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Oseltamivir-resistant pandemic A/H1N1 virus is as virulent as its wild-type counterpart in mice and ferrets.

Hamelin ME, Baz M, Abed Y, Couture C, Joubert P, Beaulieu E, Bellerose N, Plante M, Mallett C, Schumer G, Kobinger GP, Boivin G - PLoS Pathog. (2010)

Bottom Line: Such increased levels of IL-6 were also observed in lymph nodes of ferrets infected with the mutant strain.Furthermore, the H274Y mutant strain was transmitted to ferrets.In conclusion, viral fitness of the H274Y pH1N1 isolate is not substantially altered and has the potential to induce severe disease and to disseminate.

View Article: PubMed Central - PubMed

Affiliation: CHUQ-CHUL Research Center in Infectious Diseases and Laval University, Québec City, Québec, Canada.

ABSTRACT
The neuraminidase inhibitor oseltamivir is currently used for treatment of patients infected with the pandemic A/H1N1 (pH1N1) influenza virus, although drug-resistant mutants can emerge rapidly and possibly be transmitted. We describe the characteristics of a pair of oseltamivir-resistant and oseltamivir-susceptible pH1N1 clinical isolates that differed by a single change (H274Y) in the neuraminidase protein. Viral fitness of pH1N1 isolates was assessed in vitro by determining replication kinetics in MDCK alpha2,6 cells and in vivo by performing experimental infections of BALB/c mice and ferrets. Despite slightly reduced propagation of the mutant isolate in vitro during the first 24 h, the wild-type (WT) and mutant resistant viruses induced similar maximum weight loss in mice and ferrets with an identical pyrexic response in ferrets (AUC of 233.9 and 233.2, P = 0.5156). Similarly, comparable titers were obtained for the WT and the mutant strains on days 1, 3, 6 and 9 post-infection in mouse lungs and on days 1-7 in ferret nasal washes. A more important perivascular (day 6) and pleural (days 6 and 12) inflammation was noted in the lungs of mice infected with the H274Y mutant, which correlated with increased pulmonary levels of IL-6 and KC. Such increased levels of IL-6 were also observed in lymph nodes of ferrets infected with the mutant strain. Furthermore, the H274Y mutant strain was transmitted to ferrets. In conclusion, viral fitness of the H274Y pH1N1 isolate is not substantially altered and has the potential to induce severe disease and to disseminate.

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Related in: MedlinePlus

Lung histopathology of mice infected with wild-type (WT) or H274Y mutant isolates of pH1N1.Groups of mice were euthanized on days 3, 6 and 12 post-infection and one pulmonary lobe was removed and fixed with 10% formalin. Thin sections of paraffin-embedded lung tissues were cut and stained with hematoxylin and eosin. The degree of lung inflammation (mean histopathological score) was evaluated for bronchial, peribronchial, perivascular, interstitial, pleural and intra-alveolar inflammation. * P<0.05 between the WT and H274Y lung histopathological scores.
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ppat-1001015-g005: Lung histopathology of mice infected with wild-type (WT) or H274Y mutant isolates of pH1N1.Groups of mice were euthanized on days 3, 6 and 12 post-infection and one pulmonary lobe was removed and fixed with 10% formalin. Thin sections of paraffin-embedded lung tissues were cut and stained with hematoxylin and eosin. The degree of lung inflammation (mean histopathological score) was evaluated for bronchial, peribronchial, perivascular, interstitial, pleural and intra-alveolar inflammation. * P<0.05 between the WT and H274Y lung histopathological scores.

Mentions: Both pH1N1 isolates induced significant pulmonary inflammation including peribronchial, interstitial, perivascular, alveolar and pleural inflammation that peaked on day 6 post-infection (Figure S3). There was significantly more perivascular (day 6) and pleural (days 6 and 12) inflammation visualized in the lungs of mice infected with the H274Y mutant compared to the WT virus (Figure 5). A mild to moderate vascular congestion was observed in both groups of mice although pulmonary oedema was not noted in any mice. Inflammatory cellular infiltration was characterized by both acute (neutrophilic) and chronic (lymphohistiocytic) infiltrates in all mice. Thus, mouse experiments indicated that the mutant pH1N1 isolate induced more pronounced weight loss than the WT virus which correlated with increased expression of IL-6 and KC and more significant lung inflammation despite similar lung viral titers.


Oseltamivir-resistant pandemic A/H1N1 virus is as virulent as its wild-type counterpart in mice and ferrets.

Hamelin ME, Baz M, Abed Y, Couture C, Joubert P, Beaulieu E, Bellerose N, Plante M, Mallett C, Schumer G, Kobinger GP, Boivin G - PLoS Pathog. (2010)

Lung histopathology of mice infected with wild-type (WT) or H274Y mutant isolates of pH1N1.Groups of mice were euthanized on days 3, 6 and 12 post-infection and one pulmonary lobe was removed and fixed with 10% formalin. Thin sections of paraffin-embedded lung tissues were cut and stained with hematoxylin and eosin. The degree of lung inflammation (mean histopathological score) was evaluated for bronchial, peribronchial, perivascular, interstitial, pleural and intra-alveolar inflammation. * P<0.05 between the WT and H274Y lung histopathological scores.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2908621&req=5

ppat-1001015-g005: Lung histopathology of mice infected with wild-type (WT) or H274Y mutant isolates of pH1N1.Groups of mice were euthanized on days 3, 6 and 12 post-infection and one pulmonary lobe was removed and fixed with 10% formalin. Thin sections of paraffin-embedded lung tissues were cut and stained with hematoxylin and eosin. The degree of lung inflammation (mean histopathological score) was evaluated for bronchial, peribronchial, perivascular, interstitial, pleural and intra-alveolar inflammation. * P<0.05 between the WT and H274Y lung histopathological scores.
Mentions: Both pH1N1 isolates induced significant pulmonary inflammation including peribronchial, interstitial, perivascular, alveolar and pleural inflammation that peaked on day 6 post-infection (Figure S3). There was significantly more perivascular (day 6) and pleural (days 6 and 12) inflammation visualized in the lungs of mice infected with the H274Y mutant compared to the WT virus (Figure 5). A mild to moderate vascular congestion was observed in both groups of mice although pulmonary oedema was not noted in any mice. Inflammatory cellular infiltration was characterized by both acute (neutrophilic) and chronic (lymphohistiocytic) infiltrates in all mice. Thus, mouse experiments indicated that the mutant pH1N1 isolate induced more pronounced weight loss than the WT virus which correlated with increased expression of IL-6 and KC and more significant lung inflammation despite similar lung viral titers.

Bottom Line: Such increased levels of IL-6 were also observed in lymph nodes of ferrets infected with the mutant strain.Furthermore, the H274Y mutant strain was transmitted to ferrets.In conclusion, viral fitness of the H274Y pH1N1 isolate is not substantially altered and has the potential to induce severe disease and to disseminate.

View Article: PubMed Central - PubMed

Affiliation: CHUQ-CHUL Research Center in Infectious Diseases and Laval University, Québec City, Québec, Canada.

ABSTRACT
The neuraminidase inhibitor oseltamivir is currently used for treatment of patients infected with the pandemic A/H1N1 (pH1N1) influenza virus, although drug-resistant mutants can emerge rapidly and possibly be transmitted. We describe the characteristics of a pair of oseltamivir-resistant and oseltamivir-susceptible pH1N1 clinical isolates that differed by a single change (H274Y) in the neuraminidase protein. Viral fitness of pH1N1 isolates was assessed in vitro by determining replication kinetics in MDCK alpha2,6 cells and in vivo by performing experimental infections of BALB/c mice and ferrets. Despite slightly reduced propagation of the mutant isolate in vitro during the first 24 h, the wild-type (WT) and mutant resistant viruses induced similar maximum weight loss in mice and ferrets with an identical pyrexic response in ferrets (AUC of 233.9 and 233.2, P = 0.5156). Similarly, comparable titers were obtained for the WT and the mutant strains on days 1, 3, 6 and 9 post-infection in mouse lungs and on days 1-7 in ferret nasal washes. A more important perivascular (day 6) and pleural (days 6 and 12) inflammation was noted in the lungs of mice infected with the H274Y mutant, which correlated with increased pulmonary levels of IL-6 and KC. Such increased levels of IL-6 were also observed in lymph nodes of ferrets infected with the mutant strain. Furthermore, the H274Y mutant strain was transmitted to ferrets. In conclusion, viral fitness of the H274Y pH1N1 isolate is not substantially altered and has the potential to induce severe disease and to disseminate.

Show MeSH
Related in: MedlinePlus