Ectromelia Virus Lacking the E3L Ortholog is Replication-defective and Nonpathogenic but Does Induce Protective Immunity in a Mouse Strain Susceptible to Lethal Mousepox

Overview

Journal Virology

Specialty Microbiology

Date 2018 Mar 31

PMID 29602068

Citations 5

Authors

Tiffany R Frey

Katherine S Forsyth

Maura M Sheehan

Brian C De Haven

Julia G Pevarnik

Erin S Hand

Marie C Pizzorno

Laurence C Eisenlohr

Adam R Hersperger

Affiliations

Soon will be listed here.

Abstract

All known orthopoxviruses, including ectromelia virus (ECTV), contain a gene in the E3L family. The protein product of this gene, E3, is a double-stranded RNA-binding protein. It can impact host range and is used by orthopoxviruses to combat cellular defense pathways, such as PKR and RNase L. In this work, we constructed an ECTV mutant with a targeted disruption of the E3L open reading frame (ECTVΔE3L). Infection with this virus resulted in an abortive replication cycle in all cell lines tested. We detected limited transcription of late genes but no significant translation of these mRNAs. Notably, the replication defects of ECTVΔE3L were rescued in human and mouse cells lacking PKR. ECTVΔE3L was nonpathogenic in BALB/c mice, a strain susceptible to lethal mousepox disease. However, infection with ECTVΔE3L induced protective immunity upon subsequent challenge with wild-type virus. In summary, E3L is an essential gene for ECTV.

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References

FENNER F . Studies in infectious ectromelia in mice; natural transmission; the portal of entry of the virus. Aust J Exp Biol Med Sci. 2010; 25(Pt 3):275-82. DOI: 10.1038/icb.1947.39. View

Xiang Y, Condit R, Vijaysri S, Jacobs B, Williams B, Silverman R . Blockade of interferon induction and action by the E3L double-stranded RNA binding proteins of vaccinia virus. J Virol. 2002; 76(10):5251-9. PMC: 136119. DOI: 10.1128/jvi.76.10.5251-5259.2002. View

Bravo Cruz A, Han A, Roy E, Guzman A, Miller R, Driskell E . Deletion of the Gene Results in a Vaccinia Virus That Is Less Pathogenic Due to Muted Innate Immune Responses, yet Still Elicits Protective Immunity. J Virol. 2017; 91(15). PMC: 5512244. DOI: 10.1128/JVI.00542-17. View

Brennan G, Kitzman J, Rothenburg S, Shendure J, Geballe A . Adaptive gene amplification as an intermediate step in the expansion of virus host range. PLoS Pathog. 2014; 10(3):e1004002. PMC: 3953438. DOI: 10.1371/journal.ppat.1004002. View

Chang H, Watson J, Jacobs B . The E3L gene of vaccinia virus encodes an inhibitor of the interferon-induced, double-stranded RNA-dependent protein kinase. Proc Natl Acad Sci U S A. 1992; 89(11):4825-9. PMC: 49180. DOI: 10.1073/pnas.89.11.4825. View

Chang H, Jacobs B . Identification of a conserved motif that is necessary for binding of the vaccinia virus E3L gene products to double-stranded RNA. Virology. 1993; 194(2):537-47. DOI: 10.1006/viro.1993.1292. View

Fenner F . Classic paper: Fenner on the exanthemata. Rev Med Virol. 2006; 16(6):353-63. PMC: 7169171. DOI: 10.1002/rmv.506. View

Chakrabarti A, Jha B, Silverman R . New insights into the role of RNase L in innate immunity. J Interferon Cytokine Res. 2010; 31(1):49-57. PMC: 3021357. DOI: 10.1089/jir.2010.0120. View

Chen N, Danila M, Feng Z, Buller R, Wang C, Han X . The genomic sequence of ectromelia virus, the causative agent of mousepox. Virology. 2003; 317(1):165-86. DOI: 10.1016/s0042-6822(03)00520-8. View

10.

Beattie E, Denzler K, Tartaglia J, Perkus M, Paoletti E, Jacobs B . Reversal of the interferon-sensitive phenotype of a vaccinia virus lacking E3L by expression of the reovirus S4 gene. J Virol. 1995; 69(1):499-505. PMC: 188598. DOI: 10.1128/JVI.69.1.499-505.1995. View

11.

Hand E, Haller S, Peng C, Rothenburg S, Hersperger A . Ectopic expression of vaccinia virus E3 and K3 cannot rescue ectromelia virus replication in rabbit RK13 cells. PLoS One. 2015; 10(3):e0119189. PMC: 4348479. DOI: 10.1371/journal.pone.0119189. View

12.

Beattie E, Kauffman E, Martinez H, Perkus M, Jacobs B, Paoletti E . Host-range restriction of vaccinia virus E3L-specific deletion mutants. Virus Genes. 1996; 12(1):89-94. DOI: 10.1007/BF00370005. View

13.

Siciliano N, Hersperger A, Lacuanan A, Xu R, Sidney J, Sette A . Impact of distinct poxvirus infections on the specificities and functionalities of CD4+ T cell responses. J Virol. 2014; 88(17):10078-91. PMC: 4136331. DOI: 10.1128/JVI.01150-14. View

14.

Vos J, Stunnenberg H . Derepression of a novel class of vaccinia virus genes upon DNA replication. EMBO J. 1988; 7(11):3487-92. PMC: 454849. DOI: 10.1002/j.1460-2075.1988.tb03224.x. View

15.

Assarsson E, Greenbaum J, Sundstrom M, Schaffer L, Hammond J, Pasquetto V . Kinetic analysis of a complete poxvirus transcriptome reveals an immediate-early class of genes. Proc Natl Acad Sci U S A. 2008; 105(6):2140-5. PMC: 2542872. DOI: 10.1073/pnas.0711573105. View

16.

Rivas C, Gil J, Melkova Z, Esteban M, Diaz-Guerra M . Vaccinia virus E3L protein is an inhibitor of the interferon (i.f.n.)-induced 2-5A synthetase enzyme. Virology. 1998; 243(2):406-14. DOI: 10.1006/viro.1998.9072. View

17.

Symons J, Tscharke D, Price N, Smith G . A study of the vaccinia virus interferon-gamma receptor and its contribution to virus virulence. J Gen Virol. 2002; 83(Pt 8):1953-1964. DOI: 10.1099/0022-1317-83-8-1953. View

18.

Broyles S . Vaccinia virus transcription. J Gen Virol. 2003; 84(Pt 9):2293-2303. DOI: 10.1099/vir.0.18942-0. View

19.

Smith V, Alcami A . Inhibition of interferons by ectromelia virus. J Virol. 2002; 76(3):1124-34. PMC: 135801. DOI: 10.1128/jvi.76.3.1124-1134.2002. View

20.

Rosel J, Moss B . Transcriptional and translational mapping and nucleotide sequence analysis of a vaccinia virus gene encoding the precursor of the major core polypeptide 4b. J Virol. 1985; 56(3):830-8. PMC: 252654. DOI: 10.1128/JVI.56.3.830-838.1985. View