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Host genetic background strongly influences the response to influenza a virus infections.

Srivastava B, Błazejewska P, Hessmann M, Bruder D, Geffers R, Mauel S, Gruber AD, Schughart K - PLoS ONE (2009)

Bottom Line: The genetic make-up of the host has a major influence on its response to combat pathogens.Two strains in particular, DBA/2J and A/J, showed very high susceptibility to viral infections compared to all other strains.These findings indicate a major contribution of the genetic background of the host to influenza A virus infections.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental Mouse Genetics, Helmholtz Centre for Infection Research & University of Veterinary Medicine Hannover, Braunschweig, Germany.

ABSTRACT
The genetic make-up of the host has a major influence on its response to combat pathogens. For influenza A virus, several single gene mutations have been described which contribute to survival, the immune response and clearance of the pathogen by the host organism. Here, we have studied the influence of the genetic background to influenza A H1N1 (PR8) and H7N7 (SC35M) viruses. The seven inbred laboratory strains of mice analyzed exhibited different weight loss kinetics and survival rates after infection with PR8. Two strains in particular, DBA/2J and A/J, showed very high susceptibility to viral infections compared to all other strains. The LD(50) to the influenza virus PR8 in DBA/2J mice was more than 1000-fold lower than in C57BL/6J mice. High susceptibility in DBA/2J mice was also observed after infection with influenza strain SC35M. In addition, infected DBA/2J mice showed a higher viral load in their lungs, elevated expression of cytokines and chemokines, and a more severe and extended lung pathology compared to infected C57BL/6J mice. These findings indicate a major contribution of the genetic background of the host to influenza A virus infections. The overall response in highly susceptible DBA/2J mice resembled the pathology described for infections with the highly virulent influenza H1N1-1918 and newly emerged H5N1 viruses.

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Higher viral load is detected in DBA/2J mice compared to C57BL/6J mice.DBA/2J and C57BL/6J mice were infected intra-nasally with 2×103 FFU and viral load was determined at the indicated times post inoculation for infectious particles measured by foci assay (A) or by copy number of viral hemagglutinin (HA) RNA (B). Mean +/− SEM are shown. For foci assay in (A), 9 DBA/2J mice were used at all time points, and for C57BL/6J, 6 mice were used at day1, 8 mice at day 2 and 9 mice at days 3, 4, and 8. For RNA assays in (B), 10 mice were used except 15 for day 4, and 5 for day 6. DBA/2J and C57BL/6J mice were compared for statistical significant differences using non-parametric Mann-Whitney-U-test. *: p value<0.05; **: p<0.01; ***: p value<0.001.
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pone-0004857-g006: Higher viral load is detected in DBA/2J mice compared to C57BL/6J mice.DBA/2J and C57BL/6J mice were infected intra-nasally with 2×103 FFU and viral load was determined at the indicated times post inoculation for infectious particles measured by foci assay (A) or by copy number of viral hemagglutinin (HA) RNA (B). Mean +/− SEM are shown. For foci assay in (A), 9 DBA/2J mice were used at all time points, and for C57BL/6J, 6 mice were used at day1, 8 mice at day 2 and 9 mice at days 3, 4, and 8. For RNA assays in (B), 10 mice were used except 15 for day 4, and 5 for day 6. DBA/2J and C57BL/6J mice were compared for statistical significant differences using non-parametric Mann-Whitney-U-test. *: p value<0.05; **: p<0.01; ***: p value<0.001.

Mentions: The extreme susceptibility of DBA/2J mice could be due to enhanced viral replication and associated tissue damage or a detrimental immunopathology of the host response, or both. Therefore, we analyzed viral loads by determining infectious particles and viral mRNA copies of the hemagglutinin (HA) gene in the lung. On days 1 and 2, the amount of infectious virus particles was about 100- and 80-fold higher in DBA/2J mice compared to C57BL/6J mice (figure 6A). This difference decreased to about 20 and 10-fold on days 3 and 4, respectively (figure 6A). In the surviving C57BL/6J mice, virus titers were below the level of detection at day 8 (figure 6A). Similarly, viral HA mRNA was between 5- and 9-fold higher in DBA/2J mice compared to C57BL/6J mice at days 1–3 and at day 6 (figure 6B). At day 4 after infection, this difference was less pronounced (2.6-fold) (figure 6B). The reduced virus replication in DBA/2J mice on days 4 and 6 was most probably due to the severe pathology in the lungs of these mice (see also histological studies) resulting in epithelial cell necrosis which does not allow any further increase in virus replication. In C57BL/6J mice, copy numbers of viral HA RNA decreased considerably after day 6 and were below the level of detection on day 14 (figure 6B).


