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

doi:10.1073/pnas.111151098

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

^*Division of Biochemistry and Molecular Biology, The John Curtin School of Medical Research, Australian National University, Canberra ACT 2601, Australia; ^‡Department of Pathology, Division of Faculty of Medicine, Blackburn Building, D06, University of Sydney, Sydney NSW 2006, Australia; ^§Department of Host Defense, Research Institute for Microbial Disease, Osaka University, Suita-shi, Osaka 565-0871, Japan; and ^¶Department of Biochemistry, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan

Communicated by Frank J. Fenner, Australian National University, Canberra, Australia (received for review January 25, 2001)

Abstract

We inoculated BALB/c 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 BALB/c 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.

Footnotes

↵ † To whom reprint requests should be addressed. E-mail: Surendran.Mahalingam{at}anu.edu.au.
Abbreviations:

Th,

T helper;

EV,

ectromelia virus;

NK,

natural killer;

IFN,

interferon;

LN,

lymph node;

STAT6,

signal transducer and activator of transcription 6;

pfu,

plaque-forming unit(s);

p.i.,

postinfection;

RT-PCR,

reverse transcription–PCR;

HPRT,

hypoxanthine phosphoribosyltransferase;

TNF,

tumor necrosis factor;

RNI,

reactive nitrogen intermediates;

CTL,

cytotoxic T lymphocyte;

NOS2,

nitric-oxide synthase 2