Skip to main content

Advertisement

Log in

Human cytomegalovirus downregulates SLITRK6 expression through IE2

  • Published:
Journal of NeuroVirology Aims and scope Submit manuscript

Abstract

Congenital human cytomegalovirus (HCMV) infection causes sensorineural hearing loss (SNHL) and other neurological disorders, although the neuropathogenesis of HCMV infection is not well understood. Here, we show that the expression of SLITRK6, one of causative genes for hereditary SNHL, was robustly downregulated by HCMV infection in cultured neural cells. We also show that HCMV-encoded immediate-early 2 (IE2) proteins mediate this downregulation and their carboxy-terminal region, especially amino acid residue Gln548, has a critical role. These findings suggest that the downregulation of SLITRK6 expression by IE2 may have a role in HCMV-induced SNHL and other neurological disorders.

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

Access this article

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

Instant access to the full article PDF.

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

Similar content being viewed by others

References

  • Aruga J (2003) Slitrk6 expression profile in the mouse embryo and its relationship to that of Nlrr3. Gene Expr Patterns 3:727–733

    Article  CAS  PubMed  Google Scholar 

  • Aruga J, Mikoshiba K (2003) Identification and characterization of Slitrk, a novel neuronal transmembrane protein family controlling neurite outgrowth. Mol Cell Neurosci 24:117–129

    Article  CAS  PubMed  Google Scholar 

  • Beaubien F, Cloutier JF (2009) Differential expression of Slitrk family members in the mouse nervous system. Dev Dyn 238:3285–3296

    Article  CAS  PubMed  Google Scholar 

  • Bernard S, Wiener-Vacher S, Van Den Abbeele T, Teissier N (2015) Vestibular disorders in children with congenital cytomegalovirus infection. Pediatrics 136:e887–e895

    Article  PubMed  Google Scholar 

  • Cheeran MC, Lokensgard JR, Schleiss MR (2009) Neuropathogenesis of congenital cytomegalovirus infection: disease mechanisms and prospects for intervention. Clin Microbiol Rev 22:99–126 Table of Contents

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Davis LE, Johnsson LG, Kornfeld M (1981) Cytomegalovirus labyrinthitis in an infant: morphological, virological, and immunofluorescent studies. J Neuropathol Exp Neurol 40:9–19

    Article  CAS  PubMed  Google Scholar 

  • Fowler KB, Boppana SB (2006) Congenital cytomegalovirus (CMV) infection and hearing deficit. J Clin Virol 35:226–231

    Article  PubMed  Google Scholar 

  • Gabrielli L, Bonasoni MP, Santini D, Piccirilli G, Chiereghin A, Guerra B, Landini MP, Capretti MG, Lanari M, Lazzarotto T (2013) Human fetal inner ear involvement in congenital cytomegalovirus infection. Acta Neuropathol Commun 1:63

    Article  PubMed  PubMed Central  Google Scholar 

  • Gabrielli L, Bonasoni MP, Santini D, Piccirilli G, Chiereghin A, Petrisli E, Dolcetti R, Guerra B, Piccioli M, Lanari M, Landini MP, Lazzarotto T (2012) Congenital cytomegalovirus infection: patterns of fetal brain damage. Clin Microbiol Infect 18:E419–E427

    Article  CAS  PubMed  Google Scholar 

  • Iruretagoyena JI, Davis W, Bird C, Olsen J, Radue R, Teo Broman A, Kendziorski C, Splinter BonDurant S, Golos T, Bird I, Shah D (2014) Differential changes in gene expression in human brain during late first trimester and early second trimester of pregnancy. Prenat Diagn 34:431–437

    Article  CAS  PubMed  Google Scholar 

  • Karltorp E, Lofkvist U, Lewensohn-Fuchs I, Lindstrom K, Westblad ME, Fahnehjelm KT, Verrecchia L, Engman ML (2014) Impaired balance and neurodevelopmental disabilities among children with congenital cytomegalovirus infection. Acta Paediatr 103:1165–1173

    Article  PubMed  Google Scholar 

  • Katayama K, Zine A, Ota M, Matsumoto Y, Inoue T, Fritzsch B, Aruga J (2009) Disorganized innervation and neuronal loss in the inner ear of Slitrk6-deficient mice. PLoS One 4:e7786

    Article  PubMed  PubMed Central  Google Scholar 

  • Koyano S, Inoue N, Oka A, Moriuchi H, Asano K, Ito Y, Yamada H, Yoshikawa T, Suzutani T (2011) Screening for congenital cytomegalovirus infection using newborn urine samples collected on filter paper: feasibility and outcomes from a multicentre study. BMJ Open 1:e000118

    Article  PubMed  PubMed Central  Google Scholar 

  • Lee SB, Lee CF, Ou DS, Dulal K, Chang LH, Ma CH, Huang CF, Zhu H, Lin YS, Juan LJ (2011) Host-viral effects of chromatin assembly factor 1 interaction with HCMV IE2. Cell Res 21:1230–1247

