Deficiency in Th2 cytokine responses exacerbate orthopoxvirus infection.
Ectromelia virus (ECTV) causes mousepox in mice, a disease very similar to smallpox in humans. ECTV and variola virus (VARV), the agent of smallpox, are closely related orthopoxviruses. Mousepox is an excellent small animal model to study the genetic and immunologic basis for resistance and susceptibility of humans to smallpox. Resistance to mousepox is dependent on a strong polarized type 1 immune response, associated with robust natural killer (NK) cell, cytotoxic T lymphocyte (CTL) and gamma interferon (IFN-γ) responses. In contrast, ECTV-susceptible mice generate a type 2 response, associated with weak NK cell, CTL and IFN-γ responses but robust IL-4 responses. Nonetheless, susceptible strains infected with mutant ECTV lacking virus-encoded IFN-γ binding protein (vIFN-γbp) (ECTV-IFN-γbpΔ) control virus replication through generation of type 1 response. Since the IL-4/IL-13/STAT-6 signaling pathways polarize type 2/T helper 2 (Th2) responses with a corresponding suppression of IFN-γ production, we investigated whether the combined absence of vIFN-γbp, and one or more host genes involved in Th2 response development, influence generation of protective immunity. Most mutant mouse strains infected with wild-type (WT) virus succumbed to disease more rapidly than WT animals. Conversely, the disease outcome was significantly improved in WT mice infected with ECTV-IFN-γbpΔ but absence of IL-4/IL-13/STAT-6 signaling pathways did not provide any added advantage. Deficiency in IL-13 or STAT-6 resulted in defective CTL responses, higher mortality rates and accelerated deaths. Deficiencies in IL-4/IL-13/STAT-6 signaling pathways significantly reduced the numbers of IFN-γ producing CD4 and CD8 T cells, indicating an absence of a switch to a Th1-like response. Factors contributing to susceptibility or resistance to mousepox are far more complex than a balance between Th1 and Th2 responses.
Infection and Immunity Group, Department of Immunology, John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia.
Isaac G
IG
Sakala
Infection and Immunity Group, Department of Immunology, John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia.
Geeta
G
Chaudhri
Infection and Immunity Group, Department of Immunology, John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia.
Preethi
P
Eldi
Department of Molecular Microbiology and Immunology, Saint Louis University Health Sciences Center, St Louis, MO, United States of America.
R Mark
RM
Buller
Infection and Immunity Group, Department of Immunology, John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia.
Gunasegaran
G
Karupiah
D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000235:genetics* / Q000378:metabolism; D004198:Disease Susceptibility; D004481:Ectromelia virus / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity*; D004482:Ectromelia, Infectious / Q000276:immunology* / Q000401:mortality / Q000821:virology; D055785:Gene Knockdown Techniques; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D015398:Signal Transduction; D018418:Th2 Cells / Q000378:metabolism*; D014764:Viral Proteins / Q000235:genetics* / Q000276:immunology
D016207:Cytokines; D014764:Viral Proteins; D007371:Interferon-gamma