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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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Eigengenes in the kinetics of the VN1203-WT response, and MDS representations of the infected samples. (A) and (B) Profiles of the eigentranscripts and eigenproteins identified in dynamic of the host response to H5N1 VN1203 wild-type. Number of transcripts and proteins correlating with each eigentranscript and eigenprotein are indicated. All the individual shape represent the transcriptomic or proteomic profile of a mice lung infected by the VN1203 wild-type virus. Biological samples have been sorted by inoculation concentrations and then by increasing days post-infection. (C) and (D) Multidimensional Scaling representations of the transcriptomic and proteomic profiles of the H5N1 VN1203 wild-type infected samples. Each dot in the representations is the transcriptomic or proteomic profile of a biological sample plotted in the intensity space of expression signals. Pairwise distances between the dots are proportional to the transcriptomic or proteomic distances between the samples. Transcriptomic and proteomic distances have been calculated based on the signature of 5,660 transcripts and 162 proteins that significantly correlate with one eigentranscript or eigenprotein. Dots are colored in order to indicate the dosage conditions, and biological conditions are indicated by the convex hull of the set of biological replicates and labeled to indicate the time point post-infection. The Kruskal Stress shown in each representation quantifies the quality of the geometrical representation as a fraction of the information lost during the dimensionality reduction procedure. Schematic projections of the Magnitude and Velocity Coefficients are illustrated at 104 PFU in the transcriptomic MDS representation. The Magnitude Coefficient MC at 2 dpi – quantifying the transcriptomic distance between mocks and 2 dpi samples – is illustrated by a dashed red line, and the Velocity Coefficient (VC) at 4 dpi – measuring the velocity between 4 and 2 dpi samples divided by time – is illustrated by an arrow dashed red line.
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Figure 3: Eigengenes in the kinetics of the VN1203-WT response, and MDS representations of the infected samples. (A) and (B) Profiles of the eigentranscripts and eigenproteins identified in dynamic of the host response to H5N1 VN1203 wild-type. Number of transcripts and proteins correlating with each eigentranscript and eigenprotein are indicated. All the individual shape represent the transcriptomic or proteomic profile of a mice lung infected by the VN1203 wild-type virus. Biological samples have been sorted by inoculation concentrations and then by increasing days post-infection. (C) and (D) Multidimensional Scaling representations of the transcriptomic and proteomic profiles of the H5N1 VN1203 wild-type infected samples. Each dot in the representations is the transcriptomic or proteomic profile of a biological sample plotted in the intensity space of expression signals. Pairwise distances between the dots are proportional to the transcriptomic or proteomic distances between the samples. Transcriptomic and proteomic distances have been calculated based on the signature of 5,660 transcripts and 162 proteins that significantly correlate with one eigentranscript or eigenprotein. Dots are colored in order to indicate the dosage conditions, and biological conditions are indicated by the convex hull of the set of biological replicates and labeled to indicate the time point post-infection. The Kruskal Stress shown in each representation quantifies the quality of the geometrical representation as a fraction of the information lost during the dimensionality reduction procedure. Schematic projections of the Magnitude and Velocity Coefficients are illustrated at 104 PFU in the transcriptomic MDS representation. The Magnitude Coefficient MC at 2 dpi – quantifying the transcriptomic distance between mocks and 2 dpi samples – is illustrated by a dashed red line, and the Velocity Coefficient (VC) at 4 dpi – measuring the velocity between 4 and 2 dpi samples divided by time – is illustrated by an arrow dashed red line.

Mentions: We found a total of 5,660 transcripts that correlated with 3 main eigentranscripts (eigentranscript #1 contained 2,706 transcripts, eigentranscript #2 contained 2,826 transcripts, and eigentranscript #3 contained 128 transcripts). There were a total of 162 proteins that correlated with 3 main eigenproteins (eigenprotein #1 contained 59 proteins, eigenprotein #2 contained 86 proteins, and eigenprotein #3 contained 17 proteins). Additional file 3: Table S1 and Additional file 4: Table S2 provide the lists of transcripts and proteins associated with each eigentranscript and eigenprotein, respectively. The patterns of the eigentranscripts and eigenproteins identified in the VN1203-WT host response are represented in Figure 3A and B. Eigentranscript #2 was increasing over time, whereas eigentranscript #1 was decreasing over time. Eigentranscript #3 showed a distinct pattern with a transient decrease at 2 and 4 dpi, followed by an increase at 7 dpi. Eigenprotein #1 was increased in abundance over time. In brief, the dynamics of the transcriptomic and proteomic host response were captured by 3 sets of co-expressed transcripts and 3 sets of co-expressed proteins with different patterns of variations.


