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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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Effect of virus growth rates on pDC-mediated protection against disease.(A) Sensitivity of the disease severity to variations in pDC numbers (cells per spleen) and the global increase of viral replication rate in the liver (% increase). Disease severity is determined as peak ALT levels in serum within 48 h post infection following i.v. infection with 50 pfu. (B) Determination of the system's robustness against disease with respect to variations in pDC numbers (cells per spleen) and increasing viral replication rates restricted to Mφs in the spleen (Note: fold increase).
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ppat-1001017-g006: Effect of virus growth rates on pDC-mediated protection against disease.(A) Sensitivity of the disease severity to variations in pDC numbers (cells per spleen) and the global increase of viral replication rate in the liver (% increase). Disease severity is determined as peak ALT levels in serum within 48 h post infection following i.v. infection with 50 pfu. (B) Determination of the system's robustness against disease with respect to variations in pDC numbers (cells per spleen) and increasing viral replication rates restricted to Mφs in the spleen (Note: fold increase).

Mentions: Viruses can acquire mutations that result in a faster replication in target cells and a high-virulence phenotype [15], [16]. A recently published study on cytopathic influenza A virus infection [15] provides quantitative details of the scale of virulence-enhancing mutations and the resulting increase in virus growth rate. It follows from the analysis of these virus growth data that the difference in the intrinsic growth rate is about 30%. With this estimate as a reference value, we used the mathematical model of MHV infection to evaluate the limits of protection against severe disease for increasing virus replication rates. Since various MHV strains display significant differences in their ability to replicate in different organ systems [17], two complementary scenarios were considered: the increase in virus growth rate in the peripheral organs (liver) versus SLOs (spleen). Figure 6A shows that pDCs in spleen provide very limited protection against severe disease for faster replicating strains of the virus. Indeed, only a 15% increase in the growth rate of MHV in the liver leads to infection with ALT levels rising to 103 IU/L within two days. The decrease of pDC numbers in spleen makes the situation more fragile to even smaller increases in the virus growth rate. The contour lines shown in Figure 6A are the curves along which the value of ALT in serum at 48 h post infection remains the constant. The quantitative analysis of the contour lines slope suggests that 1% increase in the replication rate of the virus in the liver requires about 50% increase in the initial pDCs number in the spleen for the ALT level to have the same particular value. On the contrary, pDCs provide a robust protection against severe disease when the virulence-enhancing mutation leads to faster replication only in target cells located in spleen (Figure 6B), i.e. splenic pDCs protect against severe disease for up to 30-fold increase in the viral replication rate in splenic Mφs. Taken together, these analyses indicate that the spleen represents a robust sink system able to cope with substantially enhanced virus production as long as this gain of viral fitness remains restricted to this SLO.


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)

Effect of virus growth rates on pDC-mediated protection against disease.(A) Sensitivity of the disease severity to variations in pDC numbers (cells per spleen) and the global increase of viral replication rate in the liver (% increase). Disease severity is determined as peak ALT levels in serum within 48 h post infection following i.v. infection with 50 pfu. (B) Determination of the system's robustness against disease with respect to variations in pDC numbers (cells per spleen) and increasing viral replication rates restricted to Mφs in the spleen (Note: fold increase).
© Copyright Policy
Related In: Results  -  Collection

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

ppat-1001017-g006: Effect of virus growth rates on pDC-mediated protection against disease.(A) Sensitivity of the disease severity to variations in pDC numbers (cells per spleen) and the global increase of viral replication rate in the liver (% increase). Disease severity is determined as peak ALT levels in serum within 48 h post infection following i.v. infection with 50 pfu. (B) Determination of the system's robustness against disease with respect to variations in pDC numbers (cells per spleen) and increasing viral replication rates restricted to Mφs in the spleen (Note: fold increase).
Mentions: Viruses can acquire mutations that result in a faster replication in target cells and a high-virulence phenotype [15], [16]. A recently published study on cytopathic influenza A virus infection [15] provides quantitative details of the scale of virulence-enhancing mutations and the resulting increase in virus growth rate. It follows from the analysis of these virus growth data that the difference in the intrinsic growth rate is about 30%. With this estimate as a reference value, we used the mathematical model of MHV infection to evaluate the limits of protection against severe disease for increasing virus replication rates. Since various MHV strains display significant differences in their ability to replicate in different organ systems [17], two complementary scenarios were considered: the increase in virus growth rate in the peripheral organs (liver) versus SLOs (spleen). Figure 6A shows that pDCs in spleen provide very limited protection against severe disease for faster replicating strains of the virus. Indeed, only a 15% increase in the growth rate of MHV in the liver leads to infection with ALT levels rising to 103 IU/L within two days. The decrease of pDC numbers in spleen makes the situation more fragile to even smaller increases in the virus growth rate. The contour lines shown in Figure 6A are the curves along which the value of ALT in serum at 48 h post infection remains the constant. The quantitative analysis of the contour lines slope suggests that 1% increase in the replication rate of the virus in the liver requires about 50% increase in the initial pDCs number in the spleen for the ALT level to have the same particular value. On the contrary, pDCs provide a robust protection against severe disease when the virulence-enhancing mutation leads to faster replication only in target cells located in spleen (Figure 6B), i.e. splenic pDCs protect against severe disease for up to 30-fold increase in the viral replication rate in splenic Mφs. Taken together, these analyses indicate that the spleen represents a robust sink system able to cope with substantially enhanced virus production as long as this gain of viral fitness remains restricted to this SLO.

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