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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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MLD and phenotypical variables collected for all viruses at the 104 PFU infection dosage. (A) Median lethal dose (MLD) values of the different viruses in 6-week-old BALB/c mice. MLD values for VN1203 and mutants were performed in one experiment (3 mice per inoculation dosage), and the previously calculated MLD for CA04 is included for comparison [22]. (B) Mice body weight measurements collected each day from 1 to 7 days post-infection for the 104 PFU infection dosages. For each virus and time point, the mean and the standard deviation of the mice body weight measurements are indicated by a vertical bar. (C), (D) and (E) Viral titer, viral messenger RNA, and viral genomic RNA measurements collected at 1, 2, 4 and 7 days post-infection for the 104 PFU infection dosages. For each virus and time point the set of individual measurements are indicated by filled dots and the mean amongst the individual samples is indicated by a horizontal bar. For the experiments shown in panels B-E, four to five mice were used for all VN1203-WT and pathogenicity mutant infections, while 3–4 mice were used for the CA04 infections. The same animals were used to derive all the phenotypical data (i.e. weight loss, virus titer and virus mRNA/genomic RNA levels).
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Figure 1: MLD and phenotypical variables collected for all viruses at the 104 PFU infection dosage. (A) Median lethal dose (MLD) values of the different viruses in 6-week-old BALB/c mice. MLD values for VN1203 and mutants were performed in one experiment (3 mice per inoculation dosage), and the previously calculated MLD for CA04 is included for comparison [22]. (B) Mice body weight measurements collected each day from 1 to 7 days post-infection for the 104 PFU infection dosages. For each virus and time point, the mean and the standard deviation of the mice body weight measurements are indicated by a vertical bar. (C), (D) and (E) Viral titer, viral messenger RNA, and viral genomic RNA measurements collected at 1, 2, 4 and 7 days post-infection for the 104 PFU infection dosages. For each virus and time point the set of individual measurements are indicated by filled dots and the mean amongst the individual samples is indicated by a horizontal bar. For the experiments shown in panels B-E, four to five mice were used for all VN1203-WT and pathogenicity mutant infections, while 3–4 mice were used for the CA04 infections. The same animals were used to derive all the phenotypical data (i.e. weight loss, virus titer and virus mRNA/genomic RNA levels).

Mentions: The different viruses can be ranked based on their pathogenicity as determined by Median Lethal Dose (MLD) values in 6-week-old BALB/c mice (Figure 1A). The VN1203-WT (MLD < 1 PFU) and the VN1203-PB1F2del (MLD = 3.2 PFU) viruses were associated with the highest level of pathogenicity. The CA04-WT (MLD = 630,957 PFU; previously determined [22]) and the VN1203-HAavir (MLD = 316,228 PFU) viruses were associated with the lowest level of pathogenicity. The VN1203-NS1trunc (MLD = 631 PFU) and the VN1203-PB2627E (MLD = 6,310 PFU) viruses showed an intermediate level of pathogenicity.


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)

MLD and phenotypical variables collected for all viruses at the 104 PFU infection dosage. (A) Median lethal dose (MLD) values of the different viruses in 6-week-old BALB/c mice. MLD values for VN1203 and mutants were performed in one experiment (3 mice per inoculation dosage), and the previously calculated MLD for CA04 is included for comparison [22]. (B) Mice body weight measurements collected each day from 1 to 7 days post-infection for the 104 PFU infection dosages. For each virus and time point, the mean and the standard deviation of the mice body weight measurements are indicated by a vertical bar. (C), (D) and (E) Viral titer, viral messenger RNA, and viral genomic RNA measurements collected at 1, 2, 4 and 7 days post-infection for the 104 PFU infection dosages. For each virus and time point the set of individual measurements are indicated by filled dots and the mean amongst the individual samples is indicated by a horizontal bar. For the experiments shown in panels B-E, four to five mice were used for all VN1203-WT and pathogenicity mutant infections, while 3–4 mice were used for the CA04 infections. The same animals were used to derive all the phenotypical data (i.e. weight loss, virus titer and virus mRNA/genomic RNA levels).
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3750405&req=5

Figure 1: MLD and phenotypical variables collected for all viruses at the 104 PFU infection dosage. (A) Median lethal dose (MLD) values of the different viruses in 6-week-old BALB/c mice. MLD values for VN1203 and mutants were performed in one experiment (3 mice per inoculation dosage), and the previously calculated MLD for CA04 is included for comparison [22]. (B) Mice body weight measurements collected each day from 1 to 7 days post-infection for the 104 PFU infection dosages. For each virus and time point, the mean and the standard deviation of the mice body weight measurements are indicated by a vertical bar. (C), (D) and (E) Viral titer, viral messenger RNA, and viral genomic RNA measurements collected at 1, 2, 4 and 7 days post-infection for the 104 PFU infection dosages. For each virus and time point the set of individual measurements are indicated by filled dots and the mean amongst the individual samples is indicated by a horizontal bar. For the experiments shown in panels B-E, four to five mice were used for all VN1203-WT and pathogenicity mutant infections, while 3–4 mice were used for the CA04 infections. The same animals were used to derive all the phenotypical data (i.e. weight loss, virus titer and virus mRNA/genomic RNA levels).
Mentions: The different viruses can be ranked based on their pathogenicity as determined by Median Lethal Dose (MLD) values in 6-week-old BALB/c mice (Figure 1A). The VN1203-WT (MLD < 1 PFU) and the VN1203-PB1F2del (MLD = 3.2 PFU) viruses were associated with the highest level of pathogenicity. The CA04-WT (MLD = 630,957 PFU; previously determined [22]) and the VN1203-HAavir (MLD = 316,228 PFU) viruses were associated with the lowest level of pathogenicity. The VN1203-NS1trunc (MLD = 631 PFU) and the VN1203-PB2627E (MLD = 6,310 PFU) viruses showed an intermediate level of pathogenicity.

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