Skip to main content

Advertisement

SpringerLink
Log in

Varicella zoster virus infection of human fetal lung cells alters mitochondrial morphology

  • Published:
Journal of NeuroVirology Aims and scope Submit manuscript

Abstract

Varicella zoster virus (VZV) is a ubiquitous alphaherpesvirus that establishes latency in ganglionic neurons throughout the neuraxis after primary infection. Here, we show that VZV infection induces a time-dependent significant change in mitochondrial morphology, an important indicator of cellular health, since mitochondria are involved in essential cellular functions. VZV immediate-early protein 63 (IE63) was detected in mitochondria-rich cellular fractions extracted from infected human fetal lung fibroblasts (HFL) by Western blotting. IE63 interacted with cytochrome c oxidase in bacterial 2-hybrid analyses. Confocal microscopy of VZV-infected HFL cells at multiple times after infection revealed the presence of IE63 in the nucleus, mitochondria, and cytoplasm. Our data provide the first evidence that VZV infection induces alterations in mitochondrial morphology, including fragmentation, which may be involved in cellular damage and/or death during virus infection.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Ambagala APN, Cohen JI (2007) Varicella-zoster virus IE63, a major viral latency protein, is required to inhibit the alpha interferon-induced antiviral response. J Virol 81:7844–7851

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ambagala AP, Bosma T, Ali MA, Poustovoitov M, Chen JJ, Gershon MD, Adams PD, Cohen JI (2009) Varicella-zoster virus immediate-early 63 protein interacts with human antisilencing function 1 protein and alters its ability to bind histones h3.1 and h3.3. J Virol 83:200–209

    Article  CAS  PubMed  Google Scholar 

  • Baiker A, Fabel K, Cozzio A, Zerboni L, Fabel K, Sommer M, Uchida N, He D, Weissman I, Arvin AM (2004) Varicella-zoster virus infection of human neural cells in vivo. Proc Natl Acad Sci U S A 101:10792–10797

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Baird NL, Bowlin JL, Cohrs RJ, Gilden D, Jones KL (2014) Comparison of varicella-zoster virus RNA sequences in human neurons and fibroblasts. J Virol 88:5877–5880

    Article  PubMed  PubMed Central  Google Scholar 

  • Bozidis P, Williamson CD, Colberg-Poley AM (2007) Isolation of endoplasmic reticulum, mitochondria, and mitochondria-associated membrane fractions from transfected cells and from human cytomegalovirus-infected primary fibroblasts. Curr Protoc Cell Biol Chapter 3:Unit 3.27. doi:10.1002/0471143030.cb0327s37

  • Brazeau E, Mahalingam R, Gilden D, Wellish M, Kaufer BB, Osterrieder N, Pugazhenthi S (2010) Varicella-zoster virus-induced apoptosis in MeWo cells is accompanied by down-regulation of Bcl-2 expression. J Neurovirol 16:133–140

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Che X, Oliver SL, Sommer MH, Rajamani J, Reichelt M, Arvin AM (2011) Identification and functional characterization of the Varicella zoster virus ORF11 gene product. Virology 412:156–166

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chu VC, Bhattacharya S, Nomoto A, Lin J, Zaidi SK, Oberley TD, Weinman SA, Azhar S, Huang T-T (2011) Persistent expression of hepatitis C virus non-structural proteins leads to increased autophagy and mitochondrial injury in human hepatoma cells. PLoS One 6, e28551. doi:10.1371/journal.pone.0028551

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Davison AJ, Scott JE (1986) The complete DNA sequence of varicella-zoster virus. J Gen Virol 67:1759–1816

    Article  CAS  PubMed  Google Scholar 

  • Di Valentin E, Bontems S, Habran L, Jolois O, Markine-Goriaynoff N, Vanderplasschen A, Sadzot-Delvaux C, Piette J (2005) Varicella-zoster virus IE63 protein represses the basal transcription machinery by disorganizing the pre-initiation complex. Biol Chem 386:255–267

    Article  PubMed  Google Scholar 

  • Duguay BA, Saffran HA, Ponomarev A, Duley SA, Eaton HE, Smiley JR (2014) Elimination of mitochondrial DNA is not required for herpes simplex virus 1 replication. J Virol 88:2967–2976

