EXCEED THE SPACE PROVIDED. The innate cytokines, type 1 interferons (IFN), including interferons alpha and beta, were first identified by their anitiviral functions. It is now know that they also mediate a wide range of immunoregulatory effects. Certain of these are paradoxical, and mechanisms controlling the subset of effects induced following IFN- alpha/beta exposure remain to be elucidated. Likewise, CD8 T cell regulation is incompletely understood, but dramatic CD8 T cell responses are observed during viral infections eliciting high concentrations of type 1 IFNs. This project will test the primary hypotheses that the type 1 IFN effects elicited are controlled by regulation of access to different intracellular signaling pathways, and that this regulation is required and delivered during innate and adaptive immune responses to viral infections. Thus, these hypotheses present a picture of 'Type 1 Interferons as Links Between Innate and Adaptive Immune Responses to Viral Infections'. Based on our studies of functions for signal transducers and activators of transcription (STAT) 1 and STAT4 following infections with lymphocytic choriomeningitis virus (LCMV) and treatments with cytokines, regulation of STAT1 is proposed to be a critical mechanism for switching to different responses following type 1 IFN exposure. Focus of the planned experiments will be on effects for induction of antiviral state, IFN-alpha/beta amplification, and the CD8 T cell IFN-gamma production and proliferative responses. The work will be accomplished in three specific aims.
Aim 1 wilt evaluate the infection-induced changes in type 1 IFN effects for target gene expression.
Aim 2 will define STAT functions in pathways shaping the biological effects mediatd by type 1 IFNs.
This aim will address consequences downstream of STATs.
Aim 3 will mechnistically advance understanding of how the STATs are regulated to promote particular effects. As these studies are driven by characterization of in vivo biology, their results are likely to lead to discovery of novel pathways not predicted by in vitro studies atone. They will contribute to the understanding of the factors, particularly the innate immune components, promoting resistance to infections. They also promise to provide insights for approaches to therapeutic intervention in the treatment of infections, cancers, and immunodeficiencies. The information derived from this work will help in devising plans for readiness and defense against biD-terrorism. PERFORMANCE SITE ========================================Section End===========================================

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI055677-03
Application #
6824915
Study Section
Special Emphasis Panel (ZRG1-SSS-F (01))
Program Officer
Goodrich, Adrienne J
Project Start
2003-06-15
Project End
2007-11-30
Budget Start
2004-12-01
Budget End
2005-11-30
Support Year
3
Fiscal Year
2005
Total Cost
$385,125
Indirect Cost
Name
Brown University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
001785542
City
Providence
State
RI
Country
United States
Zip Code
02912
Biron, Christine A; Tarrio, Margarite L (2015) Immunoregulatory cytokine networks: 60 years of learning from murine cytomegalovirus. Med Microbiol Immunol 204:345-54
Wynne, Claire; Lazzari, Elisa; Smith, Siobhán et al. (2014) TRIM68 negatively regulates IFN-? production by degrading TRK fused gene, a novel driver of IFN-? downstream of anti-viral detection systems. PLoS One 9:e101503
Suarez-Ramirez, Jenny E; Tarrio, Margarite L; Kim, Kwangsin et al. (2014) CD8 T cells in innate immune responses: using STAT4-dependent but antigen-independent pathways to gamma interferon during viral infection. MBio 5:e01978-14
Tarrio, Margarite L; Lee, Seung-Hwan; Fragoso, Maria F et al. (2014) Proliferation conditions promote intrinsic changes in NK cells for an IL-10 response. J Immunol 193:354-63
Kallal, Lara E; Biron, Christine A (2013) Changing partners at the dance: Variations in STAT concentrations for shaping cytokine function and immune responses to viral infections. JAKSTAT 2:e23504
Mace, Emily M; Hsu, Amy P; Monaco-Shawver, Linda et al. (2013) Mutations in GATA2 cause human NK cell deficiency with specific loss of the CD56(bright) subset. Blood 121:2669-77
Gil, M Pilar; Ploquin, Mickael J Y; Watford, Wendy T et al. (2012) Regulating type 1 IFN effects in CD8 T cells during viral infections: changing STAT4 and STAT1 expression for function. Blood 120:3718-28
Lee, Seung-Hwan; Fragoso, Maria F; Biron, Christine A (2012) Cutting edge: a novel mechanism bridging innate and adaptive immunity: IL-12 induction of CD25 to form high-affinity IL-2 receptors on NK cells. J Immunol 189:2712-6
Vidal, Silvia M; Khakoo, Salim I; Biron, Christine A (2011) Natural killer cell responses during viral infections: flexibility and conditioning of innate immunity by experience. Curr Opin Virol 1:497-512
Mack, Ethan A; Kallal, Lara E; Demers, Delia A et al. (2011) Type 1 interferon induction of natural killer cell gamma interferon production for defense during lymphocytic choriomeningitis virus infection. MBio 2:

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