Figure 1.
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.
Figure 2.
MHV infection and IFN response kinetics in vitro.
Experimental data (open symbols) represent the geometric mean ±SEM. Virus titers (red), IFN-α concentration (green) and the fraction of live cells out of the total initial target cell number (black) were used to calibrate the model. (A) In vitro MHV infection of pDCs (MOI = 1). Fraction of infected cells in the population of live cells is shown in blue. (B) MHV infection in pDCs derived from ifnar−/− mice. Fraction of infected cells in the population of live cells is shown in blue. Experimental validation had been performed using infection of pDCs with EGFP-recombinant MHV (blue circles). (C) MHV replication in wild-type Mφs. The data on the amount of secreted IFN-α were used to validate the calibrated model (green circles). (D) Effect of IFN pre-treatment (500 IU of IFN-α, green line) on MHV replication in wt Mφs.
Table 1.
Best-fit parameter values for in vitro and in vivo MHV infection of pDC and Mφ and the corresponding 95% confidence intervals.
Figure 3.
Systemic dynamics of MHV infection in mice.
Experimental determination of virus kinetics in (A) spleen, (B) liver and (C) blood, and (D) ALT levels in serum following i.v. infection with MHV at intermediate (5×103 pfu) and high (5×105 pfu) doses (symbols). The mathematical model (solid lines) integrates the detailed virus-target cell kinetics and IFN response in spleen with compartmental virus dynamics in blood and liver.
Table 2.
Parameter estimates for a systemic spread of MHV in the anatomical compartments and 99% confidence intervals.
Figure 4.
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.
Figure 5.
Effect of type I IFN secretion rate on protection against disease.
(A) Kinetics of MHV in spleen (upper row) and liver (middle row), and impact on disease severity (bottom row) for normal (solid line), 10-fold reduced (broken line) or 100-fold (dotted line) reduced IFN secretion rate by pDCs after low (5×101 pfu), intermediate (5×103 pfu) and high (5×105 pfu) dose infection. (B) Dependence of peak virus titers in spleen (B) and liver (C) after infection with the indicated doses on the relative reduction rate of IFN secretion rate by pDCs at 48 h post infection (i.v. infection with indicated doses). (D) Disease severity determined as ALT levels in serum at 48 h post infection (i.v. infection with indicated doses) depending on the relative reduction rate of IFN secretion rate by pDCs.
Figure 6.
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).