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New Metrics for Evaluating Viral Respiratory Pathogenesis.

Menachery VD, Gralinski LE, Baric RS, Ferris MT - PLoS ONE (2015)

Bottom Line: Viral pathogenesis studies in mice have relied on markers of severe systemic disease, rather than clinically relevant measures, to evaluate respiratory virus infection; thus confounding connections to human disease.Here, whole-body plethysmography was used to directly measure changes in pulmonary function during two respiratory viral infections.Together, the work highlights the utility of examining respiratory function following infection in order to fully understand viral pathogenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States of America.

ABSTRACT
Viral pathogenesis studies in mice have relied on markers of severe systemic disease, rather than clinically relevant measures, to evaluate respiratory virus infection; thus confounding connections to human disease. Here, whole-body plethysmography was used to directly measure changes in pulmonary function during two respiratory viral infections. This methodology closely tracked with traditional pathogenesis metrics, distinguished both virus- and dose-specific responses, and identified long-term respiratory changes following both SARS-CoV and Influenza A Virus infection. Together, the work highlights the utility of examining respiratory function following infection in order to fully understand viral pathogenesis.

No MeSH data available.


Related in: MedlinePlus

Differential responses to two respiratory pathogens.C57BL/6J mice were mock-infected (Black, n = 3) or infected with 10^4 of SARS-CoV (Green, n = 4) or 10^4 IAV-H1N1-09 (Orange, n = 4), and Airflow resistance, penH (A) or the shape of the expiratory force curve, Rpef (B) were measured through 28 days post infection. Significant effects of treatment on respiratory responses were determined via partial F-test. Following significance assessment, those treatment groups different from each-other were assessed by Tukey’s HSD post-hoc analysis. All such differences are denoted at a p<0.05 level, and are marked as follows: * = mock different from all infected, # = SARS different from mock and flu; %Flu different from SARS and mock, $ = Flu different from mock.
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pone.0131451.g005: Differential responses to two respiratory pathogens.C57BL/6J mice were mock-infected (Black, n = 3) or infected with 10^4 of SARS-CoV (Green, n = 4) or 10^4 IAV-H1N1-09 (Orange, n = 4), and Airflow resistance, penH (A) or the shape of the expiratory force curve, Rpef (B) were measured through 28 days post infection. Significant effects of treatment on respiratory responses were determined via partial F-test. Following significance assessment, those treatment groups different from each-other were assessed by Tukey’s HSD post-hoc analysis. All such differences are denoted at a p<0.05 level, and are marked as follows: * = mock different from all infected, # = SARS different from mock and flu; %Flu different from SARS and mock, $ = Flu different from mock.

Mentions: In order to validate as well as expand on these findings, we conducted additional experiments that explored differences between respiratory pathogens as well as the long-term impact on breathing function. Using semi-lethal doses, we compared SARS-CoV (104) to a human isolate of 2009 Influenza A virus, (IAV-H1N1-09) (104 pfu) over a 28 day time course. Based on previous studies, weight loss for SARS-CoV occurs primarily between D2 and D5 post infection (Fig 1); in contrast, IAV-H1N1-09 weight loss is delayed with major weight loss occurring between D4 and D8 post infection (S3 Table) [4]. In regards to respiratory metrics, both viruses show similar overall magnitudes in their Penh and Rpef responses (Fig 5A and 5B, S4 Table). Similarly, EF50 showed evidence of enhancement in both SARS and flu infection relative to mock animals (S5 Table). However, the kinetics of these response curves varied, with SARS-CoV showing earlier changes and resolution compared to IAV-H1N1-09. As in our initial experiment, for both viruses, changes in respiratory physiology corresponded with weight loss and confirmed previously observed pathogenesis trends in regards to histopathology scoring (S6 Table). In contrast to prior studies, we were also able to identify significant long-term changes in both respiratory metrics following infection despite recovery from infection-induced weight loss. As far as 28 days post infection, both Penh and Rpef levels remained significantly different from those observed in mock animals. These results suggested that despite the absence of other metrics of pathogenesis, breathing function requires additional recovery time, may not return to baseline levels following respiratory virus infection, and might provide insight into chronic or secondary-infection responses attributed to both SARS and IAV [26].


