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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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Effects of variation in pDC number and activation status.(A) Virus kinetics in spleen following infection with low (5×101 pfu), intermediate (5×103 pfu) and high (5×105 pfu) dose infections under conditions of varying pDC numbers per spleen. (B) Protection of splenic Mφs determined as percentage of infected Mφs (left panel) and disease severity determined as ALT levels serum (right panel) at 48 h post infection plotted against different doses of infection. For physiological infection doses, the normal number of pDCs (blue line) and 10-fold depleted population (green line) ensure protection of more than 90% of Mφs. Further decrease of pDC population to 7×103 cells is associated with large-scale infection of Mφs (red line). (C) Effect of pre-activation of pDCs in spleen on protection of splenic Mφs determined as percentage of infected cells (left panel) and disease severity determined as ALT levels in serum (right panel) at 48 h post infection (i.v. infection with 50 pfu). Numbers of pDCs per spleen were varied as indicated. (D) Effect of the number of pDCs in spleen on the ratio of locally produced versus eliminated virus (left panel) and on sink versus source function (right panel) after low (5×101 pfu), intermediate (5×103 pfu) and high (5×105 pfu) dose infection under conditions of varying pDC numbers per spleen.
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ppat-1001017-g004: Effects of variation in pDC number and activation status.(A) Virus kinetics in spleen following infection with low (5×101 pfu), intermediate (5×103 pfu) and high (5×105 pfu) dose infections under conditions of varying pDC numbers per spleen. (B) Protection of splenic Mφs determined as percentage of infected Mφs (left panel) and disease severity determined as ALT levels serum (right panel) at 48 h post infection plotted against different doses of infection. For physiological infection doses, the normal number of pDCs (blue line) and 10-fold depleted population (green line) ensure protection of more than 90% of Mφs. Further decrease of pDC population to 7×103 cells is associated with large-scale infection of Mφs (red line). (C) Effect of pre-activation of pDCs in spleen on protection of splenic Mφs determined as percentage of infected cells (left panel) and disease severity determined as ALT levels in serum (right panel) at 48 h post infection (i.v. infection with 50 pfu). Numbers of pDCs per spleen were varied as indicated. (D) Effect of the number of pDCs in spleen on the ratio of locally produced versus eliminated virus (left panel) and on sink versus source function (right panel) after low (5×101 pfu), intermediate (5×103 pfu) and high (5×105 pfu) dose infection under conditions of varying pDC numbers per spleen.

Mentions: As a first step in the analytical modeling process, we examined the effect of pDC numbers and activation status on the protection of Mφs in spleen and the prevention of severe liver disease. As readout, i.e. the prediction of pDC performance criteria, we considered the maximum fraction of infected Mφs in spleen and the peak level of serum ALT during the first 48 hours post i.v. infection with various doses of MHV. As shown in Figure 4A, the decrease of the pDC population in spleen by 10-fold results in increased virus titers but still keeps virus growth under control. However, further depletion of pDCs leads to an overwhelming virus growth. Mφs in spleen represent about a 10-fold larger population of cells able to secrete MHV at a rate that is 10-times higher than pDCs. Therefore, protection of Mφs against the infection represents an important task that pDCs have to ensure. Indeed, antibody-mediated depletion of pDCs considerably increased infection of splenic Mφs (Figure S5). Figure 4B (left panel) shows the quantitative model predictions of how the fraction of infected Mφs in spleen depends on the number of pDCs and the dose of infection. Ten-fold reduction of pDCs in spleen still ensures that more than 90% of Mφs remain uninfected for low to intermediate infection doses. However, a further decrease of the pDC population breaks their ability to keep the number of infected Mφs below 10%. Because there is an inherent delay in activation of pDCs before the type I IFN secretion starts, we modeled the situation when a certain fraction of splenic pDCs is pre-activated at the start of the infection. Figure 4C (left panel) shows the predicted dependence of the infected Mφs on the number of pre-activated pDCs for MHV infection with 50 pfu. The results allowed us to quantify the upper limit for the protective capacity () of pDCs, if we define it as the ability to protect 90% of Mφs against infection. As few as 2000 activated pDCs suffice to protect 6×106 Mφs, which leads to the estimate of Mφ per pDC. To clarify how the pDCs in spleen contribute to control against severe disease, we evaluated the peak ALT level for i.v. infections with different MHV doses and different pDC numbers (Figure 4B, right panel). If we define the ALT threshold for protection against severe disease to be 103 IU/L, then the host is protected against infection with physiological doses when the number of pDCs in spleen is unchanged (7×105) or 10-fold reduced. The protection is lost if spleen contains only 7×103 pDCs and the dose of infection is larger than 100 pfu. This suggests that the protection unit of pDCs () required to prevent severe disease after low dose infection is around 7×103 pDCs. Pre-activation of pDCs leads to a more efficient control of the infection-associated disease as shown in Figure 4C (right panel). The reduction in the total number of non-activated splenic pDCs strongly affects the severity of disease. However, rather modest pre-activation of as few as 200 pDCs leads to a reduction of peak ALT below the threshold of severe disease ().


