Choi SH, Washicosky KJ, Eimer WA, Tucker S, Ghofrani J, et al. Amyloid-beta peptide protects against microbial infection in mouse and worm models of Alzheimer's disease. Sci Transl Med. 2016;8(340):340ra72.

Eimer WA, Vijaya Kumar DK, Navalpur Shanmugam NK, Rodriguez AS, Mitchell T, Washicosky KJ, et al. Alzheimer's disease-associated beta-amyloid is rapidly seeded by Herpesviridae to protect against brain infection. Neuron. 2018;99(1):56–63.e3. https://doi.org/10.1016/j.neuron.2018.06.030.

Haas JG, Lathe R. Microbes and Alzheimer's disease: new findings call for a paradigm change. Trends Neurosci. 2018;41(9):570–3. https://doi.org/10.1016/j.tins.2018.07.001.

Leibovitch EC, Jacobson S. Viruses in chronic progressive neurologic disease. Mult Scler. 2018;24(1):48–52. https://doi.org/10.1177/1352458517737392.

Kvestak D, Juranic Lisnic V, Lisnic B, Tomac J, Golemac M, Brizic I, et al. NK/ILC1 cells mediate neuroinflammation and brain pathology following congenital CMV infection. J Exp Med. 2021;218(5):e20201503.

Wozniak MA, Shipley SJ, Combrinck M, Wilcock GK, Itzhaki RF. Productive herpes simplex virus in brain of elderly normal subjects and Alzheimer's disease patients. J Med Virol. 2005;75(2):300–6. https://doi.org/10.1002/jmv.20271.

Wozniak MA, Mee AP, Itzhaki RF. Herpes simplex virus type 1 DNA is located within Alzheimer's disease amyloid plaques. J Pathol. 2009;217(1):131–8. https://doi.org/10.1002/path.2449.

Letenneur L, Peres K, Fleury H, Garrigue I, Barberger-Gateau P, Helmer C, et al. Seropositivity to herpes simplex virus antibodies and risk of Alzheimer's disease: a population-based cohort study. PLoS One. 2008;3(11):e3637. https://doi.org/10.1371/journal.pone.0003637.

Lovheim H, Olsson J, Weidung B, Johansson A, Eriksson S, Hallmans G, et al. Interaction between cytomegalovirus and herpes simplex virus type 1 associated with the risk of Alzheimer's disease development. J Alzheimers Dis. 2018;61(3):939–45. https://doi.org/10.3233/JAD-161305.

Rizzo R. Controversial role of herpesviruses in Alzheimer's disease. PLoS Pathog. 2020;16(6):e1008575. https://doi.org/10.1371/journal.ppat.1008575.

Allnutt MA, Johnson K, Bennett DA, Connor SM, Troncoso JC, Pletnikova O, et al. Human herpesvirus 6 detection in Alzheimer's disease cases and controls across multiple cohorts. Neuron. 2020;105(6):1027–35.e2. https://doi.org/10.1016/j.neuron.2019.12.031.

Leibovitch EC, Brunetto GS, Caruso B, Fenton K, Ohayon J, Reich DS, et al. Coinfection of human herpesviruses 6A (HHV-6A) and HHV-6B as demonstrated by novel digital droplet PCR assay. PLoS One. 2014;9(3):e92328. https://doi.org/10.1371/journal.pone.0092328.

Komaroff AL, Pellett PE, Jacobson S. Human Herpesviruses 6A and 6B in Brain Diseases: Association versus Causation. Clin Microbiol Rev. 2020;34(1):e00143-20.

Lin WR, Wozniak MA, Cooper RJ, Wilcock GK, Itzhaki RF. Herpesviruses in brain and Alzheimer's disease. J Pathol. 2002;197(3):395–402. https://doi.org/10.1002/path.1127.

Rizzo R, Bortolotti D, Gentili V, Rotola A, Bolzani S, Caselli E, et al. KIR2DS2/KIR2DL2/HLA-C1 haplotype is associated with Alzheimer's disease: implication for the role of herpesvirus infections. J Alzheimers Dis. 2019;67(4):1379–89. https://doi.org/10.3233/JAD-180777.

Readhead B, Haure-Mirande JV, Funk CC, Richards MA, Shannon P, Haroutunian V, et al. Multiscale analysis of independent Alzheimer's cohorts finds disruption of molecular, genetic, and clinical networks by human herpesvirus. Neuron. 2018;99(1):64–82.e7. https://doi.org/10.1016/j.neuron.2018.05.023.

Jeong HH, Liu Z. Are HHV-6A and HHV-7 really more abundant in Alzheimer's disease. Neuron. 2019;104(6):1034–5. https://doi.org/10.1016/j.neuron.2019.11.009.

Agut H, Bonnafous P, Gautheret-Dejean A. Update on infections with human herpesviruses 6A, 6B, and 7. Med Mal Infect. 2017;47(2):83–91. https://doi.org/10.1016/j.medmal.2016.09.004.

Cuende JI, Ruiz J, Civeira MP, Prieto J. High prevalence of HHV-6 DNA in peripheral blood mononuclear cells of healthy individuals detected by nested-PCR. J Med Virol. 1994;43(2):115–8. https://doi.org/10.1002/jmv.1890430203.

Wang B, Saito Y, Nishimura M, Ren Z, Tjan LH, Refaat A, et al. An Animal Model That Mimics Human Herpesvirus 6B Pathogenesis. J Virol. 2020;94(6):e01851-19.

Tanner A, Carlson SA, Nukui M, Murphy EA, Berges BK. Human herpesvirus 6A infection and immunopathogenesis in humanized Rag2(−)/(−) gammac(−)/(−) mice. J Virol. 2013;87(22):12020–8. https://doi.org/10.1128/JVI.01556-13.

Reynaud JM, Jegou JF, Welsch JC, Horvat B. Human herpesvirus 6A infection in CD46 transgenic mice: viral persistence in the brain and increased production of proinflammatory chemokines via toll-like receptor 9. J Virol. 2014;88(10):5421–36. https://doi.org/10.1128/JVI.03763-13.

Patel SJ, Zhao G, Penna VR, Park E, Lauron EJ, Harvey IB, et al. A Murine Herpesvirus Closely Related to Ubiquitous Human Herpesviruses Causes T-Cell Depletion. J Virol. 2017;91(9):e02463-16.

Becker SD, Bennett M, Stewart JP, Hurst JL. Serological survey of virus infection among wild house mice (Mus domesticus) in the UK. Lab Anim. 2007;41(2):229–38. https://doi.org/10.1258/002367707780378203.

Cross SS, Parker JC, Rowe WP, Robbins ML. Biology of mouse thymic virus, a herpesvirus of mice, and the antigenic relationship to mouse cytomegalovirus. Infect Immun. 1979;26(3):1186–95. https://doi.org/10.1128/iai.26.3.1186-1195.1979.

Patel SJ, Yokoyama WM. CD8(+) T cells prevent lethality from neonatal murine Roseolovirus infection. J Immunol. 2017;199(9):3212–21. https://doi.org/10.4049/jimmunol.1700982.

Oakley H, Cole SL, Logan S, Maus E, Shao P, Craft J, et al. Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer's disease mutations: potential factors in amyloid plaque formation. J Neurosci. 2006;26(40):10129–40. https://doi.org/10.1523/JNEUROSCI.1202-06.2006.

Stinski MF. Human cytomegalovirus: glycoproteins associated with virions and dense bodies. J Virol. 1976;19(2):594–609. https://doi.org/10.1128/jvi.19.2.594-609.1976.

Amen MA, Griffiths A. Identification and expression analysis of herpes B virus-encoded small RNAs. J Virol. 2011;85(14):7296–311. https://doi.org/10.1128/JVI.00505-11.

