Modeling of Interferon effector pathway after viral infection
Leire Ruiz-Cerdá (1), Eduardo Asín-Prieto (1), Marcos Vasquez Durán (2), Pedro Berraondo López (2) and Iñaki F. Trocóniz (1)
(1) Pharmacometrics & Systems Pharmacology, Department of Pharmacy and Pharmaceutical Technology, University of Navarra, Pamplona, Navarra, Spain. (2) Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Navarra Institute for Health Research (IdiSNA), Pamplona, Navarra, Spain.
Objectives and backgroud: To develop a semi-mechanistic model describing the Interferon (IFN) type I signaling pathway after the administration of a Newcastle Disease Virus (NDV) encoding green fluorescent protein (GFP) in L929 mouse fibroblasts. NDV is an oncolytic vector widely used in cancer immunotherapy [1] but it is a potent inductor of IFNs, limiting the replication of the vector and thus reducing therapy efficacy. Scavenger receptor class B member 1 (SRB1) is a critical modulator of IFN bioactivity, the use of block lipid transport 1 (BLT1), an SRB1 antagonist, have an impact on virus replication [2], and allows to get insights on the regulation pathways of the system.
Methods: Data were obtained from in-vitro experiments performed in L929 mouse fibroblast model and include: (i) GFP expression by infected cells (as indication of virus proliferation), (ii) expression fold change of Interferon b (IFN b) and (iii) fold change expression of 25OAS (2',5'-Oligoadenylate synthetase), an Interferon-stimulated gene (ISG), at 6, 12, 24, 48 hours (h) [1]. Moreover, the interferon- a/ b receptor (IFNAR) expression was measured at (i) a serial of halving doses of BLT1 from 100 to 0 μM, and (ii) different time points (0, 0.5, 1, 2, 3, 4, 5 h), using 25 μM of BLT1. Data were analyzed with NONMEM 7.2 [3].
Results: The following mechanisms were described using turn-over based models: (i) virus replication, (ii) increased intracellular expression of IFN b triggered by viral replication, (iii) binding of IFN b to IFNAR promoting ISGs expression through intracellular signaling pathways, and (iv) IFNAR recycling inhibition and its overexpression as a consequence of exposure to BLT1.
The virus first order rate constant of proliferation (0.067h-1) was raised to 0.123 h-1 when INFa,b pathway activity was decreased by BLT1. Consequently the synthesis rate of 25OAS (3.8E-3h-1) diminished a 30% in presence of BLT1. After a BLT1 treatment IFNAR expression was up-regulated. The model predicts a 15% IFNAR overexpression at 24h.
Conclusion: A quantitative model has been developed for the type I IFN signaling pathway using in vitro data. This model provides mechanistic insights in cancer immunotherapy with oncolytic viruses and paves the way to better understand the clinical implications of the modulation of the type I IFN receptor.
References:
[1] Zhao, Lixiang, and Haiyan Liu. 2012. “Newcastle Disease Virus: A Promising Agent for Tumour Immunotherapy.” Clinical and Experimental Pharmacology & Physiology 39 (8): 725–30
[2] Vasquez, M., Fioravanti, J., Aranda, F., Paredes, V., Gomar, C., Ardaiz, N., Berraondo, P. (2016). Interferon alpha bioactivity critically depends on Scavenger receptor class B type I function. OncoImmunology, 5(8). doi:10.1080/2162402X.2016.11963
[3] Beal SL, Sheiner LB, Boeckmann AJ & Bauer RJ (Eds.) NONMEM Users Guides. 1989-2011. Icon Development Solutions, Ellicott City, Maryland, USA.