    Article  PubMed  PubMed Central  Google Scholar 

  • Goodwin TJ, McCarthy M, Osterrieder N, Cohrs RJ, Kaufer BB (2013) Three-dimensional normal human neural progenitor tissue-like assemblies: a model of persistent varicella-zoster virus infection. PLoS Pathog 9, e1003512. doi:10.1371/journal.ppat.1003512

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Guo Y, Meng X, Ma J, Zheng Y, Wang Q, Wang Y, Shang H (2014) Human papillomavirus 16 E6 contributes HIF-1α induced Warburg effect by attenuating the VHL-HIF-1α interaction. Int J Mol Sci 15:7974–7986

    Article  PubMed  PubMed Central  Google Scholar 

  • Habran L, El Mjiyad N, Di Valentin E, Sadzot-Delvaux C, Bontems S, Piette J (2007) The varicella-zoster virus immediate-early 63 protein affects chromatin-controlled gene transcription in a cell-type dependent manner. BMC Mol Biol 8:99

    Article  PubMed  PubMed Central  Google Scholar 

  • Hood C, Cunningham AL, Slobedman B, Arvin AM, Sommer MH, Kinchington PR, Abendroth A (2006) Varicella-zoster virus ORF63 inhibits apoptosis of primary human neurons. J Virol 80:1025–1031

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hsieh Y-C, Chen Y-M, Li C-Y, Chang Y-H, Liang S-Y, Lin S-Y, Lin C-Y, Chang S-H, Wang Y-J, Khoo K-H, Aoki T, Wang H-C (2015) To complete its replication cycle, a shrimp virus changes the population of long chain fatty acids during infection via the PI3K-Akt-mTOR-HIF1α pathway. Dev Comp Immunol 53:85–95

    Article  CAS  PubMed  Google Scholar 

  • Huang C-Y, Chiang S-F, Lin T-Y, Chiou S-H, Chow K-C (2012) HIV-1 Vpr triggers mitochondrial destruction by impairing Mfn2-mediated ER-mitochondria interaction. PLoS One 7, e33657. doi:10.1371/journal.pone.0033657

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jackers P, Defechereux P, Baudoux L, Lambert C, Massaer M, Merville-Louis MP, Rentier B, Piette J (1992) Characterization of regulatory functions of the varicella-zoster virus gene 63-encoded protein. J Virol 66:3899–3903

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kadenbach B, Ramzan R, Vogt S (2013) High efficiency versus maximal performance—the cause of oxidative stress in eukaryotes: a hypothesis. Mitochondrion 13:1–6

    Article  CAS  PubMed  Google Scholar 

  • Kaarbø M, Ager-Wick E, Osenbroch PØ, Kilander A, Skinnes R, Müller F, Eide L (2011) Human cytomegalovirus infection increases mitochondrial biogenesis. Mitochondrion 11:935–945

    Article  PubMed  Google Scholar 

  • Keller AC, Knaub LA, McClatchey PM, Connon CA, Bouchard R, Miller MW, Geary KE, Walker LA, Klemm DJ, Reuch JE (2016) Differential mitochondrial adaptation in primary vascular smooth muscle cells from a diabetic rat model. Oxid Med Cell Longev, in press

  • Khalil MI, Sommer M, Arvin A, Hay J, Ruyechan WT (2013) Regulation of the varicella-zoster virus ORF3 promoter by cellular and viral factors. Virology 440:171–181

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kinchington PR, Bookey D, Turse SE (1995) The transcriptional regulatory proteins encoded by varicella-zoster virus open reading frames (ORFs) 4 and 63, but not ORF 61, are associated with purified virus particles. J Virol 69:4274–4282

    CAS  PubMed  PubMed Central  Google Scholar 

  • Korenaga M, Wang T, Li Y, Showalter LA, Chan T, Sun J, Weinman SA (2005) Hepatitis C virus core protein inhibits mitochondrial electron transport and increases reactive oxygen species (ROS) production. J Biol Chem 280:37481–37488

    Article  CAS  PubMed  Google Scholar 

  • Kramer T, Enquist LW (2012) Alphaherpesvirus infection disrupts mitochondrial transport in neurons. Cell Host Microbe 11:504–514

