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

Bocharov G, Züst R, Cervantes-Barragan L, Luzyanina T, Chiglintsev E, Chereshnev VA, Thiel V, Ludewig B - PLoS Pathog. (2010)

Bottom Line: 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.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.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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Numerical Mathematics, Russian Academy of Sciences, Moscow, Russia.

ABSTRACT
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.

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Related in: MedlinePlus

Conceptual scheme of type I IFN responses during cytopathic coronavirus infection.(A) Systemic view of the processes determining the early kinetics of mouse hepatitis virus (MHV) infection. (B) Schematic depiction of the ‘sink’ versus ‘source’ function of spleen in coronavirus infection.
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ppat-1001017-g001: Conceptual scheme of type I IFN responses during cytopathic coronavirus infection.(A) Systemic view of the processes determining the early kinetics of mouse hepatitis virus (MHV) infection. (B) Schematic depiction of the ‘sink’ versus ‘source’ function of spleen in coronavirus infection.

Mentions: The mouse hepatitis virus (MHV) infection represents a well-understood paradigmatic system for the analysis of type I IFN responses. MHV is a member of the Coronaviridae family that harbor a number of viruses causing severe diseases in animals and humans, such as acute hepatitis, encephalitis, infectious bronchitis, lethal infectious peritonitis, and the severe acute respiratory syndrome (SARS) [6], [7]. In systemic MHV infection, spleen and liver represent major target organs [8], and primarily hematopoietic cell-derived type I IFN controls viral replication and virus-induced liver disease [9]. We could recently show that pDCs are the major cell population generating IFN-α during the initial phase of mouse coronavirus infection [8]. Importantly, mainly macrophages (Mφ) and, to a lesser extent conventional DCs, respond most efficiently to the pDC-derived type I IFN and thereby secure containment of MHV within SLOs [10]. Thus, the type I IFN-mediated crosstalk between pDCs and Mφs represents an essential cellular pathway for the protection against MHV-induced liver disease. In system biology terms, MHV infection triggers a complex array of processes at different biological scales such as protein expression, cellular migration, or pathological organ damage. To focus on the front edge of the virus-host interaction, the present analysis specifically addresses the early dynamics (i.e. the first 48 h) of the type I IFN response to MHV since this is decisive for the outcome of the infection. The reductionist's view of the most essential processes underlying the early systemic dynamics of MHV infection, liver pathology and the first wave of type I IFN production is summarized in Figure 1A.


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

Bocharov G, Züst R, Cervantes-Barragan L, Luzyanina T, Chiglintsev E, Chereshnev VA, Thiel V, Ludewig B - PLoS Pathog. (2010)

Conceptual scheme of type I IFN responses during cytopathic coronavirus infection.(A) Systemic view of the processes determining the early kinetics of mouse hepatitis virus (MHV) infection. (B) Schematic depiction of the ‘sink’ versus ‘source’ function of spleen in coronavirus infection.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2908624&req=5

ppat-1001017-g001: Conceptual scheme of type I IFN responses during cytopathic coronavirus infection.(A) Systemic view of the processes determining the early kinetics of mouse hepatitis virus (MHV) infection. (B) Schematic depiction of the ‘sink’ versus ‘source’ function of spleen in coronavirus infection.
Mentions: The mouse hepatitis virus (MHV) infection represents a well-understood paradigmatic system for the analysis of type I IFN responses. MHV is a member of the Coronaviridae family that harbor a number of viruses causing severe diseases in animals and humans, such as acute hepatitis, encephalitis, infectious bronchitis, lethal infectious peritonitis, and the severe acute respiratory syndrome (SARS) [6], [7]. In systemic MHV infection, spleen and liver represent major target organs [8], and primarily hematopoietic cell-derived type I IFN controls viral replication and virus-induced liver disease [9]. We could recently show that pDCs are the major cell population generating IFN-α during the initial phase of mouse coronavirus infection [8]. Importantly, mainly macrophages (Mφ) and, to a lesser extent conventional DCs, respond most efficiently to the pDC-derived type I IFN and thereby secure containment of MHV within SLOs [10]. Thus, the type I IFN-mediated crosstalk between pDCs and Mφs represents an essential cellular pathway for the protection against MHV-induced liver disease. In system biology terms, MHV infection triggers a complex array of processes at different biological scales such as protein expression, cellular migration, or pathological organ damage. To focus on the front edge of the virus-host interaction, the present analysis specifically addresses the early dynamics (i.e. the first 48 h) of the type I IFN response to MHV since this is decisive for the outcome of the infection. The reductionist's view of the most essential processes underlying the early systemic dynamics of MHV infection, liver pathology and the first wave of type I IFN production is summarized in Figure 1A.

Bottom Line: 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.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.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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Numerical Mathematics, Russian Academy of Sciences, Moscow, Russia.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus