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International Immunology Advance Access originally published online on November 11, 2008
International Immunology 2009 21(1):19-28; doi:10.1093/intimm/dxn119
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© The Japanese Society for Immunology. 2008. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Francisella inhibits STAT1-mediated signaling in macrophages and prevents activation of antigen-specific T cells

Kimberly M. Roth1, John S. Gunn2,3, William Lafuse3 and Abhay R. Satoskar1,2,3

1 Department of Microbiology
2 Center for Microbial Interface Biology
3 Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University, Columbus, OH, USA

Correspondence to: A. R. Satoskar; E-mail: satoskar.2{at}osu.edu

Signal transducer and activator of transcription-1 (STAT1) signaling mediate most biological functions of IFN{alpha}, IFNβ and IFN{gamma} although recent studies indicate that IFN{gamma} can alter expression of several genes via a STAT1-independent pathway. STAT1 is critical for immunity against a variety of intracellular pathogens and some studies show that pathogens evade host immunity by interfering with STAT1 signaling. Here, we have investigated the role of STAT1 in host defense against pulmonary Francisella novicida infection using STAT1–/– mice. In addition, we examined the effect of F. novicida on STAT1 signaling in macrophages and on their ability to activate antigen-specific T cells. Both wild-type (WT) and STAT1–/– BALB/c mice were susceptible to aerosol challenge with 103 F. novicida and displayed 100% mortality. However, STAT1–/– mice developed more severe pneumonia, liver pathology and succumbed to infection faster than WT mice. The lungs, liver and hearts from F. novicida-infected STAT1–/– mice also contained more bacteria than WT mice at the time of death. In vitro studies showed that F. novicida suppressed IFN{gamma}R{alpha} (alpha subunit of IFN{gamma} receptor) and MHC class II expression, down-regulated IFN{gamma}-induced STAT1 activation and reduced nuclear binding of STAT1 in RAW264.7 macrophages. Furthermore, F. novicida-infected BMDM loaded with ovalbumin (OVA) were less efficient in activating OVA-specific CD4+ T cells in vitro. These findings demonstrate that STAT1-mediated signaling participates in the host defense against pulmonary F. novicida infection but it is not sufficient to prevent mortality associated with this infection. Moreover, our results show that F. novicida attenuates STAT1-mediated IFN{gamma} signaling in macrophages and impairs their ability to activate antigen-specific CD4+ T cells.

Keywords: Francisella novicida, IFN{gamma}, STAT1

Transmitting editor: C. Terhorst

Received 1 May 2008, accepted 4 October 2008.


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