Abstract 19841: Gut Microbiome Influences Immune Modulating Therapy for Inflammatory Vasculitis in a Lethal Herpesviral Infection
Introduction: The role of the microbiome on vascular disease, viral infections, and immune modulating therapy is not well defined. Changes in bacterial signatures are seen in inflammatory vasculitic syndromes (IVS), Takayasu’s disease and Giant Cell arteritis, with excessive innate immune cell activation, invading dendritic cells, macrophages, giant cells and T lymphocytes. Mouse gamma herpesviral (MHV68) infection is a model for IVS. We have previously showed that a myxomavirus-derived drug, a serine protease inhibitor, Serp-1, improves survival and reduces vascular inflammation after MHV68 infection. Serp-1 inhibits thrombotic and thrombolytic proteases and reduces inflammatory macrophage and T cell responses. Further, a naturally processed reactive center loop peptide from Serp-1, S-7 (G305TTASSDTAITLIPR319) also improves survival.
Method: We examined disease progression in MHV68 infection in interferon gamma receptor deficient (IFNγR-/-) mice, both with and without anti-inflammatory serpin treatments and with and without suppression of the gut bacterial population.
Results: We detected a marked acceleration in MHV68 infection and IVS with earlier mortality after antibiotic depletion of gut bacteria. Broad-spectrum oral antibiotics shortened survival in MHV68 infected mice from 60 days to 20 days (N = 14, P < 0.036). Antibiotic treatment also reduced efficacy of Serp-1 and also S-7 treatment reducing survival from 70% at 150 days to 20% at 30 days for Serp-1 (N = 15, P < 0.0028) and to 0% at 30 days for S-7 (N = 19; P < 0.0001). A second peptide, S-2 remained inactive while a third peptide S-8 had improved survival from 0% to 40% after antibiotics were given but this improved survival with S-8 (M363AVLYPQVIVDHPFFFLIRNR383) was not significant (N = 14). Antibiotic treatment suppressed aerobic stool bacterial growth, but did not alter Serp-1 inhibitory activity for proteases in vitro. In a 3 day follow up, cell infiltrates in lungs showed trends towards decreased numbers (N = 3-4) with Serp-1 (88.3±16.5) and S-7 (84.3±3.2) compared to saline (92.6±4.6).
Conclusion: This work suggests a central role for the endogenous microbiota in MHV68 infection and potentially in IVS progression, immune responses and efficacy of immune modulating therapies.
Author Disclosures: S. Ambadapadi: None. R. Thomas: None. C. Jobin: None. S. Morshed: None. K. Grau: None. S. Karst: None. S. Tibbetts: None. G. McFadden: None. A. Lucas: None.
- © 2016 by American Heart Association, Inc.