Patients with systemic lupus (SLE) often excessive type I interferon production, with activation of interferon-inducible genes (interferon signature). The mitochondrial adaptor protein MAVS (IPS1, VISA or CARDIF) is a key intermediary in the RIG-I pathway, where viral RNA triggers a conformational change in RIG-I, leading to MAVS activation and activation of IKK and TBK1, with subsequent interferon production driven by IRF-3 and NFkB activation and translocation. A recent report using in vitro methods demonstrated that MAVS may form large prion-like aggregates which might stimulate IFN-I activation in a potent and prolonged fashion. Remarkably, we have found that cells from ~40% of SLE patients showed clear MAVS aggregation, with essentially all of their MAVS protein in a high molecular weight form. Such MAVS aggregation is not seen in cells from normal individuals. In this proposal, we will extend and confirm our observations, and will correlate aggregate-positive samples with clinical disease patterns and disease activity. We will examine interferon type I production of cells isolated from patients with MAVS aggregation for enhanced production of IFN, and will perform array analysis to measure their interferon signature. We will determine the source of aggregated MAVS by analysis of separated cell populations from the blood of SLE patients. We will ask if the MAVS-inhibitory protein NLRX1 is under-expressed in lupus patient cells. Finally, we will determine the significance of MAVS on IFN-I production by measuring IFN production after blocking MAVS activation through intervening in several signaling pathways involving MAVS. These studies address a fundamental question in lupus pathogenesis and should give insight into the innate immune response driving the disease.

Public Health Relevance

Systemic lupus (SLE) is a severe autoimmune disease of unknown cause. Over the past decade, scientists have found that blood cells from SLE patients make proteins similar to what is seen during certain viral infections, and this has been called the interferon signature. No virus has reproducibly been isolated from lupus patients. We have recently observed that, in many lupus patients, a key protein that is involved in responding to viral infection (MAVS) seems to be abnormally persistent in a very large, activated form. We will determine the clinical significance of this finding and explore the reasons why SLE patients may be responding differently to viruses. This project has the potential for developing ways of intervening in the virus response pathway, and thereby reducing the severity of SLE.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AR065692-01
Application #
8623970
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Mancini, Marie
Project Start
2014-09-19
Project End
2016-08-31
Budget Start
2014-09-19
Budget End
2015-08-31
Support Year
1
Fiscal Year
2014
Total Cost
$205,920
Indirect Cost
$73,920
Name
Temple University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
057123192
City
Philadelphia
State
PA
Country
United States
Zip Code
19122