The objective is to elucidate the effects of influenza (flu) virus infection and flu vaccines on a natural host T cell regulatory mechanism involving expression of indoleamine 2,3 dioxygenase (IDO). IDO-mediated T cell suppression contributes to chronic inflammatory syndromes of clinical relevance, including tumor growth, autoimmune, allergic, and graft-versus-host diseases. IDO activity blocks T cell responses to fetal tissues during pregnancy, and IDO over-expression enhances transplant survival. Flu infection induces a dramatic increase in IDO activity in lungs, and IDO activity facilitates secondary infections such as pneumonia. We hypothesize that IDO attenuates effector T cell immune responses to flu infection and to preventative vaccines. Such effects may promote tissue healing, but may blunt T cell responses to flu infection, impede generation protective immunity, and increase the risk of secondary infections. IDO expression by some plasmacytoid dendritic cells (pDCs) inhibits T cell responses at sites of inflammation. In preliminary studies we show that chemically-induced skin inflammation induced pDCs in skin draining lymph nodes (dLNs) to express IDO. IDO+ pDCs acquired potent T cell regulatory functions that blocked T cell clonal expansion, and triggered regulatory T cells (Tregs) to acquire suppressor activity. In studies proposed, we will employ new mouse strains and viral vectors to ablate IDO in an established murine flu infection model, and assess the effects of IDO ablation on flu-specific immunity, memory generation, and infection kinetics. We will identify lung cells expressing IDO, and inflammatory signals that stimulate IDO (Aim 1). In parallel, we will elucidate the effects of lung IDO+ cells on flu-specific effector and memory T cells (Aim 2). Related studies will focus on the effects of IDO ablation on flu vaccine prophylaxis and efficacy (Aim 3), and a novel means to enhance therapeutic vaccination to combat flu infections (Aim 4). Completion of studies proposed will improve understanding of the role of IDO in regulating T cell responses to flu, and will create novel opportunities for improving therapeutic interventions protect against flu.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AI083005-04
Application #
8261985
Study Section
Special Emphasis Panel (ZAI1-BDP-I (J4))
Program Officer
Miller, Lara R
Project Start
2009-05-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
4
Fiscal Year
2012
Total Cost
$2,544,175
Indirect Cost
$488,002
Name
Georgia Regents University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
966668691
City
Augusta
State
GA
Country
United States
Zip Code
30912
Fox, Julie M; Sage, Leo K; Poore, Spencer et al. (2014) Drug analog inhibition of indoleamine 2,3-dioxygenase (IDO) activity modifies pattern recognition receptor expression and proinflammatory cytokine responses early during influenza virus infection. J Leukoc Biol 96:447-52
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Huang, Lei; Mellor, Andrew L (2014) Metabolic control of tumour progression and antitumour immunity. Curr Opin Oncol 26:92-9
Sage, Leo K; Fox, Julie M; Mellor, Andrew L et al. (2014) Indoleamine 2,3-dioxygenase (IDO) activity during the primary immune response to influenza infection modifies the memory T cell response to influenza challenge. Viral Immunol 27:112-23
Barnett, Lisa G; Simkins, Helen M A; Barnett, Burton E et al. (2014) B cell antigen presentation in the initiation of follicular helper T cell and germinal center differentiation. J Immunol 192:3607-17
Ding, Zhi-Chun; Lu, Xiaoyun; Yu, Miao et al. (2014) Immunosuppressive myeloid cells induced by chemotherapy attenuate antitumor CD4+ T-cell responses through the PD-1-PD-L1 axis. Cancer Res 74:3441-53
Lemos, Henrique; Huang, Lei; Chandler, Phillip R et al. (2014) Activation of the STING adaptor attenuates experimental autoimmune encephalitis. J Immunol 192:5571-8
Huang, Lei; Li, Lingqian; Lemos, Henrique et al. (2013) Cutting edge: DNA sensing via the STING adaptor in myeloid dendritic cells induces potent tolerogenic responses. J Immunol 191:3509-13
Fox, Julie M; Sage, Leo K; Huang, Lei et al. (2013) Inhibition of indoleamine 2,3-dioxygenase enhances the T-cell response to influenza virus infection. J Gen Virol 94:1451-61
Huang, Lei; Li, Lingqian; Klonowski, Kim D et al. (2013) Induction and role of indoleamine 2,3 dioxygenase in mouse models of influenza a virus infection. PLoS One 8:e66546

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