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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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Profiles of Magnitude Coefficients and Velocity Coefficients for the different viruses and dosage conditions. (A) Variation of Magnitude Coefficients over time for the different viruses. (B) Variation of Velocity Coefficients over time for the different viruses. Profiles are colored by viral strain and line types represent the different doses. The Magnitude Coefficient (MC) quantifies the magnitude effect as the transcriptomic or proteomic distance from one biological condition to the matched mock-infected condition. The Velocity Coefficient (VC) quantifies the velocity effect as the speed of the transcriptomic host response to move from one time point to the next one. Both the MC and VC were calculated based on the centroids of the biological conditions and the transcriptomic or proteomic distances are calculated based on the lists of transcripts associated with the kinetics of the host response to VN1203 wild-type.
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Figure 4: Profiles of Magnitude Coefficients and Velocity Coefficients for the different viruses and dosage conditions. (A) Variation of Magnitude Coefficients over time for the different viruses. (B) Variation of Velocity Coefficients over time for the different viruses. Profiles are colored by viral strain and line types represent the different doses. The Magnitude Coefficient (MC) quantifies the magnitude effect as the transcriptomic or proteomic distance from one biological condition to the matched mock-infected condition. The Velocity Coefficient (VC) quantifies the velocity effect as the speed of the transcriptomic host response to move from one time point to the next one. Both the MC and VC were calculated based on the centroids of the biological conditions and the transcriptomic or proteomic distances are calculated based on the lists of transcripts associated with the kinetics of the host response to VN1203 wild-type.

Mentions: In order to quantify these magnitude and velocity effects in the kinetics of the host response, we defined two criteria, the Magnitude Coefficient (MC) and the Velocity Coefficient (VC). The MC quantifies the magnitude effect as the transcriptomic distance from one biological condition to the matched mock-infected condition. The VC quantifies the velocity effect as the speed of the transcriptomic host response moving from one time point to the next in the succession of infection. Both the MC and VC were calculated based on the centroids (arithmetic means) of the biological conditions and the transcriptomic distances (Euclidean distances) based on the signatures of transcripts associated with the kinetics of the host response to VN1203-WT (Additional file 5: Table S3, Figure 4). MC and VC were calculated only for the transcriptomic data, as we were unable to discriminate proteomic samples at early time-points (1 and 2 dpi), resulting in a lack of sensitivity for the analysis. We first observed that increasing the inoculation dose was related to an increase in magnitude of the host response. Indeed, at each dpi, infection with 102 PFU triggered a lower MC compared to 103 PFU, while 104 PFU triggered the strongest MC. Moreover, different inoculation dosages also resulted in different velocities of the host response changes. With regards to time, the greatest transcriptomic VC difference was found at 2 dpi, followed by the difference quantified between 1 and 2 dpi. With regards to dosage, the lowest transcriptomic VC coefficient difference was found for 102 PFU and the greatest transcriptomic VC coefficient difference was found for 104 PFU.


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)

Profiles of Magnitude Coefficients and Velocity Coefficients for the different viruses and dosage conditions. (A) Variation of Magnitude Coefficients over time for the different viruses. (B) Variation of Velocity Coefficients over time for the different viruses. Profiles are colored by viral strain and line types represent the different doses. The Magnitude Coefficient (MC) quantifies the magnitude effect as the transcriptomic or proteomic distance from one biological condition to the matched mock-infected condition. The Velocity Coefficient (VC) quantifies the velocity effect as the speed of the transcriptomic host response to move from one time point to the next one. Both the MC and VC were calculated based on the centroids of the biological conditions and the transcriptomic or proteomic distances are calculated based on the lists of transcripts associated with the kinetics of the host response to VN1203 wild-type.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Profiles of Magnitude Coefficients and Velocity Coefficients for the different viruses and dosage conditions. (A) Variation of Magnitude Coefficients over time for the different viruses. (B) Variation of Velocity Coefficients over time for the different viruses. Profiles are colored by viral strain and line types represent the different doses. The Magnitude Coefficient (MC) quantifies the magnitude effect as the transcriptomic or proteomic distance from one biological condition to the matched mock-infected condition. The Velocity Coefficient (VC) quantifies the velocity effect as the speed of the transcriptomic host response to move from one time point to the next one. Both the MC and VC were calculated based on the centroids of the biological conditions and the transcriptomic or proteomic distances are calculated based on the lists of transcripts associated with the kinetics of the host response to VN1203 wild-type.
Mentions: In order to quantify these magnitude and velocity effects in the kinetics of the host response, we defined two criteria, the Magnitude Coefficient (MC) and the Velocity Coefficient (VC). The MC quantifies the magnitude effect as the transcriptomic distance from one biological condition to the matched mock-infected condition. The VC quantifies the velocity effect as the speed of the transcriptomic host response moving from one time point to the next in the succession of infection. Both the MC and VC were calculated based on the centroids (arithmetic means) of the biological conditions and the transcriptomic distances (Euclidean distances) based on the signatures of transcripts associated with the kinetics of the host response to VN1203-WT (Additional file 5: Table S3, Figure 4). MC and VC were calculated only for the transcriptomic data, as we were unable to discriminate proteomic samples at early time-points (1 and 2 dpi), resulting in a lack of sensitivity for the analysis. We first observed that increasing the inoculation dose was related to an increase in magnitude of the host response. Indeed, at each dpi, infection with 102 PFU triggered a lower MC compared to 103 PFU, while 104 PFU triggered the strongest MC. Moreover, different inoculation dosages also resulted in different velocities of the host response changes. With regards to time, the greatest transcriptomic VC difference was found at 2 dpi, followed by the difference quantified between 1 and 2 dpi. With regards to dosage, the lowest transcriptomic VC coefficient difference was found for 102 PFU and the greatest transcriptomic VC coefficient difference was found for 104 PFU.

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