Stine WB, Jungbauer L, Yu C, LaDu MJ. Preparing synthetic Abeta in different aggregation states. Methods Mol Biol. 2011;670:13–32. https://doi.org/10.1007/978-1-60761-744-0_2.

Xiong M, Jiang H, Serrano JR, Gonzales ER, Wang C, Gratuze M, et al. APOE immunotherapy reduces cerebral amyloid angiopathy and amyloid plaques while improving cerebrovascular function. Sci Transl Med. 2021;13(581):eabd7522.

Liao F, Li A, Xiong M, Bien-Ly N, Jiang H, Zhang Y, et al. Targeting of nonlipidated, aggregated apoE with antibodies inhibits amyloid accumulation. J Clin Invest. 2018;128(5):2144–55. https://doi.org/10.1172/JCI96429.

Dube U, Del-Aguila JL, Li Z, Budde JP, Jiang S, Hsu S, et al. An atlas of cortical circular RNA expression in Alzheimer disease brains demonstrates clinical and pathological associations. Nat Neurosci. 2019;22(11):1903–12. https://doi.org/10.1038/s41593-019-0501-5.

Li Z, Del-Aguila JL, Dube U, Budde J, Martinez R, Black K, et al. Genetic variants associated with Alzheimer's disease confer different cerebral cortex cell-type population structure. Genome Med. 2018;10(1):43. https://doi.org/10.1186/s13073-018-0551-4.

Del-Aguila JL, Benitez BA, Li Z, Dube U, Mihindukulasuriya KA, Budde JP, et al. TREM2 brain transcript-specific studies in AD and TREM2 mutation carriers. Mol Neurodegener. 2019;14(1):18. https://doi.org/10.1186/s13024-019-0319-3.

Li Z, Farias FHG, Dube U, Del-Aguila JL, Mihindukulasuriya KA, Fernandez MV, et al. The TMEM106B FTLD-protective variant, rs1990621, is also associated with increased neuronal proportion. Acta Neuropathol. 2020;139(1):45–61. https://doi.org/10.1007/s00401-019-02066-0.

Harrow J, Frankish A, Gonzalez JM, Tapanari E, Diekhans M, Kokocinski F, et al. GENCODE: the reference human genome annotation for the ENCODE project. Genome Res. 2012;22(9):1760–74. https://doi.org/10.1101/gr.135350.111.

Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013;29(1):15–21. https://doi.org/10.1093/bioinformatics/bts635.

Wickham H. ggplot2: Elegant Graphics for Data Analysis: Springer-Verlag; 2016. https://ggplot2-book.org/.

Haynes W. Wilcoxon Rank Sum Test. In: WO DW, Cho KH, Yokota H, editors. Encyclopedia of Systems Biology. New York: Springer; 2013.

Walker MA, Pedamallu CS, Ojesina AI, Bullman S, Sharpe T, Whelan CW, et al. GATK PathSeq: a customizable computational tool for the discovery and identification of microbial sequences in libraries from eukaryotic hosts. Bioinformatics. 2018;34(24):4287–9. https://doi.org/10.1093/bioinformatics/bty501.

Gruffat H, Marchione R, Manet E. Herpesvirus late gene expression: a viral-specific pre-initiation complex is key. Front Microbiol. 2016;7:869. https://doi.org/10.3389/fmicb.2016.00869.

Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland TK, et al. A unique microglia type associated with restricting development of Alzheimer's disease. Cell. 2017;169(7):1276–90.e17. https://doi.org/10.1016/j.cell.2017.05.018.

Habib N, McCabe C, Medina S, Varshavsky M, Kitsberg D, Dvir-Szternfeld R, et al. Disease-associated astrocytes in Alzheimer's disease and aging. Nat Neurosci. 2020;23(6):701–6. https://doi.org/10.1038/s41593-020-0624-8.

White MR, Kandel R, Tripathi S, Condon D, Qi L, Taubenberger J, et al. Alzheimer's associated beta-amyloid protein inhibits influenza a virus and modulates viral interactions with phagocytes. PLoS One. 2014;9(7):e101364. https://doi.org/10.1371/journal.pone.0101364.

