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Specific mutations in H5N1 mainly impact the magnitude and velocity of the host response in mice.

Tchitchek N, Eisfeld AJ, Tisoncik-Go J, Josset L, Gralinski LE, Bécavin C, Tilton SC, Webb-Robertson BJ, Ferris MT, Totura AL, Li C, Neumann G, Metz TO, Smith RD, Waters KM, Baric R, Kawaoka Y, Katze MG - BMC Syst Biol (2013)

Bottom Line: Using a new geometrical representation method and two criteria, we show that inoculation concentrations and four specific mutations in VN1203 mainly impact the magnitude and velocity of the host response kinetics, rather than specific sets of up- and down- regulated genes.These kinetic properties imply that time-matched comparisons of 'omics profiles to viral infections give limited views to differentiate host-responses.Moreover, these results demonstrate that a fast activation of the host-response at the earliest time points post-infection is critical for protective mechanisms against fast replicating viruses.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Microbiology, University of Washington, Seattle, WA 98195 USA.

ABSTRACT

Background: Influenza infection causes respiratory disease that can lead to death. The complex interplay between virus-encoded and host-specific pathogenicity regulators - and the relative contributions of each toward viral pathogenicity - is not well-understood.

Results: By analyzing a collection of lung samples from mice infected by A/Vietnam/1203/2004 (H5N1; VN1203), we characterized a signature of transcripts and proteins associated with the kinetics of the host response. Using a new geometrical representation method and two criteria, we show that inoculation concentrations and four specific mutations in VN1203 mainly impact the magnitude and velocity of the host response kinetics, rather than specific sets of up- and down- regulated genes. We observed analogous kinetic effects using lung samples from mice infected with A/California/04/2009 (H1N1), and we show that these effects correlate with morbidity and viral titer.

Conclusions: We have demonstrated the importance of the kinetics of the host response to H5N1 pathogenesis and its relationship with clinical disease severity and virus replication. These kinetic properties imply that time-matched comparisons of 'omics profiles to viral infections give limited views to differentiate host-responses. Moreover, these results demonstrate that a fast activation of the host-response at the earliest time points post-infection is critical for protective mechanisms against fast replicating viruses.

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Spearman’s coefficients between MC and body weight, and between VC and titer changes. (A) Scatter plot between the Magnitude Coefficients and the mice body weight loss measurements. (B) Scatter plot between the Velocity Coefficients and the changes in viral titer measurements at the previous time-point. Each dot represents a couple of values for a single biological condition and is colored in order to indicate the viral strain according to the nomenclature of Figure 1. For each scatter plot the Spearman’s coefficient of correlation is indicated as well as the associated p-value.
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Figure 6: Spearman’s coefficients between MC and body weight, and between VC and titer changes. (A) Scatter plot between the Magnitude Coefficients and the mice body weight loss measurements. (B) Scatter plot between the Velocity Coefficients and the changes in viral titer measurements at the previous time-point. Each dot represents a couple of values for a single biological condition and is colored in order to indicate the viral strain according to the nomenclature of Figure 1. For each scatter plot the Spearman’s coefficient of correlation is indicated as well as the associated p-value.

Mentions: To determine whether the VC and MC were related to disease outcome and viral pathogenicity, we performed a correlation analysis between these coefficients and the phenotypic variables. All biological conditions were considered together in these analyses to assess the correlations with a large significance. For each biological condition, we determined the mean body weight of the animals, viral titer, viral messenger RNA and viral genomic RNA measurements in the lung, and calculated the difference between the means of any two consecutive time-points for viral titer (Δ mean viral titer), viral RNA (Δ mean viral mRNA), and viral genomic RNA (Δ mean viral gRNA). For each transcriptomic biological condition the associated MC, VC, mean body weight, Δ mean viral titer, Δ mean viral mRNA, and Δ mean viral gRNA values are shown in Additional file 5: Table S3. A significant association was found between MC and mean body weight (Spearman’s rho = −0.7984), suggesting that the magnitude of host response is significantly associated with morbidity (Figure 6A). The VC was not significantly associated with any criteria when considering phenotypic variables within a given time-point; however, the VC was significantly associated with Δ mean viral titer (Spearman’s rho= 0.8459, Figure 6B), Δ mean viral mRNA (rho =0.8544), and Δ mean viral gRNA (rho =0.8426) at the previous time-point. This suggests that the velocity of the host response can be predicted by changes in viral replication at the preceding time-point.


