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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

The shape of the exhalatory flow curve (Rpef) indicated changes following infection with SARS-CoV.(A) Rpef measures the ratio of time to peak expiratory follow (PEF) relative to the total expiratory time. For both hypoxia (gray) and SARS-CoV infection (red), the time to PEF decreases relative to normal (black). However, the length of breath expands following SARS-CoV infection, causing significant drop in Rpef values relative to baseline. (B) Following SARS-CoV infection of C57BL/6J animals, we identified significant differences in Rpef across a range of doses relative to mock animals (black = mock, blue = 10^3 SARS, green = 10^4, red = 10^5; four animals per group). Significant effects of treatment on Rpef was 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, # = 10^5 dose different from all others.
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pone.0131451.g004: The shape of the exhalatory flow curve (Rpef) indicated changes following infection with SARS-CoV.(A) Rpef measures the ratio of time to peak expiratory follow (PEF) relative to the total expiratory time. For both hypoxia (gray) and SARS-CoV infection (red), the time to PEF decreases relative to normal (black). However, the length of breath expands following SARS-CoV infection, causing significant drop in Rpef values relative to baseline. (B) Following SARS-CoV infection of C57BL/6J animals, we identified significant differences in Rpef across a range of doses relative to mock animals (black = mock, blue = 10^3 SARS, green = 10^4, red = 10^5; four animals per group). Significant effects of treatment on Rpef was 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, # = 10^5 dose different from all others.

Mentions: The final respiratory metric that we focused on was Rpef, the ratio of time to peak expiratory flow (PEF) relative to total expiratory time (Te). Similar to both Penh and EF50, Rpef provides a calculated index of the breath curve combining the time needed to reach maximum expiratory flow divided by the total length of the breath (Fig 4A). While less utilized than the previous two metrics, Rpef values have been shown to increase in the context of hypoxia in vivo [25]. However, in our studies, SARS-CoV infection results in a robust decline of Rpef relative to mock controls which remain static over the time course (Fig 4B). Similar to the kinetics of Penh, reduction in Rpef values corresponded with (103, 104 dose) or preceded (105) changes in weight loss. As the time course continued, Rpef recovery was equivalent at each dose through D5, but diverged thereafter. Examining the underlying respiratory parameters revealed a more rapid time to PEF following SARS-CoV infection, consistent with previous studies of hypoxia. However, the increase in time to PEF also corresponded with a longer breath (Te), resulting in an increased denominator in the ratio and driving significant reductions in Rpef values. Importantly, the kinetics of the Rpef response illustrated a dose dependent impact of SARS-CoV infection and provides a third, clinically relevant respiratory metric for evaluating pathogenesis in vivo.


New Metrics for Evaluating Viral Respiratory Pathogenesis.

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

The shape of the exhalatory flow curve (Rpef) indicated changes following infection with SARS-CoV.(A) Rpef measures the ratio of time to peak expiratory follow (PEF) relative to the total expiratory time. For both hypoxia (gray) and SARS-CoV infection (red), the time to PEF decreases relative to normal (black). However, the length of breath expands following SARS-CoV infection, causing significant drop in Rpef values relative to baseline. (B) Following SARS-CoV infection of C57BL/6J animals, we identified significant differences in Rpef across a range of doses relative to mock animals (black = mock, blue = 10^3 SARS, green = 10^4, red = 10^5; four animals per group). Significant effects of treatment on Rpef was 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, # = 10^5 dose different from all others.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4482571&req=5

pone.0131451.g004: The shape of the exhalatory flow curve (Rpef) indicated changes following infection with SARS-CoV.(A) Rpef measures the ratio of time to peak expiratory follow (PEF) relative to the total expiratory time. For both hypoxia (gray) and SARS-CoV infection (red), the time to PEF decreases relative to normal (black). However, the length of breath expands following SARS-CoV infection, causing significant drop in Rpef values relative to baseline. (B) Following SARS-CoV infection of C57BL/6J animals, we identified significant differences in Rpef across a range of doses relative to mock animals (black = mock, blue = 10^3 SARS, green = 10^4, red = 10^5; four animals per group). Significant effects of treatment on Rpef was 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, # = 10^5 dose different from all others.
Mentions: The final respiratory metric that we focused on was Rpef, the ratio of time to peak expiratory flow (PEF) relative to total expiratory time (Te). Similar to both Penh and EF50, Rpef provides a calculated index of the breath curve combining the time needed to reach maximum expiratory flow divided by the total length of the breath (Fig 4A). While less utilized than the previous two metrics, Rpef values have been shown to increase in the context of hypoxia in vivo [25]. However, in our studies, SARS-CoV infection results in a robust decline of Rpef relative to mock controls which remain static over the time course (Fig 4B). Similar to the kinetics of Penh, reduction in Rpef values corresponded with (103, 104 dose) or preceded (105) changes in weight loss. As the time course continued, Rpef recovery was equivalent at each dose through D5, but diverged thereafter. Examining the underlying respiratory parameters revealed a more rapid time to PEF following SARS-CoV infection, consistent with previous studies of hypoxia. However, the increase in time to PEF also corresponded with a longer breath (Te), resulting in an increased denominator in the ratio and driving significant reductions in Rpef values. Importantly, the kinetics of the Rpef response illustrated a dose dependent impact of SARS-CoV infection and provides a third, clinically relevant respiratory metric for evaluating pathogenesis in vivo.

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