Tweet
J Virol. 2015 Jun 10. pii: JVI.00817-15. [Epub ahead of print]
Lower Respiratory Tract Infection of the Ferret by 2009 H1N1 Pandemic Influenza A Virus Triggers Biphasic, Systemic and Local Neutrophil Recruitment.
Camp JV1, Bagci U2, Chu YK3, Squier B4, Fraig M5, Uriarte SM6, Guo H7, Mollura DJ2, Jonsson CB8.
Author information
Abstract
Infection of the lower respiratory tract by influenza A viruses results in an increase in inflammation and immune cell infiltration in the lung. The dynamic relationships among the lung microenvironments, the lung and systemic host responses during infection remain poorly understood. Herein, we used an extensive systematic histologic analysis coupled with live imaging to gain access to these relationships in ferrets infected with the pandemic A(H1N1)2009 virus [H1N1pdm]. Neutrophil levels rose in lungs of H1N1pdm-infected ferrets 6 hours post-infection and became concentrated at areas of H1N1pdm-infected bronchiolar epithelium by 1 dpi (days post-infection). In addition, neutrophils were increased throughout the alveolar spaces during the first 3 dpi, and returned to baseline density by 6 dpi. Histochemical staining revealed neutrophil infiltration in the lungs occurred in two waves, at 1 and 3 dpi, and gene expression within microenvironments suggested two types of neutrophils. Specifically, CCL3, but not CXCL8/IL-8, levels were greater within discrete lung microenvironments, and coincided with increased infiltration of neutrophils in the lung. We used live imaging of ferrets to monitor host responses within the lung over time with 18fluorodeoxyglucose (FDG). Sites within the H1N1pdm-infected ferret lung with high FDG had high levels of proliferative epithelium. In summary, neutrophils invaded the H1N1pdm-infected ferret lung, globally, and focally, at sites of infection. The microenvironments with increased neutrophils, did not correlate with FDG, and hence, FDG-uptake may reflect prior infection and inflammation that has experienced damage as reflected by bronchial regeneration of tissues in the lungs at sites of high FDG.
IMPORTANCE:
Severe influenza disease is characterized by an acute infection of the lower airways that may rapidly progress to organ failure and death. Well-developed animal models that mimic human disease are essential to understanding the complex relationships of the microenvironment, organ and system in controlling virus replication, inflammation, and disease progression. Employing the ferret model of H1N1pdm infection, we used live imaging and comprehensive histological analyses to address specific hypothesis regarding spatial and temporal relationships that occur over the progression of infection and inflammation. We show the general invasion of neutrophils at the organ level (lung), but a distinct pattern of localized accumulation within the local microenvironment at the site of infection. Moreover, we show that these responses were biphasic within the lung. Finally, live imaging revealed an early and sustained host metabolic response at sites of infection that may reflect damage and repair of tissues in the lungs.
Copyright ? 2015, American Society for Microbiology. All Rights Reserved.
PMID: 26063430 [PubMed - as supplied by publisher]
Lower Respiratory Tract Infection of the Ferret by 2009 H1N1 Pandemic Influenza A Virus Triggers Biphasic, Systemic and Local Neutrophil Recruitment.
Camp JV1, Bagci U2, Chu YK3, Squier B4, Fraig M5, Uriarte SM6, Guo H7, Mollura DJ2, Jonsson CB8.
Author information
Abstract
Infection of the lower respiratory tract by influenza A viruses results in an increase in inflammation and immune cell infiltration in the lung. The dynamic relationships among the lung microenvironments, the lung and systemic host responses during infection remain poorly understood. Herein, we used an extensive systematic histologic analysis coupled with live imaging to gain access to these relationships in ferrets infected with the pandemic A(H1N1)2009 virus [H1N1pdm]. Neutrophil levels rose in lungs of H1N1pdm-infected ferrets 6 hours post-infection and became concentrated at areas of H1N1pdm-infected bronchiolar epithelium by 1 dpi (days post-infection). In addition, neutrophils were increased throughout the alveolar spaces during the first 3 dpi, and returned to baseline density by 6 dpi. Histochemical staining revealed neutrophil infiltration in the lungs occurred in two waves, at 1 and 3 dpi, and gene expression within microenvironments suggested two types of neutrophils. Specifically, CCL3, but not CXCL8/IL-8, levels were greater within discrete lung microenvironments, and coincided with increased infiltration of neutrophils in the lung. We used live imaging of ferrets to monitor host responses within the lung over time with 18fluorodeoxyglucose (FDG). Sites within the H1N1pdm-infected ferret lung with high FDG had high levels of proliferative epithelium. In summary, neutrophils invaded the H1N1pdm-infected ferret lung, globally, and focally, at sites of infection. The microenvironments with increased neutrophils, did not correlate with FDG, and hence, FDG-uptake may reflect prior infection and inflammation that has experienced damage as reflected by bronchial regeneration of tissues in the lungs at sites of high FDG.
IMPORTANCE:
Severe influenza disease is characterized by an acute infection of the lower airways that may rapidly progress to organ failure and death. Well-developed animal models that mimic human disease are essential to understanding the complex relationships of the microenvironment, organ and system in controlling virus replication, inflammation, and disease progression. Employing the ferret model of H1N1pdm infection, we used live imaging and comprehensive histological analyses to address specific hypothesis regarding spatial and temporal relationships that occur over the progression of infection and inflammation. We show the general invasion of neutrophils at the organ level (lung), but a distinct pattern of localized accumulation within the local microenvironment at the site of infection. Moreover, we show that these responses were biphasic within the lung. Finally, live imaging revealed an early and sustained host metabolic response at sites of infection that may reflect damage and repair of tissues in the lungs.
Copyright ? 2015, American Society for Microbiology. All Rights Reserved.
PMID: 26063430 [PubMed - as supplied by publisher]