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee H, Yoon Y (2014) Mitochondrial fission: regulation and ER connection. Mol Cells 37:89–94

    Article  PubMed  PubMed Central  Google Scholar 

  • Lyman MG, Enquist LW (2009) Herpesvirus interactions with the host cytoskeleton. J Virol 83:2058–2066

    Article  CAS  PubMed  Google Scholar 

  • Lynch JM, Kenyon TK, Grose C, Hay J, Ruyechan WT (2002) Physical and functional interaction between the varicella zoster virus IE63 and IE62 proteins. Virology 302:71–82

    Article  CAS  PubMed  Google Scholar 

  • Mahalingam R, Wellish M, Cohrs R, Debrus S, Piette J, Rentier B, Gilden DH (1996) Expression of protein encoded by varicella-zoster virus open reading frame 63 in latently infected human ganglionic neurons. Proc Natl Acad Sci U S A 93:2122–2124

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McClatchey PM, Keller AC, Bouchard R, Knaub LA, Reusch JEB (2015) Fully automated software for quantitative measurements of mitochondrial morphology. Mitochondrion 26:58–71

    Article  PubMed  Google Scholar 

  • Mueller NH, Graf LL, Orlicky D, Gilden D, Cohrs RJ (2009) Phosphorylation of the nuclear form of varicella-zoster virus immediate-early protein 63 by casein kinase II at serine 186. J Virol 83:12094–12100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mueller NH, Walters MS, Marcus RA, Graf LL, Prenni J, Gilden D, Silverstein SJ, Cohrs RJ (2010) Identification of phosphorylated residues on varicella-zoster virus immediate-early protein ORF63. J Gen Virol 91:1133–1137

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mueller NH, Bos NL, Seitz S, Wellish M, Mahalingam R, Gilden D, Cohrs RJ (2012) Recombinant monoclonal antibody recognizes a unique epitope on varicella-zoster virus immediate-early 63 protein. J Virol 86:6345–6349

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nykky J, Vuento M, Gilbert L (2014) Role of mitochondria in parvovirus pathology. PLoS One 9, e86124

    Article  PubMed  PubMed Central  Google Scholar 

  • Okazaki N, Kikuno R, Ohara R, Inamoto S, Aizawa H, Yuasa S, Nakajima D, Nagase T, Ohara O, Koga H (2003) Prediction of the coding sequences of mouse homologues of KIAA gene: II. The complete nucleotide sequences of mouse KIAA-homologous cDNAs identified by screening of terminal sequences of cDNA clones randomly sampled from size-fractionated libraries. DNA Res 10:35–48

    Article  CAS  PubMed  Google Scholar 

  • Otsu NA (1979) A threshold selection method from gray-level histograms. IEEE Trans Syst Man Cybern 9:62–66

    Article  Google Scholar 

  • Peng J-Y, Lin C-C, Hsu C-N (2010) Adaptive image enhancement for fluorescence microscopy. In: 2010 International Conference on Technologies and Applications of Artificial Intelligence. IEEE Computer Soc, pp 9–16. doi:10.1109/TAAI.2010.13

  • Pugazhenthi S, Nair S, Velmurugan K, Liang Q, Mahalingam R, Cohrs RJ, Nagel MA, Gilden D (2011) Varicella-zoster virus infection of differentiated human neural stem cells. J Virol 85:6678–6686

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Saffran HA, Pare JM, Corcoran JA, Weller SK, Smiley JR (2007) Herpes simplex virus eliminates host mitochondrial DNA. EMBO Rep 8:188–193

    Article  CAS  PubMed  Google Scholar 

  • Takahashi MN, Jackson W, Laird DT, Culp TD, Grose C, Haynes JI, Benetti L (2009) Varicella-zoster virus infection induces autophagy in both cultured cells and human skin vesicles. J Virol 83:5466–5476

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tischer BK, von Einem J, Kaufer B, Osterrieder N (2006) Two-step red-mediated recombination for versatile high-efficiency markerless DNA manipulation in Escherichia coli. Biotechniques 40:191–197

