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Exploring cell tropism as a possible contributor to influenza infection severity.

Dobrovolny HM, Baron MJ, Gieschke R, Davies BE, Jumbe NL, Beauchemin CA - PLoS ONE (2010)

Bottom Line: Several mechanisms have been proposed to account for the marked increase in severity of human infections with avian compared to human influenza strains, including increased cytokine expression, poor immune response, and differences in target cell receptor affinity.Here, the potential effect of target cell tropism on disease severity is studied using a mathematical model for in-host influenza viral infection in a cell population consisting of two different cell types.This finding suggests that differences in cell tropism between influenza strains could be sufficient to cause significant differences in viral titer profiles, similar to those observed in infections with certain strains of influenza A virus.

View Article: PubMed Central - PubMed

Affiliation: Department of Physics, Ryerson University, Toronto, Ontario, Canada.

ABSTRACT
Several mechanisms have been proposed to account for the marked increase in severity of human infections with avian compared to human influenza strains, including increased cytokine expression, poor immune response, and differences in target cell receptor affinity. Here, the potential effect of target cell tropism on disease severity is studied using a mathematical model for in-host influenza viral infection in a cell population consisting of two different cell types. The two cell types differ only in their susceptibility to infection and rate of virus production. We show the existence of a parameter regime which is characterized by high viral loads sustained long after the onset of infection. This finding suggests that differences in cell tropism between influenza strains could be sufficient to cause significant differences in viral titer profiles, similar to those observed in infections with certain strains of influenza A virus. The two target cell mathematical model offers good agreement with experimental data from severe influenza infections, as does the usual, single target cell model albeit with biologically unrealistic parameters. Both models predict that while neuraminidase inhibitors and adamantanes are only effective when administered early to treat an uncomplicated seasonal infection, they can be effective against more severe influenza infections even when administered late.

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Model parameter fits to experimental influenza infection in mice.Results of parameter fits of the single target cell (solid line) and two target cell (dashed line) eclipse model to human-strain (A/Texas/36/1991 and A/1918) and avian-strain (A/Thai/SP/83/2004 and A/Thai/16/2004) influenza infections in mice. The percentage of cells expressing the SA2,6 Gal receptor, , is fixed to 10%, and the best fit parameters are presented in Table 2. For the single target cell model, the SSRs are (from left to right and top to bottom) 0.45, 2.8, 7.8, and 3.3 while the  are −35, −72, −56, and −71. For the two target cell model, the SSRs are 0.29, 2.1, 2.3, and 7.4 while the  are −32, −240, −56, and −74. Data is taken from [52].
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pone-0013811-g004: Model parameter fits to experimental influenza infection in mice.Results of parameter fits of the single target cell (solid line) and two target cell (dashed line) eclipse model to human-strain (A/Texas/36/1991 and A/1918) and avian-strain (A/Thai/SP/83/2004 and A/Thai/16/2004) influenza infections in mice. The percentage of cells expressing the SA2,6 Gal receptor, , is fixed to 10%, and the best fit parameters are presented in Table 2. For the single target cell model, the SSRs are (from left to right and top to bottom) 0.45, 2.8, 7.8, and 3.3 while the are −35, −72, −56, and −71. For the two target cell model, the SSRs are 0.29, 2.1, 2.3, and 7.4 while the are −32, −240, −56, and −74. Data is taken from [52].

Mentions: Figure 4 shows our model fits to influenza infections in mice, with the solid line indicating the best fit for the single target cell model and the dashed line indicating the best fit for the two target cell model. Parameters for the best fits are given in Table 2. Visually, it appears that both models can adequately capture the dynamics of both human- and avian-strain influenza infections in mice. While the SSR are always smaller for the two target cell models because it has two additional free parameters, the are comparable between the two models suggesting that the two target cell model is equally well supported by the experimental data despite its additional parameters.


Exploring cell tropism as a possible contributor to influenza infection severity.

Dobrovolny HM, Baron MJ, Gieschke R, Davies BE, Jumbe NL, Beauchemin CA - PLoS ONE (2010)

Model parameter fits to experimental influenza infection in mice.Results of parameter fits of the single target cell (solid line) and two target cell (dashed line) eclipse model to human-strain (A/Texas/36/1991 and A/1918) and avian-strain (A/Thai/SP/83/2004 and A/Thai/16/2004) influenza infections in mice. The percentage of cells expressing the SA2,6 Gal receptor, , is fixed to 10%, and the best fit parameters are presented in Table 2. For the single target cell model, the SSRs are (from left to right and top to bottom) 0.45, 2.8, 7.8, and 3.3 while the  are −35, −72, −56, and −71. For the two target cell model, the SSRs are 0.29, 2.1, 2.3, and 7.4 while the  are −32, −240, −56, and −74. Data is taken from [52].
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2990709&req=5

pone-0013811-g004: Model parameter fits to experimental influenza infection in mice.Results of parameter fits of the single target cell (solid line) and two target cell (dashed line) eclipse model to human-strain (A/Texas/36/1991 and A/1918) and avian-strain (A/Thai/SP/83/2004 and A/Thai/16/2004) influenza infections in mice. The percentage of cells expressing the SA2,6 Gal receptor, , is fixed to 10%, and the best fit parameters are presented in Table 2. For the single target cell model, the SSRs are (from left to right and top to bottom) 0.45, 2.8, 7.8, and 3.3 while the are −35, −72, −56, and −71. For the two target cell model, the SSRs are 0.29, 2.1, 2.3, and 7.4 while the are −32, −240, −56, and −74. Data is taken from [52].
Mentions: Figure 4 shows our model fits to influenza infections in mice, with the solid line indicating the best fit for the single target cell model and the dashed line indicating the best fit for the two target cell model. Parameters for the best fits are given in Table 2. Visually, it appears that both models can adequately capture the dynamics of both human- and avian-strain influenza infections in mice. While the SSR are always smaller for the two target cell models because it has two additional free parameters, the are comparable between the two models suggesting that the two target cell model is equally well supported by the experimental data despite its additional parameters.

Bottom Line: Several mechanisms have been proposed to account for the marked increase in severity of human infections with avian compared to human influenza strains, including increased cytokine expression, poor immune response, and differences in target cell receptor affinity.Here, the potential effect of target cell tropism on disease severity is studied using a mathematical model for in-host influenza viral infection in a cell population consisting of two different cell types.This finding suggests that differences in cell tropism between influenza strains could be sufficient to cause significant differences in viral titer profiles, similar to those observed in infections with certain strains of influenza A virus.

View Article: PubMed Central - PubMed

Affiliation: Department of Physics, Ryerson University, Toronto, Ontario, Canada.

ABSTRACT
Several mechanisms have been proposed to account for the marked increase in severity of human infections with avian compared to human influenza strains, including increased cytokine expression, poor immune response, and differences in target cell receptor affinity. Here, the potential effect of target cell tropism on disease severity is studied using a mathematical model for in-host influenza viral infection in a cell population consisting of two different cell types. The two cell types differ only in their susceptibility to infection and rate of virus production. We show the existence of a parameter regime which is characterized by high viral loads sustained long after the onset of infection. This finding suggests that differences in cell tropism between influenza strains could be sufficient to cause significant differences in viral titer profiles, similar to those observed in infections with certain strains of influenza A virus. The two target cell mathematical model offers good agreement with experimental data from severe influenza infections, as does the usual, single target cell model albeit with biologically unrealistic parameters. Both models predict that while neuraminidase inhibitors and adamantanes are only effective when administered early to treat an uncomplicated seasonal infection, they can be effective against more severe influenza infections even when administered late.

Show MeSH
Related in: MedlinePlus