Arnusch CJ, Branderhorst H, de Kruijff B, Liskamp RM, Breukink E, Pieters RJ. Enhanced membrane pore formation by multimeric/oligomeric antimicrobial peptides. Biochemistry. 2007;46(46):13437–42. https://doi.org/10.1021/bi7015553.

Moir RD, Lathe R, Tanzi RE. The antimicrobial protection hypothesis of Alzheimer's disease. Alzheimers Dement. 2018;14(12):1602–14. https://doi.org/10.1016/j.jalz.2018.06.3040.

Hoover DM, Rajashankar KR, Blumenthal R, Puri A, Oppenheim JJ, Chertov O, et al. The structure of human beta-defensin-2 shows evidence of higher order oligomerization. J Biol Chem. 2000;275(42):32911–8. https://doi.org/10.1074/jbc.M006098200.

Sy M, Kitazawa M, Medeiros R, Whitman L, Cheng D, Lane TE, et al. Inflammation induced by infection potentiates tau pathological features in transgenic mice. Am J Pathol. 2011;178(6):2811–22. https://doi.org/10.1016/j.ajpath.2011.02.012.

Romeo MA, Gilardini Montani MS, Gaeta A, D'Orazi G, Faggioni A, Cirone M. HHV-6A infection dysregulates autophagy/UPR interplay increasing beta amyloid production and tau phosphorylation in astrocytoma cells as well as in primary neurons, possible molecular mechanisms linking viral infection to Alzheimer's disease. Biochim Biophys Acta Mol basis Dis. 1866;2020(3):165647. https://doi.org/10.1016/j.bbadis.2019.165647.

Wozniak MA, Frost AL, Itzhaki RF. Alzheimer's disease-specific tau phosphorylation is induced by herpes simplex virus type 1. J Alzheimers Dis. 2009;16(2):341–50. https://doi.org/10.3233/JAD-2009-0963.

Eimer WA, Vijaya Kumar DK, Navalpur Shanmugam NK, Rodriguez AS, Mitchell T, Washicosky KJ, et al. Alzheimer's disease-associated beta-amyloid is rapidly seeded by Herpesviridae to protect against brain infection. Neuron. 2018;100(6):1527–32. https://doi.org/10.1016/j.neuron.2018.11.043.

Agostini S, Mancuso R, Baglio F, Cabinio M, Hernis A, Guerini FR, et al. Lack of evidence for a role of HHV-6 in the pathogenesis of Alzheimer's disease. J Alzheimers Dis. 2016;49(1):229–35. https://doi.org/10.3233/JAD-150464.

Hemling N, Roytta M, Rinne J, Pollanen P, Broberg E, Tapio V, et al. Herpesviruses in brains in Alzheimer's and Parkinson's diseases. Ann Neurol. 2003;54(2):267–71. https://doi.org/10.1002/ana.10662.

St-Pierre Y, Potworowski EF, Lussier G. Transmission of mouse thymic virus. J Gen Virol. 1987;68(Pt 4):1173–6. https://doi.org/10.1099/0022-1317-68-4-1173.

De Chiara G, Piacentini R, Fabiani M, Mastrodonato A, Marcocci ME, Limongi D, et al. Recurrent herpes simplex virus-1 infection induces hallmarks of neurodegeneration and cognitive deficits in mice. PLoS Pathog. 2019;15(3):e1007617. https://doi.org/10.1371/journal.ppat.1007617.

Bocharova OM, Molesworth K, Pandit NP, Baskakov IV. Alzheimer's Disease-Associated β-Amyloid Does Not Protect Against Herpesviridae Brain Infection: Cell Press Sneak Peek; 2021. https://doi.org/10.1016/j.jbc.2021.100845.

Lopatko Lindman K, Hemmingsson ES, Weidung B, Brannstrom J, Josefsson M, Olsson J, et al. Herpesvirus infections, antiviral treatment, and the risk of dementia-a registry-based cohort study in Sweden. Alzheimers Dement (N Y). 2021;7(1):e12119.