    Article  CAS  PubMed  Google Scholar 

  • Tischer BK, Kaufer BB, Sommer M, Wussow F, Arvin AM, Osterrieder N (2007) A self-excisable infectious bacterial artificial chromosome clone of varicella-zoster virus allows analysis of the essential tegument protein encoded by ORF9. J Virol 81:13200–13208

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tse MCL, Lane C, Mott K, Onlamoon N, Hsiao H-M, Perng GC (2009) ICAM-5 modulates cytokine/chemokine production in the CNS during the course of herpes simplex virus type 1 infection. J Neuroimmunol 213:12–19

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • West AP, Khoury-Hanold W, Staron M, Tal MC, Pineda CM, Lang SM, Bestwick M, Duguay BA, Raimundo N, MacDuff DA, Kaech SM, Smiley JR, Means RE, Iwasaki A, Shadel GS (2015) Mitochondrial DNA stress primes the antiviral innate immune response. Nature 520:553–557

    Article  PubMed  PubMed Central  Google Scholar 

  • Williamson CD, Colberg-Poley AM (2009) Access of viral proteins to mitochondria via mitochondria-associated membranes. Rev Med Virol 19:147–164

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang A, Hildreth RL, Colberg-Poley AM (2013) Human cytomegalovirus inhibits apoptosis by proteasome-mediated degradation of Bax at endoplasmic reticulum-mitochondrion contacts. J Virol 87:5657–5668

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zuranski T, Nawar H, Czechowski D, Lynch JM, Arvin A, Hay J, Ruyechan WT (2005) Cell-type-dependent activation of the cellular EF-1alpha promoter by the varicella-zoster virus IE63 protein. Virology 338:35–42

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by Public Health Service grants AG093716 (D.G.), AG032958 (D.G. and R.J.C.), and NS082228 (R.J.C.) from the National Institutes of Health, and VA Merit grant, CCTSI (UL1RR025780) and the Center for Women’s Health Research (J.E.B.R.). Drs. H. Badani and N. L. Baird were supported by training grant NS007321 to Dr. Gilden from the National Institutes of Health. Dr. Keller was supported by training fellowship 1P01HL14985 from the National Institutes of Health. Mr. McClatchey is supported by a VA Merit grant (J.E.B.R.).

Author information

Authors and Affiliations

  1. Division of Endocrinology, University of Colorado School of Medicine, Aurora, 80045, CO, USA

    Amy C. Keller, P. Mason McClatchey & Jane E. B. Reusch

  2. Department of Neurology, University of Colorado School of Medicine, 12700 E. 19th Avenue, Box B182, Aurora, 80045, CO, USA

    Hussain Badani, Nicholas L. Baird, Jacqueline L. Bowlin, Don Gilden & Randall J. Cohrs

  3. Department of Medicine, Denver VA Medical Center, Denver, 80220, CO, USA

    Ron Bouchard & Jane E. B. Reusch

  4. Department of Microbiology and Immunology, College of Medicine, and Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan

    Guey-Chuen Perng

  5. Institut für Virologie, Freie Universität, Berlin, Germany

    Benedikt B. Kaufer

  6. Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, 80045, CO, USA

    Don Gilden & Randall J. Cohrs

  7. Department of Biomolecular Structural Chemistry, Max F. Perutz Laboratories, University of Vienna, Vienna, Austria

    Aamir Shahzad

  8. Glasgow University Department of Neurology, Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, Scotland, UK

    Peter G. E. Kennedy

Authors
  1. Amy C. Keller
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hussain Badani
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. P. Mason McClatchey
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nicholas L. Baird
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jacqueline L. Bowlin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ron Bouchard
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Guey-Chuen Perng
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jane E. B. Reusch
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Benedikt B. Kaufer
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Don Gilden
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Aamir Shahzad
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Peter G. E. Kennedy
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Randall J. Cohrs
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Randall J. Cohrs.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

The co-first authors are Amy C. Keller and Hussain Badani.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Keller, A.C., Badani, H., McClatchey, P.M. et al. Varicella zoster virus infection of human fetal lung cells alters mitochondrial morphology. J. Neurovirol. 22, 674–682 (2016). https://doi.org/10.1007/s13365-016-0457-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13365-016-0457-0

Keywords

Search

Navigation