title: The ectromelia virus SPI-2 protein causes lethal mousepox by preventing NK cell responses.
abstract: Ectromelia virus (ECTV) is a natural pathogen of mice that causes mousepox, and many of its genes have been implicated in the modulation of host immune responses. Serine protease inhibitor 2 (SPI-2) is one of these putative ECTV host response modifier proteins. SPI-2 is conserved across orthopoxviruses, but results defining its mechanism of action and in vivo function are lacking or contradictory. We studied the role of SPI-2 in mousepox by deleting the SPI-2 gene or its serine protease inhibitor reactive site. We found that SPI-2 does not affect viral replication or cell-intrinsic apoptosis pathways, since mutant viruses replicate in vitro as efficiently as wild-type virus. However, in the absence of SPI-2 protein, ECTV is attenuated in mousepox-susceptible mice, resulting in lower viral loads in the liver, decreased spleen pathology, and substantially improved host survival. This attenuation correlates with more effective immune responses in the absence of SPI-2, including an earlier serum gamma interferon (IFN-γ) response, raised serum interleukin 18 (IL-18), increased numbers of granzyme B(+) CD8(+) T cells, and, most notably, increased numbers and activation of NK cells. Both virus attenuation and the improved immune responses associated with SPI-2 deletion from ECTV are lost when mice are depleted of NK cells. Consequently, SPI-2 renders mousepox lethal in susceptible strains by preventing protective NK cell defenses.
authors.affiliation: Department of Emerging Pathogens and Vaccines, John Curtin School of Medical Research, Australian National University, Canberra ACT, Australia.
authors.forename: Carolina R
authors.initials: CR
authors.lastname: Melo-Silva
authors.forename: David C
authors.initials: DC
authors.lastname: Tscharke
authors.forename: Mario
authors.initials: M
authors.lastname: Lobigs
authors.forename: Aulikki
authors.initials: A
authors.lastname: Koskinen
authors.forename: Yik Chun
authors.initials: YC
authors.lastname: Wong
authors.forename: R Mark
authors.initials: RM
authors.lastname: Buller
authors.forename: Arno
authors.initials: A
authors.lastname: Müllbacher
authors.forename: Matthias
authors.initials: M
authors.lastname: Regner
mesh_terms: D000818:Animals; D004481:Ectromelia virus / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity*; D004482:Ectromelia, Infectious / Q000401:mortality* / Q000821:virology; D017353:Gene Deletion; D054884:Host-Pathogen Interactions; D007371:Interferon-gamma / Q000378:metabolism; D020382:Interleukin-18 / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology*; D008099:Liver / Q000821:virology; D016131:Lymphocyte Subsets / Q000737:chemistry / Q000276:immunology; D051379:Mice; D015843:Serpins / Q000235:genetics / Q000378:metabolism*; D013154:Spleen / Q000473:pathology; D016019:Survival Analysis; D019562:Viral Load; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D037521:Virulence Factors / Q000378:metabolism*; D014779:Virus Replication
chemical_list: D020382:Interleukin-18; D015843:Serpins; D014764:Viral Proteins; D037521:Virulence Factors; D007371:Interferon-gamma; C074641:interleukin-1beta-converting enzyme inhibitor