Poxvirus-Encoded Gamma Interferon Binding Protein Dampens the Host Immune Response to Infection

Abstract

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-␥) receptor 1. We generated an IFN-␥ binding protein (IFN-␥bp) deletion mutant of ECTV to study the role of viral IFN-␥bp (vIFN-␥bp) 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-␥bp 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-␥bp from ECTV allowed the generation of an effective host immune response that was otherwise diminished by this viral protein. Mice infected with a vIFN-␥bp deletion mutant virus, designated ECTV-IFN-␥bp⌬ , produced increased levels of IFN-␥ 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-␥ and the virus' ability to dampen its effects.

IL-12p40 and IL-18 Play Pivotal Roles in Orchestrating the Cell-Mediated Immune Response to a Poxvirus Infection

“…In susceptible mouse strains, ECTV infection predominantly elicits a Th2 response with weak NK cell responses and a delayed or even absent CTL response (22,29). Furthermore, susceptible BALB/c mice do not express IL-12p40 mRNA or protein (30) in response to ECTV infection, consistent with the idea that the IL-12/IL-23 axis may be important for generation of optimal antiviral responses in this model.…”

“…A clear link exists among the early production of IFN-␥, the nature of the cellular immune response, and the disease outcome in the ECTV model (22,29). We have previously shown that distinct differences exist in the cytokine profiles expressed in resistant B6 and in susceptible BALB/c mouse strains infected with ECTV (22).…”

“…IFN-␥ production, NK cell responses, as well as CTL responses, are all important for recovery of B6 mice from ECTV infection (22,23,(25)(26)(27)(28), and IFN-␥ influences both the NK cell and antiviral CTL responses (22,29). Using several strains of mice exhibiting differential degrees of resistance to mousepox, we established that recovery or death from ECTV infection is determined by a balance between the host's ability to produce IFN-␥ and the virus's ability to dampen its effects (29).…”

“…The ECTV determinant EVM158 20 -27 (B8R 20 -27 ; TSYKFESV) tetramer was synthesized at JCSMR Biomolecular Resources Facility and used as described previously (29). Intranuclear Foxp3 staining was performed following manufacturer's instruction (eBioscience).…”

“…Ex vivo NK and CTL activity of leukocytes from popliteal lymph nodes (LN) or spleens was determined by using standard 51 Cr release assay as described previously (29,38). YAC-1 cells (ATCC TIB-160) were used as targets for NK assay.…”