Enhanced resistance in STAT6-deficient mice to infection with ectromelia virus

Abstract

We inoculated BALB͞c mice deficient in STAT6 (STAT6 ؊/؊ ) and their wild-type (wt) littermates (STAT6 ؉/؉ ) with the natural mouse pathogen, ectromelia virus (EV). STAT6 ؊/؊ mice exhibited increased resistance to generalized infection with EV when compared with STAT6 ؉/؉ mice. In the spleens and lymph nodes of STAT6 ؊/؊ mice, T helper 1 (Th1) cytokines were induced at earlier time points and at higher levels postinfection when compared with those in STAT6 ؉/؉ mice. Elevated levels of NO were evident in plasma and splenocyte cultures of EV-infected STAT6 ؊/؊ mice in comparison with STAT6 ؉/؉ mice. The induction of high levels of Th1 cytokines in the mutant mice correlated with a strong natural killer cell response. We demonstrate in genetically susceptible BALB͞c mice that the STAT6 locus is critical for progression of EV infection. Furthermore, in the absence of this transcription factor, the immune system defaults toward a protective Th1-like response, conferring pronounced resistance to EV infection and disease progression.

Evidence Inconsistent with a Negative Influence of T Helper 2 Cells on Protection Afforded by a Dominant T Helper 1 Response againstMycobacterium tuberculosisLung Infection in Mice

“…Indeed, the demonstration here that IL-4 gene expression was subservient to IL-12, IFN-␥, and NOS2 gene expression and was no higher in Stat6 Ϫ/Ϫ BALB/c mice than in WT BALB/c mice might mean that in both types of mice, transcription of the IL-4 gene was activated via the Stat6-independent pathway. This is a different situation than that seen in BALB/c mice infected with certain pathogens, such as Leishmania mexicana (40), Trypanosoma cruzi (44), or ectromelia virus (25), where the absence of Stat6 results in a larger and more protective Th1 response. On the other hand, according to the present study, IL-4/IL-13 Ϫ/Ϫ mice did generate significantly higher levels of Th1-mediated immunity than did WT mice on day 50 of infection, as measured by the levels of IFN-␥ and NOS2 gene expression.…”

Inhibition of Interferons by Ectromelia Virus

“…In the second study, BALB/c mice deficient in the STAT6 transcription factor, which is essential in the development of T helper 2 (Th2) responses, were more resistant to EV infection than wild-type mice. Increased resistance to EV correlated with enhanced expression of Th1 cytokines, including IFN-␥ (48). Additionally, the attenuation of an EV with an inactivated vIL-18BP gene correlated with increased IFN-␥ production in infected mice (14).…”

STATs in NK-Cells: The Good, the Bad, and the Ugly

“…In line, studies with Stat6 −/− mice showed increased viral resistance and higher cytolytic activity of NK-cells in the absence of STAT6 (105). However, a positive correlation of STAT6 expression and IFN-γ production was reported after costimulating murine NK-cells with IL-4 and IL-2 (106).…”