A systems immunology approach to plasmacytoid dendritic cell function in cytopathic virus infections

• Published in: PLoS pathogens Vol. 6; no. 7; p. e1001017
• Main Authors: Bocharov, Gennady, Züst, Roland, Cervantes-Barragan, Luisa, Luzyanina, Tatyana, Chiglintsev, Egor, Chereshnev, Valery A, Thiel, Volker, Ludewig, Burkhard
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01-07-2010; Public Library of Science (PLoS)
• Subjects: Allergy and Immunology; Antiviral Agents; Computational Biology/Systems Biology; Computer Science/Numerical Analysis and Theoretical Computing; Dendritic cells; Dendritic Cells - immunology; Disease; Dosage and administration; Drug Delivery Systems; Drug dosages; Experiments; Genetic aspects; Hepatitis; Hepatitis viruses; Host-Pathogen Interactions - immunology; Immune system; Immunogenetics; Immunology; Immunology/Innate Immunity; Interferon; Liver; Liver - virology; Liver diseases; Macrophages - immunology; Macrophages - virology; Mathematical models; Models, Biological; Models, Theoretical; Murine hepatitis virus; Parameter estimation; Spleen; Systems Biology - methods; Viral infections; Virology/Animal Models of Infection; Virology/Host Antiviral Responses; Virus Diseases - drug therapy; Virus Diseases - immunology; Viruses; United States
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1001017

Plasmacytoid dendritic cell (pDC)-mediated protection against cytopathic virus infection involves various molecular, cellular, tissue-scale, and organism-scale events. In order to better understand such multiscale interactions, we have implemented a systems immunology approach focusing on the analysis of the structure, dynamics and operating principles of virus-host interactions which constrain the initial spread of the pathogen. Using high-resolution experimental data sets coming from the well-described mouse hepatitis virus (MHV) model, we first calibrated basic modules including MHV infection of its primary target cells, i.e. pDCs and macrophages (Mphis). These basic building blocks were used to generate and validate an integrative mathematical model for in vivo infection dynamics. Parameter estimation for the system indicated that on a per capita basis, one infected pDC secretes sufficient type I IFN to protect 10(3) to 10(4) Mphis from cytopathic viral infection. This extremely high protective capacity of pDCs secures the spleen's capability to function as a 'sink' for the virus produced in peripheral organs such as the liver. Furthermore, our results suggest that the pDC population in spleen ensures a robust protection against virus variants which substantially down-modulate IFN secretion. However, the ability of pDCs to protect against severe disease caused by virus variants exhibiting an enhanced liver tropism and higher replication rates appears to be rather limited. Taken together, this systems immunology analysis suggests that antiviral therapy against cytopathic viruses should primarily limit viral replication within peripheral target organs.