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Matsumoto Y, Katayama K, Okamoto T, Yamada K, Takashima N, Nagao S, Aruga J (2011) Impaired auditory-vestibular functions and behavioral abnormalities of Slitrk6-deficient mice. PLoS One 6:e16497

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mitchell KJ (2011) The genetics of neurodevelopmental disease. Curr Opin Neurobiol 21:197–203

    Article  CAS  PubMed  Google Scholar 

  • Morlet T, Rabinowitz MR, Looney LR, Riegner T, Greenwood LA, Sherman EA, Achilly N, Zhu A, Yoo E, O’Reilly RC, Jinks RN, Puffenberger EG, Heaps A, Morton H, Strauss KA (2014) A homozygous SLITRK6 nonsense mutation is associated with progressive auditory neuropathy in humans. Laryngoscope 124:E95–103

    Article  CAS  PubMed  Google Scholar 

  • Morton CC, Nance WE (2006) Newborn hearing screening—a silent revolution. N Engl J Med 354:2151–2164

    Article  CAS  PubMed  Google Scholar 

  • Nakamura H, Liao H, Minami K, Toyoda M, Akutsu H, Miyagawa Y, Okita H, Kiyokawa N, Umezawa A, Imadome K, Inoue N, Fujiwara S (2013) Human cytomegalovirus induces apoptosis in neural stem/progenitor cells derived from induced pluripotent stem cells by generating mitochondrial dysfunction and endoplasmic reticulum stress. Herpesviridae 4:2

    Article  PubMed  PubMed Central  Google Scholar 

  • Nakamura H, Lu M, Gwack Y, Souvlis J, Zeichner SL, Jung JU (2003) Global changes in Kaposi’s sarcoma-associated virus gene expression patterns following expression of a tetracycline-inducible Rta transactivator. J Virol 77:4205–4220

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ornoy A, Diav-Citrin O (2006) Fetal effects of primary and secondary cytomegalovirus infection in pregnancy. Reprod Toxicol 21:399–409

    Article  CAS  PubMed  Google Scholar 

  • Petrik DT, Schmitt KP, Stinski MF (2006) Inhibition of cellular DNA synthesis by the human cytomegalovirus IE86 protein is necessary for efficient virus replication. J Virol 80:3872–3883

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Plachter B, Britt W, Vornhagen R, Stamminger T, Jahn G (1993) Analysis of proteins encoded by IE regions 1 and 2 of human cytomegalovirus using monoclonal antibodies generated against recombinant antigens. Virology 193:642–652

    Article  CAS  PubMed  Google Scholar 

  • Puchtler E, Stamminger T (1991) An inducible promoter mediates abundant expression from the immediate-early 2 gene region of human cytomegalovirus at late times after infection. J Virol 65:6301–6306

    CAS  PubMed  PubMed Central  Google Scholar 

  • Stagno S, Reynolds DW, Amos CS, Dahle AJ, McCollister FP, Mohindra I, Ermocilla R, Alford CA (1977) Auditory and visual defects resulting from symptomatic and subclinical congenital cytomegaloviral and toxoplasma infections. Pediatrics 59:669–678

    CAS  PubMed  Google Scholar 

  • Stenberg RM, Depto AS, Fortney J, Nelson JA (1989) Regulated expression of early and late RNAs and proteins from the human cytomegalovirus immediate-early gene region. J Virol 63:2699–2708

    CAS  PubMed  PubMed Central  Google Scholar 

  • Teissier N, Delezoide AL, Mas AE, Khung-Savatovsky S, Bessieres B, Nardelli J, Vauloup-Fellous C, Picone O, Houhou N, Oury JF, Van Den Abbeele T, Gressens P, Adle-Biassette H (2011) Inner ear lesions in congenital cytomegalovirus infection of human fetuses. Acta Neuropathol 122:763–774

    Article  PubMed  Google Scholar 

  • Tekin M, Chioza BA, Matsumoto Y, Diaz-Horta O, Cross HE, Duman D, Kokotas H, Moore-Barton HL, Sakoori K, Ota M, Odaka YS, Foster J 2nd, Cengiz FB, Tokgoz-Yilmaz S, Tekeli O, Grigoriadou M, Petersen MB, Sreekantan-Nair A, Gurtz K, Xia XJ, Pandya A, Patton MA, Young JI, Aruga J, Crosby AH (2013) SLITRK6 mutations cause myopia and deafness in humans and mice. J Clin Invest 123:2094–2102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

We thank M. Iikura for the excellent technical assistance. We also thank N. Inoue for providing the reagents.

This work was partly supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (24591616) to H.N., the Ministry of Health, Labour and Welfare of Japan (H23-Jisedai-Ippan-001) to H.N., and the Grants of National Center for Child Health and Development (24-17 and 27-18 to H.N., 25-9 to S.F.).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Hiroyuki Nakamura.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liao, H., Sato, H., Chiba, R. et al. Human cytomegalovirus downregulates SLITRK6 expression through IE2. J. Neurovirol. 23, 79–86 (2017). https://doi.org/10.1007/s13365-016-0475-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13365-016-0475-y

Keywords

Navigation