Specific mutations in H5N1 mainly impact the magnitude and velocity of the host response in mice.

Tchitchek N, Eisfeld AJ, Tisoncik-Go J, Josset L, Gralinski LE, Bécavin C, Tilton SC, Webb-Robertson BJ, Ferris MT, Totura AL, Li C, Neumann G, Metz TO, Smith RD, Waters KM, Baric R, Kawaoka Y, Katze MG - BMC Syst Biol (2013)

Spearman’s coefficients between MC and body weight, and between VC and titer changes. (A) Scatter plot between the Magnitude Coefficients and the mice body weight loss measurements. (B) Scatter plot between the Velocity Coefficients and the changes in viral titer measurements at the previous time-point. Each dot represents a couple of values for a single biological condition and is colored in order to indicate the viral strain according to the nomenclature of Figure 1. For each scatter plot the Spearman’s coefficient of correlation is indicated as well as the associated p-value.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3750405&req=5

Figure 6: Spearman’s coefficients between MC and body weight, and between VC and titer changes. (A) Scatter plot between the Magnitude Coefficients and the mice body weight loss measurements. (B) Scatter plot between the Velocity Coefficients and the changes in viral titer measurements at the previous time-point. Each dot represents a couple of values for a single biological condition and is colored in order to indicate the viral strain according to the nomenclature of Figure 1. For each scatter plot the Spearman’s coefficient of correlation is indicated as well as the associated p-value.
Mentions: To determine whether the VC and MC were related to disease outcome and viral pathogenicity, we performed a correlation analysis between these coefficients and the phenotypic variables. All biological conditions were considered together in these analyses to assess the correlations with a large significance. For each biological condition, we determined the mean body weight of the animals, viral titer, viral messenger RNA and viral genomic RNA measurements in the lung, and calculated the difference between the means of any two consecutive time-points for viral titer (Δ mean viral titer), viral RNA (Δ mean viral mRNA), and viral genomic RNA (Δ mean viral gRNA). For each transcriptomic biological condition the associated MC, VC, mean body weight, Δ mean viral titer, Δ mean viral mRNA, and Δ mean viral gRNA values are shown in Additional file 5: Table S3. A significant association was found between MC and mean body weight (Spearman’s rho = −0.7984), suggesting that the magnitude of host response is significantly associated with morbidity (Figure 6A). The VC was not significantly associated with any criteria when considering phenotypic variables within a given time-point; however, the VC was significantly associated with Δ mean viral titer (Spearman’s rho= 0.8459, Figure 6B), Δ mean viral mRNA (rho =0.8544), and Δ mean viral gRNA (rho =0.8426) at the previous time-point. This suggests that the velocity of the host response can be predicted by changes in viral replication at the preceding time-point.

Bottom Line: Using a new geometrical representation method and two criteria, we show that inoculation concentrations and four specific mutations in VN1203 mainly impact the magnitude and velocity of the host response kinetics, rather than specific sets of up- and down- regulated genes.These kinetic properties imply that time-matched comparisons of 'omics profiles to viral infections give limited views to differentiate host-responses.Moreover, these results demonstrate that a fast activation of the host-response at the earliest time points post-infection is critical for protective mechanisms against fast replicating viruses.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Microbiology, University of Washington, Seattle, WA 98195 USA.

ABSTRACT

Background: Influenza infection causes respiratory disease that can lead to death. The complex interplay between virus-encoded and host-specific pathogenicity regulators - and the relative contributions of each toward viral pathogenicity - is not well-understood.

Results: By analyzing a collection of lung samples from mice infected by A/Vietnam/1203/2004 (H5N1; VN1203), we characterized a signature of transcripts and proteins associated with the kinetics of the host response. Using a new geometrical representation method and two criteria, we show that inoculation concentrations and four specific mutations in VN1203 mainly impact the magnitude and velocity of the host response kinetics, rather than specific sets of up- and down- regulated genes. We observed analogous kinetic effects using lung samples from mice infected with A/California/04/2009 (H1N1), and we show that these effects correlate with morbidity and viral titer.

Conclusions: We have demonstrated the importance of the kinetics of the host response to H5N1 pathogenesis and its relationship with clinical disease severity and virus replication. These kinetic properties imply that time-matched comparisons of 'omics profiles to viral infections give limited views to differentiate host-responses. Moreover, these results demonstrate that a fast activation of the host-response at the earliest time points post-infection is critical for protective mechanisms against fast replicating viruses.

Show MeSH
Related in: MedlinePlus