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

Abstract:

:Signal transducer and activator of transcription-1 (STAT1) signaling mediate most biological functions of IFNalpha, IFNbeta and IFNgamma although recent studies indicate that IFNgamma 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 10(3) 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 IFNgammaRalpha (alpha subunit of IFNgamma receptor) and MHC class II expression, down-regulated IFNgamma-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 IFNgamma signaling in macrophages and impairs their ability to activate antigen-specific CD4+ T cells.

journal_name

Int Immunol

journal_title

International immunology

authors

Roth KM,Gunn JS,Lafuse W,Satoskar AR

doi

10.1093/intimm/dxn119

subject

Has Abstract

pub_date

2009-01-01 00:00:00

pages

19-28

issue

1

eissn

0953-8178

issn

1460-2377

pii

dxn119

journal_volume

21

pub_type

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