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)

Effects of variation in pDC number and activation status.(A) Virus kinetics in spleen following infection with low (5×101 pfu), intermediate (5×103 pfu) and high (5×105 pfu) dose infections under conditions of varying pDC numbers per spleen. (B) Protection of splenic Mφs determined as percentage of infected Mφs (left panel) and disease severity determined as ALT levels serum (right panel) at 48 h post infection plotted against different doses of infection. For physiological infection doses, the normal number of pDCs (blue line) and 10-fold depleted population (green line) ensure protection of more than 90% of Mφs. Further decrease of pDC population to 7×103 cells is associated with large-scale infection of Mφs (red line). (C) Effect of pre-activation of pDCs in spleen on protection of splenic Mφs determined as percentage of infected cells (left panel) and disease severity determined as ALT levels in serum (right panel) at 48 h post infection (i.v. infection with 50 pfu). Numbers of pDCs per spleen were varied as indicated. (D) Effect of the number of pDCs in spleen on the ratio of locally produced versus eliminated virus (left panel) and on sink versus source function (right panel) after low (5×101 pfu), intermediate (5×103 pfu) and high (5×105 pfu) dose infection under conditions of varying pDC numbers per spleen.
© Copyright Policy
Related In: Results  -  Collection

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

ppat-1001017-g004: Effects of variation in pDC number and activation status.(A) Virus kinetics in spleen following infection with low (5×101 pfu), intermediate (5×103 pfu) and high (5×105 pfu) dose infections under conditions of varying pDC numbers per spleen. (B) Protection of splenic Mφs determined as percentage of infected Mφs (left panel) and disease severity determined as ALT levels serum (right panel) at 48 h post infection plotted against different doses of infection. For physiological infection doses, the normal number of pDCs (blue line) and 10-fold depleted population (green line) ensure protection of more than 90% of Mφs. Further decrease of pDC population to 7×103 cells is associated with large-scale infection of Mφs (red line). (C) Effect of pre-activation of pDCs in spleen on protection of splenic Mφs determined as percentage of infected cells (left panel) and disease severity determined as ALT levels in serum (right panel) at 48 h post infection (i.v. infection with 50 pfu). Numbers of pDCs per spleen were varied as indicated. (D) Effect of the number of pDCs in spleen on the ratio of locally produced versus eliminated virus (left panel) and on sink versus source function (right panel) after low (5×101 pfu), intermediate (5×103 pfu) and high (5×105 pfu) dose infection under conditions of varying pDC numbers per spleen.
Mentions: As a first step in the analytical modeling process, we examined the effect of pDC numbers and activation status on the protection of Mφs in spleen and the prevention of severe liver disease. As readout, i.e. the prediction of pDC performance criteria, we considered the maximum fraction of infected Mφs in spleen and the peak level of serum ALT during the first 48 hours post i.v. infection with various doses of MHV. As shown in Figure 4A, the decrease of the pDC population in spleen by 10-fold results in increased virus titers but still keeps virus growth under control. However, further depletion of pDCs leads to an overwhelming virus growth. Mφs in spleen represent about a 10-fold larger population of cells able to secrete MHV at a rate that is 10-times higher than pDCs. Therefore, protection of Mφs against the infection represents an important task that pDCs have to ensure. Indeed, antibody-mediated depletion of pDCs considerably increased infection of splenic Mφs (Figure S5). Figure 4B (left panel) shows the quantitative model predictions of how the fraction of infected Mφs in spleen depends on the number of pDCs and the dose of infection. Ten-fold reduction of pDCs in spleen still ensures that more than 90% of Mφs remain uninfected for low to intermediate infection doses. However, a further decrease of the pDC population breaks their ability to keep the number of infected Mφs below 10%. Because there is an inherent delay in activation of pDCs before the type I IFN secretion starts, we modeled the situation when a certain fraction of splenic pDCs is pre-activated at the start of the infection. Figure 4C (left panel) shows the predicted dependence of the infected Mφs on the number of pre-activated pDCs for MHV infection with 50 pfu. The results allowed us to quantify the upper limit for the protective capacity () of pDCs, if we define it as the ability to protect 90% of Mφs against infection. As few as 2000 activated pDCs suffice to protect 6×106 Mφs, which leads to the estimate of Mφ per pDC. To clarify how the pDCs in spleen contribute to control against severe disease, we evaluated the peak ALT level for i.v. infections with different MHV doses and different pDC numbers (Figure 4B, right panel). If we define the ALT threshold for protection against severe disease to be 103 IU/L, then the host is protected against infection with physiological doses when the number of pDCs in spleen is unchanged (7×105) or 10-fold reduced. The protection is lost if spleen contains only 7×103 pDCs and the dose of infection is larger than 100 pfu. This suggests that the protection unit of pDCs () required to prevent severe disease after low dose infection is around 7×103 pDCs. Pre-activation of pDCs leads to a more efficient control of the infection-associated disease as shown in Figure 4C (right panel). The reduction in the total number of non-activated splenic pDCs strongly affects the severity of disease. However, rather modest pre-activation of as few as 200 pDCs leads to a reduction of peak ALT below the threshold of severe disease ().

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