1887

Abstract

Murine gammaherpesvirus 68 (MHV-68), a widely used small-animal model for the analysis of gammaherpesvirus pathogenesis, encodes the MHV-68-specific ORFs M12 and M13. The function of M12 and M13 has not been investigated so far. Therefore, we constructed and analysed recombinant MHV-68 with mutations in either M12, M13 or M12/M13. Both the M12 and M13 mutants did not display any phenotype or . However, although the M12/13 double mutant showed similar lytic growth in fibroblasts and in the lungs of infected mice as wild-type MHV-68, it was significantly attenuated during latency. This phenotype was completely restored in a revertant of the M12/13 double mutant. Thus, it appears that M12 and M13 might have redundant functions that are only revealed if both genes are lacking. The observation that M12/13 have a function during latency not only contributes to the further understanding of the pathogenesis of MHV-68 infection but might also be of interest considering that M12/13 are located at a genomic position similar to that of LMP2A and K15. The latter are important proteins of their respective human gammaherpesviruses EBV and KSHV that contribute to cellular survival, cell activation and proliferation, which was deduced from studies.

Keyword(s): gammaherpesvirus , MHV-68 , ORF M12 and ORF M13
Loading

Article metrics loading...

/content/journal/jgv/10.1099/jgv.0.001880
2023-08-08
2024-05-13
Loading full text...

Full text loading...

