Chronic inflammation in response to persistent virus infection is associated with autoimmune disease. Patients with autoimmune disease often exhibit dysregulated expression of anti-viral cytokines, including the interferon (IFN) system, however the mechanisms linking persistent virus infection and autoimmunity remain poorly defined. The TNF receptor superfamily member, Lymphotoxin-? receptor (LT?R) and its related signaling pathways, control lymphoid tissue homeostasis and are essential for host innate and adaptive defenses to herpesviruses. The LT?R is a critical pathway for the initial induction of the type I IFN (IFN??) in response to human or mouse cytomegalovirus. In mice, the LT-IFN axis is essential for lymphocyte survival during CMV infection and is mediated between naive B lymphocytes acting as innate effectors that induce IFN?? in virus-infected LT?R+ stromal cells in lymphoid tissues. The TNFR superfamily member, herpesvirus entry mediator (HVEM), and its unconventional ligands, BTLA and CD160, both Ig superfamily members, counter regulate the LT?R pathway and functions as an inhibitory cosignaling pathways for T and B cells. Diverse viruses from herpesviruses to retroviruses have evolved specific mechanisms that modulate LT?R and HVEM-BTLA systems. We hypothesize that viral targeting of the LT?R-IFN axis in persistent infections may disrupt immune homeostasis, promoting the development of autoimmune disease. In this project, we seek to define the LT?R and HVEM-BTLA pathways that regulate the IFN system in response to CMV infection in human and mouse models. Our goal is to develop counter strategies by understanding and altering immune evasion mechanisms. We developed new molecular reagents to specifically probe the LT-IFN and HVEM-BTLA pathways, and engineered viral mutants to use in different mouse genetic models to address the regulation of the LT-IFN system. We have established a highly interactive group of virologists and autoimmune disease specialists as collaborators to assist in the experimental approach and data analysis.

Public Health Relevance

This project studies how viruses alter the function of the immune system. Some viruses disrupt communication signals causing confusion among cells of the immune system. The confused immune system redirects its power to destroy normal tissues rather than virus infected cells. Understanding how viruses confuse the immune system may provide new ways to intervene in autoimmune diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI048073-12A1
Application #
8239191
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Beisel, Christopher E
Project Start
2000-07-01
Project End
2016-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
12
Fiscal Year
2012
Total Cost
$487,500
Indirect Cost
$237,500
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Ward-Kavanagh, Lindsay K; Lin, Wai Wai; Šedý, John R et al. (2016) The TNF Receptor Superfamily in Co-stimulating and Co-inhibitory Responses. Immunity 44:1005-19
Šedý, John; Bekiaris, Vasileios; Ware, Carl F (2015) Tumor necrosis factor superfamily in innate immunity and inflammation. Cold Spring Harb Perspect Biol 7:a016279
Lau, E; Sedy, J; Sander, C et al. (2015) Transcriptional repression of IFNβ1 by ATF2 confers melanoma resistance to therapy. Oncogene 34:5739-48
Li, Hao; Fu, Yang-Xin; Wu, Qi et al. (2015) Interferon-induced mechanosensing defects impede apoptotic cell clearance in lupus. J Clin Invest 125:2877-90
Allen, Sariah J; Rhode-Kurnow, Antje; Mott, Kevin R et al. (2014) Interactions between herpesvirus entry mediator (TNFRSF14) and latency-associated transcript during herpes simplex virus 1 latency. J Virol 88:1961-71
Bekiaris, Vasileios; Šedý, John R; Ware, Carl F (2014) Mixing Signals: Molecular Turn Ons and Turn Offs for Innate γδ T-Cells. Front Immunol 5:654
Gommerman, Jennifer L; Browning, Jeffrey L; Ware, Carl F (2014) The Lymphotoxin Network: orchestrating a type I interferon response to optimize adaptive immunity. Cytokine Growth Factor Rev 25:139-45
Bekiaris, Vasileios; Šedy, John R; Rossetti, Maura et al. (2013) Human CD4+CD3- innate-like T cells provide a source of TNF and lymphotoxin-αβ and are elevated in rheumatoid arthritis. J Immunol 191:4611-8
Ware, Carl F (2013) Protein therapeutics targeted at the TNF superfamily. Adv Pharmacol 66:51-80
Šedý, John R; Bjordahl, Ryan L; Bekiaris, Vasileios et al. (2013) CD160 activation by herpesvirus entry mediator augments inflammatory cytokine production and cytolytic function by NK cells. J Immunol 191:828-36

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