New Metrics for Evaluating Viral Respiratory Pathogenesis.

Menachery VD, Gralinski LE, Baric RS, Ferris MT - PLoS ONE (2015)

Differential responses to two respiratory pathogens.C57BL/6J mice were mock-infected (Black, n = 3) or infected with 10^4 of SARS-CoV (Green, n = 4) or 10^4 IAV-H1N1-09 (Orange, n = 4), and Airflow resistance, penH (A) or the shape of the expiratory force curve, Rpef (B) were measured through 28 days post infection. Significant effects of treatment on respiratory responses were determined via partial F-test. Following significance assessment, those treatment groups different from each-other were assessed by Tukey’s HSD post-hoc analysis. All such differences are denoted at a p<0.05 level, and are marked as follows: * = mock different from all infected, # = SARS different from mock and flu; %Flu different from SARS and mock, $ = Flu different from mock.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4482571&req=5

pone.0131451.g005: Differential responses to two respiratory pathogens.C57BL/6J mice were mock-infected (Black, n = 3) or infected with 10^4 of SARS-CoV (Green, n = 4) or 10^4 IAV-H1N1-09 (Orange, n = 4), and Airflow resistance, penH (A) or the shape of the expiratory force curve, Rpef (B) were measured through 28 days post infection. Significant effects of treatment on respiratory responses were determined via partial F-test. Following significance assessment, those treatment groups different from each-other were assessed by Tukey’s HSD post-hoc analysis. All such differences are denoted at a p<0.05 level, and are marked as follows: * = mock different from all infected, # = SARS different from mock and flu; %Flu different from SARS and mock, $ = Flu different from mock.
Mentions: In order to validate as well as expand on these findings, we conducted additional experiments that explored differences between respiratory pathogens as well as the long-term impact on breathing function. Using semi-lethal doses, we compared SARS-CoV (104) to a human isolate of 2009 Influenza A virus, (IAV-H1N1-09) (104 pfu) over a 28 day time course. Based on previous studies, weight loss for SARS-CoV occurs primarily between D2 and D5 post infection (Fig 1); in contrast, IAV-H1N1-09 weight loss is delayed with major weight loss occurring between D4 and D8 post infection (S3 Table) [4]. In regards to respiratory metrics, both viruses show similar overall magnitudes in their Penh and Rpef responses (Fig 5A and 5B, S4 Table). Similarly, EF50 showed evidence of enhancement in both SARS and flu infection relative to mock animals (S5 Table). However, the kinetics of these response curves varied, with SARS-CoV showing earlier changes and resolution compared to IAV-H1N1-09. As in our initial experiment, for both viruses, changes in respiratory physiology corresponded with weight loss and confirmed previously observed pathogenesis trends in regards to histopathology scoring (S6 Table). In contrast to prior studies, we were also able to identify significant long-term changes in both respiratory metrics following infection despite recovery from infection-induced weight loss. As far as 28 days post infection, both Penh and Rpef levels remained significantly different from those observed in mock animals. These results suggested that despite the absence of other metrics of pathogenesis, breathing function requires additional recovery time, may not return to baseline levels following respiratory virus infection, and might provide insight into chronic or secondary-infection responses attributed to both SARS and IAV [26].

Bottom Line: Viral pathogenesis studies in mice have relied on markers of severe systemic disease, rather than clinically relevant measures, to evaluate respiratory virus infection; thus confounding connections to human disease.Here, whole-body plethysmography was used to directly measure changes in pulmonary function during two respiratory viral infections.Together, the work highlights the utility of examining respiratory function following infection in order to fully understand viral pathogenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States of America.

ABSTRACT
Viral pathogenesis studies in mice have relied on markers of severe systemic disease, rather than clinically relevant measures, to evaluate respiratory virus infection; thus confounding connections to human disease. Here, whole-body plethysmography was used to directly measure changes in pulmonary function during two respiratory viral infections. This methodology closely tracked with traditional pathogenesis metrics, distinguished both virus- and dose-specific responses, and identified long-term respiratory changes following both SARS-CoV and Influenza A Virus infection. Together, the work highlights the utility of examining respiratory function following infection in order to fully understand viral pathogenesis.

No MeSH data available.


Related in: MedlinePlus