References

  1. Rickinson AB, Kieff E et al. Epstein-Barr Virus. In Fields - Virology Philadelphia: Lippincott Williams & Wilkins; 2001 pp 2575–2627
    [Google Scholar]
  2. Schulz TF. Kaposi’s sarcoma-associated herpesvirus (human herpesvirus-8). J Gen Virol 1998; 79 (Pt 7):1573–1591 [View Article] [PubMed]
    [Google Scholar]
  3. Barton E, Mandal P, Speck SH. Pathogenesis and host control of gammaherpesviruses: lessons from the mouse. Annu Rev Immunol 2011; 29:351–397 [View Article] [PubMed]
    [Google Scholar]
  4. Simas JP, Efstathiou S. Murine gammaherpesvirus 68: a model for the study of gammaherpesvirus pathogenesis. Trends Microbiol 1998; 6:276–282 [View Article] [PubMed]
    [Google Scholar]
  5. Wang Y, Tibbetts SA, Krug LT. Conquering the host: determinants of pathogenesis learned from murine gammaherpesvirus 68. Annu Rev Virol 2021; 8:349–371 [View Article] [PubMed]
    [Google Scholar]
  6. Virgin HW 4th, Latreille P, Wamsley P, Hallsworth K, Weck KE et al. Complete sequence and genomic analysis of murine gammaherpesvirus 68. J Virol 1997; 71:5894–5904 [View Article] [PubMed]
    [Google Scholar]
  7. Epstein MA, Rickinson AB, Weiss RA, Nash AA, Dutia BM et al. Natural history of murine γ-herpesvirus infection. Phil Trans R Soc Lond B 2001; 356:569–579 [View Article]
    [Google Scholar]
  8. Steinbrück L, Gustems M, Medele S, Schulz TF, Lutter D et al. K1 and K15 of Kaposi’s sarcoma-associated herpesvirus are partial functional homologues of latent membrane protein 2A of Epstein-barr virus. J Virol 2015; 89:7248–7261 [View Article] [PubMed]
    [Google Scholar]
  9. Adler H, Messerle M, Wagner M, Koszinowski UH. Cloning and mutagenesis of the murine gammaherpesvirus 68 genome as an infectious bacterial artificial chromosome. J Virol 2000; 74:6964–6974 [View Article] [PubMed]
    [Google Scholar]
  10. Zhang Y, Muyrers JP, Testa G, Stewart AF. DNA cloning by homologous recombination in Escherichia coli. Nat Biotechnol 2000; 18:1314–1317 [View Article] [PubMed]
    [Google Scholar]
  11. Adler H, Messerle M, Koszinowski UH. Virus reconstituted from infectious bacterial artificial chromosome (BAC)-cloned murine gammaherpesvirus 68 acquires wild-type properties in vivo only after excision of BAC vector sequences. J Virol 2001; 75:5692–5696 [View Article] [PubMed]
    [Google Scholar]
  12. Flach B, Steer B, Thakur NN, Haas J, Adler H. The M10 locus of murine gammaherpesvirus 68 contributes to both the lytic and the latent phases of infection. J Virol 2009; 83:8163–8172 [View Article] [PubMed]
    [Google Scholar]
  13. Virgin HW. Immune regulation of viral infection and vice versa. Immunol Res 2005; 32:293–315 [View Article] [PubMed]
    [Google Scholar]
  14. Farnsworth A, Goldsmith K, Johnson DC. Herpes simplex virus glycoproteins gD and gE/gI serve essential but redundant functions during acquisition of the virion envelope in the cytoplasm. J Virol 2003; 77:8481–8494 [View Article] [PubMed]
    [Google Scholar]
  15. Johnson DC, Wisner TW, Wright CC. Herpes simplex virus glycoproteins gB and gD function in a redundant fashion to promote secondary envelopment. J Virol 2011; 85:4910–4926 [View Article] [PubMed]
    [Google Scholar]
  16. Lemmermann NAW, Krmpotic A, Podlech J, Brizic I, Prager A et al. Non-redundant and redundant roles of cytomegalovirus gH/gL complexes in host organ entry and intra-tissue spread. PLoS Pathog 2015; 11:e1004640 [View Article] [PubMed]
    [Google Scholar]
  17. Isern E, Gustems M, Messerle M, Borst E, Ghazal P et al. The activator protein 1 binding motifs within the human cytomegalovirus major immediate-early enhancer are functionally redundant and act in a cooperative manner with the NF-{kappa}B sites during acute infection. J Virol 2011; 85:1732–1746 [View Article] [PubMed]
    [Google Scholar]
  18. Ahn JW, Powell KL, Kellam P, Alber DG. Gammaherpesvirus lytic gene expression as characterized by DNA array. J Virol 2002; 76:6244–6256 [View Article] [PubMed]
    [Google Scholar]
  19. Johnson LS, Willert EK, Virgin HW. Redefining the genetics of murine gammaherpesvirus 68 via transcriptome-based annotation. Cell Host Microbe 2010; 7:516–526 [View Article] [PubMed]
    [Google Scholar]
  20. Song MJ, Hwang S, Wong WH, Wu T-T, Lee S et al. Identification of viral genes essential for replication of murine gamma-herpesvirus 68 using signature-tagged mutagenesis. Proc Natl Acad Sci U S A 2005; 102:3805–3810 [View Article] [PubMed]
    [Google Scholar]
  21. Moorman NJ, Lin CY, Speck SH. Identification of candidate gammaherpesvirus 68 genes required for virus replication by signature-tagged transposon mutagenesis. J Virol 2004; 78:10282–10290 [View Article] [PubMed]
    [Google Scholar]
  22. Canny SP, Reese TA, Johnson LS, Zhang X, Kambal A et al. Pervasive transcription of a herpesvirus genome generates functionally important RNAs. mBio 2014; 5:e01033–13 [View Article] [PubMed]
    [Google Scholar]
  23. O’Grady T, Feswick A, Hoffman BA, Wang Y, Medina EM et al. Genome-wide transcript structure resolution reveals abundant alternate isoform usage from murine gammaherpesvirus 68. Cell Rep 2019; 27:3988–4002 [View Article] [PubMed]
    [Google Scholar]
  24. Mancao C, Altmann M, Jungnickel B, Hammerschmidt W. Rescue of “crippled” germinal center B cells from apoptosis by Epstein-Barr virus. Blood 2005; 106:4339–4344 [View Article] [PubMed]
    [Google Scholar]
  25. Mancao C, Hammerschmidt W. Epstein-Barr virus latent membrane protein 2A is a B-cell receptor mimic and essential for B-cell survival. Blood 2007; 110:3715–3721 [View Article] [PubMed]
    [Google Scholar]
  26. Habison AC, de Miranda MP, Beauchemin C, Tan M, Cerqueira SA et al. Cross-species conservation of episome maintenance provides a basis for in vivo investigation of Kaposi’s sarcoma herpesvirus LANA. PLoS Pathog 2017; 13:e1006555 [View Article] [PubMed]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/jgv.0.001880
Loading
/content/journal/jgv/10.1099/jgv.0.001880
Loading

Data & Media loading...

Supplements

Supplementary material 1

PDF
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error