Giuseppe
Emeritus
[Source: The Journal of Infectious Diseases, full text: (LINK). Abstract, edited.]
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Heterozygosity for the F508del Mutation in the Cystic Fibrosis Transmembrane Conductance Regulator Anion Channel Attenuates Influenza Severity
Famke Aeffner 1, Basant Abdulrahman 2, Judy M. Hickman-Davis 3, Paul M. Janssen 4, Amal Amer 2, David M. Bedwell 5, Eric J. Sorscher 6 and Ian C. Davis 1
Author Affiliations: <SUP>1</SUP>Department of Veterinary Biosciences <SUP>2</SUP>Department of Pulmonary and Critical Care Medicine <SUP>3</SUP>Department of Veterinary Preventive Medicine, <SUP>4</SUP>Department of Physiology and Cell Biology, The Ohio State University, Columbus <SUP>5</SUP>Department of Microbiology <SUP>6</SUP>Department of Medicine, University of Alabama at Birmingham
Correspondence: Ian C. Davis, DVM, PhD, The Ohio State University, 331 Goss Lab, 1925 Coffey Rd, Columbus, OH 43210 (ian.davis@cvm.osu.edu).
Abstract
Background.
Seasonal and pandemic influenza are significant public health concerns. Influenza stimulates respiratory epithelial Cl<SUP>−</SUP> secretion via the cystic fibrosis transmembrane conductance regulator (CFTR). The purpose of this study was to determine the contribution of this effect to influenza pathogenesis in mice with reduced CFTR activity.
Methods.
C57BL/6-congenic mice heterozygous for the F508del CFTR mutation (HET) and wild-type (WT) controls were infected intranasally with 10 000 focus-forming units of influenza A/WSN/33 (H1N1) per mouse. Body weight, arterial O<SUB>2</SUB> saturation, and heart rate were monitored daily. Pulmonary edema and lung function parameters were derived from ratios of wet weight to dry weight and the forced-oscillation technique, respectively. Levels of cytokines and chemokines in bronchoalveolar lavage fluid were measured by enzyme-linked immunosorbent assay.
Results.
Relative to WT mice, influenza virus?infected HET mice showed significantly delayed mortality, which was accompanied by attenuated hypoxemia, cardiopulmonary dysfunction, and pulmonary edema. However, viral replication and weight loss did not differ. The protective HET phenotype was correlated with exaggerated alveolar macrophage and interleukin 6 responses to infection and was abrogated by alveolar macrophage depletion, using clodronate liposomes.
Conclusions.
Reduced CFTR expression modulates the innate immune response to influenza and alters disease pathogenesis. CFTR-mediated Cl<SUP>−</SUP> secretion is therefore an important host determinant of disease, and CFTR inhibition may be of therapeutic benefit in influenza.
Received November 20, 2012. Accepted December 27, 2012.
? The Author 2013. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved.
For Permissions, please e-mail: journals.permissions@oup.com.
-Famke Aeffner 1, Basant Abdulrahman 2, Judy M. Hickman-Davis 3, Paul M. Janssen 4, Amal Amer 2, David M. Bedwell 5, Eric J. Sorscher 6 and Ian C. Davis 1
Author Affiliations: <SUP>1</SUP>Department of Veterinary Biosciences <SUP>2</SUP>Department of Pulmonary and Critical Care Medicine <SUP>3</SUP>Department of Veterinary Preventive Medicine, <SUP>4</SUP>Department of Physiology and Cell Biology, The Ohio State University, Columbus <SUP>5</SUP>Department of Microbiology <SUP>6</SUP>Department of Medicine, University of Alabama at Birmingham
Correspondence: Ian C. Davis, DVM, PhD, The Ohio State University, 331 Goss Lab, 1925 Coffey Rd, Columbus, OH 43210 (ian.davis@cvm.osu.edu).
Abstract
Background.
Seasonal and pandemic influenza are significant public health concerns. Influenza stimulates respiratory epithelial Cl<SUP>−</SUP> secretion via the cystic fibrosis transmembrane conductance regulator (CFTR). The purpose of this study was to determine the contribution of this effect to influenza pathogenesis in mice with reduced CFTR activity.
Methods.
C57BL/6-congenic mice heterozygous for the F508del CFTR mutation (HET) and wild-type (WT) controls were infected intranasally with 10 000 focus-forming units of influenza A/WSN/33 (H1N1) per mouse. Body weight, arterial O<SUB>2</SUB> saturation, and heart rate were monitored daily. Pulmonary edema and lung function parameters were derived from ratios of wet weight to dry weight and the forced-oscillation technique, respectively. Levels of cytokines and chemokines in bronchoalveolar lavage fluid were measured by enzyme-linked immunosorbent assay.
Results.
Relative to WT mice, influenza virus?infected HET mice showed significantly delayed mortality, which was accompanied by attenuated hypoxemia, cardiopulmonary dysfunction, and pulmonary edema. However, viral replication and weight loss did not differ. The protective HET phenotype was correlated with exaggerated alveolar macrophage and interleukin 6 responses to infection and was abrogated by alveolar macrophage depletion, using clodronate liposomes.
Conclusions.
Reduced CFTR expression modulates the innate immune response to influenza and alters disease pathogenesis. CFTR-mediated Cl<SUP>−</SUP> secretion is therefore an important host determinant of disease, and CFTR inhibition may be of therapeutic benefit in influenza.
Received November 20, 2012. Accepted December 27, 2012.
? The Author 2013. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved.
For Permissions, please e-mail: journals.permissions@oup.com.
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