Tzeng NS, Chung CH, Lin FH, Chiang CP, Yeh CB, Huang SY, et al. Anti-herpetic medications and reduced risk of dementia in patients with herpes simplex virus infections-a nationwide, population-based cohort study in Taiwan. Neurotherapeutics. 2018;15(2):417–29. https://doi.org/10.1007/s13311-018-0611-x.

Bae S, Yun SC, Kim MC, Yoon W, Lim JS, Lee SO, et al. Association of herpes zoster with dementia and effect of antiviral therapy on dementia: a population-based cohort study. Eur Arch Psychiatry Clin Neurosci. 2020;271(5):987–97. https://doi.org/10.1007/s00406-020-01157-4.

Schnier C, Janbek J, Williams L, Wilkinson T, Laursen TM, Waldemar G, et al. Antiherpetic medication and incident dementia: observational cohort studies in four countries. Eur J Neurol. 2021;28(6):1840–8. https://doi.org/10.1111/ene.14795.

Kikuta H, Lu H, Matsumoto S. Susceptibility of human herpesvirus 6 to acyclovir. Lancet. 1989;2(8667):861. https://doi.org/10.1016/S0140-6736(89)93019-5.

Agut H, Huraux JM, Collandre H, Montagnier L. Susceptibility of human herpesvirus 6 to acyclovir and ganciclovir. Lancet. 1989;2(8663):626. https://doi.org/10.1016/S0140-6736(89)90754-X.

Burns WH, Sandford GR. Susceptibility of human herpesvirus 6 to antivirals in vitro. J Infect Dis. 1990;162(3):634–7. https://doi.org/10.1093/infdis/162.3.634.

Mori Y, Koike M, Moriishi E, Kawabata A, Tang H, Oyaizu H, et al. Human herpesvirus-6 induces MVB formation, and virus egress occurs by an exosomal release pathway. Traffic. 2008;9(10):1728–42. https://doi.org/10.1111/j.1600-0854.2008.00796.x.

Marsh SE, Abud EM, Lakatos A, Karimzadeh A, Yeung ST, Davtyan H, et al. The adaptive immune system restrains Alzheimer's disease pathogenesis by modulating microglial function. Proc Natl Acad Sci U S A. 2016;113(9):E1316–25. https://doi.org/10.1073/pnas.1525466113.

Bhela S, Mulik S, Reddy PB, Richardson RL, Gimenez F, Rajasagi NK, et al. Critical role of microRNA-155 in herpes simplex encephalitis. J Immunol. 2014;192(6):2734–43. https://doi.org/10.4049/jimmunol.1302326.

Rizzo R, Soffritti I, D'Accolti M, Bortolotti D, Di Luca D, Caselli E. HHV-6A/6B infection of NK cells modulates the expression of miRNAs and transcription factors potentially associated to impaired NK activity. Front Microbiol. 2017;8:2143. https://doi.org/10.3389/fmicb.2017.02143.

Caselli E, Soffritti I, D’Accolti M, Bortolotti D, Rizzo R, Sighinolfi G, et al. HHV-6A Infection and Systemic Sclerosis: Clues of a Possible Association. Microorganisms. 2019;8(1):39.

Sun XW, Liu CM, Teng ZQ. Commentary: multiscale analysis of independent Alzheimer's cohorts finds disruption of molecular, genetic, and clinical networks by human herpesvirus. Front Mol Neurosci. 2018;11:340. https://doi.org/10.3389/fnmol.2018.00340.

Gewurz BE, Marty FM, Baden LR, Katz JT. Human herpesvirus 6 encephalitis. Curr Infect Dis Rep. 2008;10(4):292–9. https://doi.org/10.1007/s11908-008-0048-1.

Thông tin
Thông tin xuất bản

Springer Science and Business Media LLC

Tập 17 Số 1

Thông tin tác giả