Poxvirus-encoded gamma interferon binding protein dampens the host immune response to infection.
Ectromelia virus (ECTV), a natural mouse pathogen and the causative agent of mousepox, is closely related to variola virus (VARV), which causes smallpox in humans. Mousepox is an excellent surrogate small-animal model for smallpox. Both ECTV and VARV encode a multitude of host response modifiers that target components of the immune system and that are thought to contribute to the high mortality rates associated with infection. Like VARV, ECTV encodes a protein homologous to the ectodomain of the host gamma interferon (IFN-gamma) receptor 1. We generated an IFN-gamma binding protein (IFN-gammabp) deletion mutant of ECTV to study the role of viral IFN-gammabp (vIFN-gammabp) in host-virus interaction and also to elucidate the contribution of this molecule to the outcome of infection. Our data show that the absence of vIFN-gammabp does not affect virus replication per se but does have a profound effect on virus replication and pathogenesis in mice. BALB/c mice, which are normally susceptible to infection with ECTV, were able to control replication of the mutant virus and survive infection. Absence of vIFN-gammabp from ECTV allowed the generation of an effective host immune response that was otherwise diminished by this viral protein. Mice infected with a vIFN-gammabp deletion mutant virus, designated ECTV-IFN-gammabp(Delta), produced increased levels of IFN-gamma and generated robust cell-mediated and antibody responses. Using several strains of mice that exhibit differential degrees of resistance to mousepox, we show that recovery or death from ECTV infection is determined by a balance between the host's ability to produce IFN-gamma and the virus' ability to dampen its effects.
Sakala
Isaac G
IG
The John Curtin School of Medical Research, Australian National University, Acton, ACT 0200, Australia. Guna.Karupiah@anu.edu.au
Chaudhri
Geeta
G
Buller
R Mark
RM
Nuara
Anthony A
AA
Bai
Hongdong
H
Chen
Nanhai
N
Karupiah
Gunasegaran
G
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D004198:Disease Susceptibility; D005260:Female; D017353:Gene Deletion; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology* / Q000378:metabolism*; D007700:Kinetics; D051379:Mice; D018345:Mice, Knockout; D011212:Poxviridae / Q000502:physiology; D011213:Poxviridae Infections / Q000276:immunology* / Q000378:metabolism* / Q000821:virology; D011485:Protein Binding; D017186:Titrimetry; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D014779:Virus Replication
D018398:Homeodomain Proteins; D014764:Viral Proteins; C064658:RAG-1 protein; D007371:Interferon-gamma