Deficiency in Th2 Cytokine Responses Exacerbate Orthopoxvirus Infection
Sakala, IG and Chaudri, G and Eldi, P and Buller, RM and Karupiah, G, Deficiency in Th2 Cytokine Responses Exacerbate Orthopoxvirus Infection, PloS one, 10, (3) Article e0118685. ISSN 1932-6203 (2015) [Refereed Article]
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.
Th1/Th2 cytokines, CD8 T cells, NK cells, antiviral immunity