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)

Eigengenes in the kinetics of the VN1203-WT response, and MDS representations of the infected samples. (A) and (B) Profiles of the eigentranscripts and eigenproteins identified in dynamic of the host response to H5N1 VN1203 wild-type. Number of transcripts and proteins correlating with each eigentranscript and eigenprotein are indicated. All the individual shape represent the transcriptomic or proteomic profile of a mice lung infected by the VN1203 wild-type virus. Biological samples have been sorted by inoculation concentrations and then by increasing days post-infection. (C) and (D) Multidimensional Scaling representations of the transcriptomic and proteomic profiles of the H5N1 VN1203 wild-type infected samples. Each dot in the representations is the transcriptomic or proteomic profile of a biological sample plotted in the intensity space of expression signals. Pairwise distances between the dots are proportional to the transcriptomic or proteomic distances between the samples. Transcriptomic and proteomic distances have been calculated based on the signature of 5,660 transcripts and 162 proteins that significantly correlate with one eigentranscript or eigenprotein. Dots are colored in order to indicate the dosage conditions, and biological conditions are indicated by the convex hull of the set of biological replicates and labeled to indicate the time point post-infection. The Kruskal Stress shown in each representation quantifies the quality of the geometrical representation as a fraction of the information lost during the dimensionality reduction procedure. Schematic projections of the Magnitude and Velocity Coefficients are illustrated at 104 PFU in the transcriptomic MDS representation. The Magnitude Coefficient MC at 2 dpi – quantifying the transcriptomic distance between mocks and 2 dpi samples – is illustrated by a dashed red line, and the Velocity Coefficient (VC) at 4 dpi – measuring the velocity between 4 and 2 dpi samples divided by time – is illustrated by an arrow dashed red line.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
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Figure 3: Eigengenes in the kinetics of the VN1203-WT response, and MDS representations of the infected samples. (A) and (B) Profiles of the eigentranscripts and eigenproteins identified in dynamic of the host response to H5N1 VN1203 wild-type. Number of transcripts and proteins correlating with each eigentranscript and eigenprotein are indicated. All the individual shape represent the transcriptomic or proteomic profile of a mice lung infected by the VN1203 wild-type virus. Biological samples have been sorted by inoculation concentrations and then by increasing days post-infection. (C) and (D) Multidimensional Scaling representations of the transcriptomic and proteomic profiles of the H5N1 VN1203 wild-type infected samples. Each dot in the representations is the transcriptomic or proteomic profile of a biological sample plotted in the intensity space of expression signals. Pairwise distances between the dots are proportional to the transcriptomic or proteomic distances between the samples. Transcriptomic and proteomic distances have been calculated based on the signature of 5,660 transcripts and 162 proteins that significantly correlate with one eigentranscript or eigenprotein. Dots are colored in order to indicate the dosage conditions, and biological conditions are indicated by the convex hull of the set of biological replicates and labeled to indicate the time point post-infection. The Kruskal Stress shown in each representation quantifies the quality of the geometrical representation as a fraction of the information lost during the dimensionality reduction procedure. Schematic projections of the Magnitude and Velocity Coefficients are illustrated at 104 PFU in the transcriptomic MDS representation. The Magnitude Coefficient MC at 2 dpi – quantifying the transcriptomic distance between mocks and 2 dpi samples – is illustrated by a dashed red line, and the Velocity Coefficient (VC) at 4 dpi – measuring the velocity between 4 and 2 dpi samples divided by time – is illustrated by an arrow dashed red line.
Mentions: We found a total of 5,660 transcripts that correlated with 3 main eigentranscripts (eigentranscript #1 contained 2,706 transcripts, eigentranscript #2 contained 2,826 transcripts, and eigentranscript #3 contained 128 transcripts). There were a total of 162 proteins that correlated with 3 main eigenproteins (eigenprotein #1 contained 59 proteins, eigenprotein #2 contained 86 proteins, and eigenprotein #3 contained 17 proteins). Additional file 3: Table S1 and Additional file 4: Table S2 provide the lists of transcripts and proteins associated with each eigentranscript and eigenprotein, respectively. The patterns of the eigentranscripts and eigenproteins identified in the VN1203-WT host response are represented in Figure 3A and B. Eigentranscript #2 was increasing over time, whereas eigentranscript #1 was decreasing over time. Eigentranscript #3 showed a distinct pattern with a transient decrease at 2 and 4 dpi, followed by an increase at 7 dpi. Eigenprotein #1 was increased in abundance over time. In brief, the dynamics of the transcriptomic and proteomic host response were captured by 3 sets of co-expressed transcripts and 3 sets of co-expressed proteins with different patterns of variations.

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