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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

Penh shows increased sensitivity in dose-dependent responses following SARS-CoV infection.Penh is a classically used, and derived measure of respiratory distress. (A) Penh is derived by assessing several measures of the respiratory response curve (peak expiratory flow of breath (PEF), peak inspiratory flow of breath (PIF), time of expiratory portion of breath (Te) and time required to exhale 65% of breath volume (Tr) (B) Following SARS-CoV infection of C57BL/6J animals, we identified significant differences in Penh 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). Within a time point, letters indicate groups that are NOT significantly different from each other. Significant effects of treatment on Penh 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, % = mock different from all doses, 10^3 different from 10^4 and 10^5 doses.
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pone.0131451.g002: Penh shows increased sensitivity in dose-dependent responses following SARS-CoV infection.Penh is a classically used, and derived measure of respiratory distress. (A) Penh is derived by assessing several measures of the respiratory response curve (peak expiratory flow of breath (PEF), peak inspiratory flow of breath (PIF), time of expiratory portion of breath (Te) and time required to exhale 65% of breath volume (Tr) (B) Following SARS-CoV infection of C57BL/6J animals, we identified significant differences in Penh 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). Within a time point, letters indicate groups that are NOT significantly different from each other. Significant effects of treatment on Penh 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, % = mock different from all doses, 10^3 different from 10^4 and 10^5 doses.

Mentions: The first respiratory metric that we focused on is enhanced pause (Penh), a unit-less index of calculated airway function [16]. The equation for Penh (Fig 2A) takes into account four breathing parameters including peak expiratory flow of breath (PEF), peak inspiratory flow of breath (PIF), time of expiratory portion of breath (Te), and time required to exhale 65% of breath volume (Tr). While a novel metric for in vivo infection, penH derived from mouse whole body plethysmography is not without controversy in the asthma field. Supporters suggests that penH serves as an indirect measure of airway resistance while critics argue it fails to measure airway constriction and at best provides non-specific assessment of breathing patterns [16–18]. In this study, SARS-CoV infection resulted in a dose responsive change in Penh values (Fig 2B). While mock-infected animals maintained baseline levels, SARS-CoV infection at each dose produced increased Penh values during the early portion of the infection time course. While PEF, PIF and Tr values showed variability, changes in Penh were primarily driven by increases in Te during SARS-CoV infection (Fig 1C). Importantly, the increases in Penh corresponded with, and in the case of the 105 dose, preceded changes in weight loss (Fig 1A), providing an additional metric for the onset of pathogenesis. Notably, our study shows high (values greater than 10) and sustained values of Penh, which exceed previously reported values in both viral and asthma airway responsiveness studies, which typically result in transitive levels of Penh in the 1–3 range with mock animals typically showing values <<1 [19–21]. As the time course continued, Penh values also began to decline in a dose-dependent manner, but remained significantly elevated at the termination of the experiment. Despite the surrounding controversy, Penh provides a novel respiratory metric of pathogenesis in the context of SARS-CoV infection that is highly discriminating of variation in viral doses, and also corresponds with and/or precedes changes in weight loss.


New Metrics for Evaluating Viral Respiratory Pathogenesis.

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

Penh shows increased sensitivity in dose-dependent responses following SARS-CoV infection.Penh is a classically used, and derived measure of respiratory distress. (A) Penh is derived by assessing several measures of the respiratory response curve (peak expiratory flow of breath (PEF), peak inspiratory flow of breath (PIF), time of expiratory portion of breath (Te) and time required to exhale 65% of breath volume (Tr) (B) Following SARS-CoV infection of C57BL/6J animals, we identified significant differences in Penh 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). Within a time point, letters indicate groups that are NOT significantly different from each other. Significant effects of treatment on Penh 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, % = mock different from all doses, 10^3 different from 10^4 and 10^5 doses.
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pone.0131451.g002: Penh shows increased sensitivity in dose-dependent responses following SARS-CoV infection.Penh is a classically used, and derived measure of respiratory distress. (A) Penh is derived by assessing several measures of the respiratory response curve (peak expiratory flow of breath (PEF), peak inspiratory flow of breath (PIF), time of expiratory portion of breath (Te) and time required to exhale 65% of breath volume (Tr) (B) Following SARS-CoV infection of C57BL/6J animals, we identified significant differences in Penh 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). Within a time point, letters indicate groups that are NOT significantly different from each other. Significant effects of treatment on Penh 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, % = mock different from all doses, 10^3 different from 10^4 and 10^5 doses.
Mentions: The first respiratory metric that we focused on is enhanced pause (Penh), a unit-less index of calculated airway function [16]. The equation for Penh (Fig 2A) takes into account four breathing parameters including peak expiratory flow of breath (PEF), peak inspiratory flow of breath (PIF), time of expiratory portion of breath (Te), and time required to exhale 65% of breath volume (Tr). While a novel metric for in vivo infection, penH derived from mouse whole body plethysmography is not without controversy in the asthma field. Supporters suggests that penH serves as an indirect measure of airway resistance while critics argue it fails to measure airway constriction and at best provides non-specific assessment of breathing patterns [16–18]. In this study, SARS-CoV infection resulted in a dose responsive change in Penh values (Fig 2B). While mock-infected animals maintained baseline levels, SARS-CoV infection at each dose produced increased Penh values during the early portion of the infection time course. While PEF, PIF and Tr values showed variability, changes in Penh were primarily driven by increases in Te during SARS-CoV infection (Fig 1C). Importantly, the increases in Penh corresponded with, and in the case of the 105 dose, preceded changes in weight loss (Fig 1A), providing an additional metric for the onset of pathogenesis. Notably, our study shows high (values greater than 10) and sustained values of Penh, which exceed previously reported values in both viral and asthma airway responsiveness studies, which typically result in transitive levels of Penh in the 1–3 range with mock animals typically showing values <<1 [19–21]. As the time course continued, Penh values also began to decline in a dose-dependent manner, but remained significantly elevated at the termination of the experiment. Despite the surrounding controversy, Penh provides a novel respiratory metric of pathogenesis in the context of SARS-CoV infection that is highly discriminating of variation in viral doses, and also corresponds with and/or precedes changes in weight loss.

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