Host genetic background strongly influences the response to influenza a virus infections.

Srivastava B, Błazejewska P, Hessmann M, Bruder D, Geffers R, Mauel S, Gruber AD, Schughart K - PLoS ONE (2009)

Higher viral load is detected in DBA/2J mice compared to C57BL/6J mice.DBA/2J and C57BL/6J mice were infected intra-nasally with 2×103 FFU and viral load was determined at the indicated times post inoculation for infectious particles measured by foci assay (A) or by copy number of viral hemagglutinin (HA) RNA (B). Mean +/− SEM are shown. For foci assay in (A), 9 DBA/2J mice were used at all time points, and for C57BL/6J, 6 mice were used at day1, 8 mice at day 2 and 9 mice at days 3, 4, and 8. For RNA assays in (B), 10 mice were used except 15 for day 4, and 5 for day 6. DBA/2J and C57BL/6J mice were compared for statistical significant differences using non-parametric Mann-Whitney-U-test. *: p value<0.05; **: p<0.01; ***: p value<0.001.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2654507&req=5

pone-0004857-g006: Higher viral load is detected in DBA/2J mice compared to C57BL/6J mice.DBA/2J and C57BL/6J mice were infected intra-nasally with 2×103 FFU and viral load was determined at the indicated times post inoculation for infectious particles measured by foci assay (A) or by copy number of viral hemagglutinin (HA) RNA (B). Mean +/− SEM are shown. For foci assay in (A), 9 DBA/2J mice were used at all time points, and for C57BL/6J, 6 mice were used at day1, 8 mice at day 2 and 9 mice at days 3, 4, and 8. For RNA assays in (B), 10 mice were used except 15 for day 4, and 5 for day 6. DBA/2J and C57BL/6J mice were compared for statistical significant differences using non-parametric Mann-Whitney-U-test. *: p value<0.05; **: p<0.01; ***: p value<0.001.
Mentions: The extreme susceptibility of DBA/2J mice could be due to enhanced viral replication and associated tissue damage or a detrimental immunopathology of the host response, or both. Therefore, we analyzed viral loads by determining infectious particles and viral mRNA copies of the hemagglutinin (HA) gene in the lung. On days 1 and 2, the amount of infectious virus particles was about 100- and 80-fold higher in DBA/2J mice compared to C57BL/6J mice (figure 6A). This difference decreased to about 20 and 10-fold on days 3 and 4, respectively (figure 6A). In the surviving C57BL/6J mice, virus titers were below the level of detection at day 8 (figure 6A). Similarly, viral HA mRNA was between 5- and 9-fold higher in DBA/2J mice compared to C57BL/6J mice at days 1–3 and at day 6 (figure 6B). At day 4 after infection, this difference was less pronounced (2.6-fold) (figure 6B). The reduced virus replication in DBA/2J mice on days 4 and 6 was most probably due to the severe pathology in the lungs of these mice (see also histological studies) resulting in epithelial cell necrosis which does not allow any further increase in virus replication. In C57BL/6J mice, copy numbers of viral HA RNA decreased considerably after day 6 and were below the level of detection on day 14 (figure 6B).

Bottom Line: The genetic make-up of the host has a major influence on its response to combat pathogens.Two strains in particular, DBA/2J and A/J, showed very high susceptibility to viral infections compared to all other strains.These findings indicate a major contribution of the genetic background of the host to influenza A virus infections.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental Mouse Genetics, Helmholtz Centre for Infection Research & University of Veterinary Medicine Hannover, Braunschweig, Germany.

ABSTRACT
The genetic make-up of the host has a major influence on its response to combat pathogens. For influenza A virus, several single gene mutations have been described which contribute to survival, the immune response and clearance of the pathogen by the host organism. Here, we have studied the influence of the genetic background to influenza A H1N1 (PR8) and H7N7 (SC35M) viruses. The seven inbred laboratory strains of mice analyzed exhibited different weight loss kinetics and survival rates after infection with PR8. Two strains in particular, DBA/2J and A/J, showed very high susceptibility to viral infections compared to all other strains. The LD(50) to the influenza virus PR8 in DBA/2J mice was more than 1000-fold lower than in C57BL/6J mice. High susceptibility in DBA/2J mice was also observed after infection with influenza strain SC35M. In addition, infected DBA/2J mice showed a higher viral load in their lungs, elevated expression of cytokines and chemokines, and a more severe and extended lung pathology compared to infected C57BL/6J mice. These findings indicate a major contribution of the genetic background of the host to influenza A virus infections. The overall response in highly susceptible DBA/2J mice resembled the pathology described for infections with the highly virulent influenza H1N1-1918 and newly emerged H5N1 viruses.

Show MeSH
Related in: MedlinePlus