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H5N1 and 1918 pandemic influenza virus infection results in early and excessive infiltration of macrophages and neutrophils in the lungs of mice.

Perrone LA, Plowden JK, García-Sastre A, Katz JM, Tumpey TM - PLoS Pathog. (2008)

Bottom Line: Fatal human respiratory disease associated with the 1918 pandemic influenza virus and potentially pandemic H5N1 viruses is characterized by severe lung pathology, including pulmonary edema and extensive inflammatory infiltrate.Interestingly, while these similarities were observed, the HP H5N1 virus consistently elicited significantly higher levels of pro-inflammatory cytokines in whole lungs and primary human macrophages, revealing a potentially critical difference in the pathogenesis of H5N1 infections.These results together indicate that infection with HP influenza viruses such as H5N1 and the 1918 pandemic virus leads to a rapid cell recruitment of macrophages and neutrophils into the lungs, suggesting that these cells play a role in acute lung inflammation associated with HP influenza virus infection.

View Article: PubMed Central - PubMed

Affiliation: Immunology and Pathogenesis Branch, Influenza Division, National Center for Immunization and Respiratory Diseases, Collaborating Centers for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America.

ABSTRACT
Fatal human respiratory disease associated with the 1918 pandemic influenza virus and potentially pandemic H5N1 viruses is characterized by severe lung pathology, including pulmonary edema and extensive inflammatory infiltrate. Here, we quantified the cellular immune response to infection in the mouse lung by flow cytometry and demonstrate that mice infected with highly pathogenic (HP) H1N1 and H5N1 influenza viruses exhibit significantly high numbers of macrophages and neutrophils in the lungs compared to mice infected with low pathogenic (LP) viruses. Mice infected with the 1918 pandemic virus and a recent H5N1 human isolate show considerable similarities in overall lung cellularity, lung immune cell sub-population composition, and cellular immune temporal dynamics. Interestingly, while these similarities were observed, the HP H5N1 virus consistently elicited significantly higher levels of pro-inflammatory cytokines in whole lungs and primary human macrophages, revealing a potentially critical difference in the pathogenesis of H5N1 infections. Primary mouse and human macrophages and dendritic cells were also susceptible to 1918 and H5N1 influenza virus infection in vitro. These results together indicate that infection with HP influenza viruses such as H5N1 and the 1918 pandemic virus leads to a rapid cell recruitment of macrophages and neutrophils into the lungs, suggesting that these cells play a role in acute lung inflammation associated with HP influenza virus infection.

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Lung virus titers.Female BALB/c mice were infected intranasally with 102 PFU of influenza viruses and lungs were harvested for virus titration at various times post-inoculation. Lungs were homogenized in 1 ml of PBS and virus titers determined by plaque assay (+ TPCK trypsin 1 µg/ml) on MDCK cells in duplicate (n = 3 mice per time point). * p<0.05 between 1918 and Thai/16 infected lungs and TX/91 and SP/83 infected lungs.
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ppat-1000115-g001: Lung virus titers.Female BALB/c mice were infected intranasally with 102 PFU of influenza viruses and lungs were harvested for virus titration at various times post-inoculation. Lungs were homogenized in 1 ml of PBS and virus titers determined by plaque assay (+ TPCK trypsin 1 µg/ml) on MDCK cells in duplicate (n = 3 mice per time point). * p<0.05 between 1918 and Thai/16 infected lungs and TX/91 and SP/83 infected lungs.

Mentions: Female BALB/c mice were infected intranasally with either highly pathogenic (HP) or low-pathogenic (LP) influenza viruses (Table 1, Methods) based on known LD50's and phenotypes of disease in mouse [21] and ferret [18],[22] models. As shown in Figure 1, the 1918 (H1N1) and A/Thailand/16/2004 (Thai/16, H5N1) viruses replicated to high titers that were at least 5-fold higher than the respective LP viruses, A/Texas/36/91 (TX/91, H1N1) and A/Thailand/SP/83/2004 (SP/83, H5N1) as early as 1 day post-infection (p.i.) and sustained higher levels of replication than the LP viruses throughout the course of infection. 1918 and TX/91 virus infected lungs reached peak titers on day 3 p.i. and remained elevated for the duration of the study. The HP Thai/16 virus reached peak titers later than the 1918 virus at day 5 pi. while the less mouse-virulent SP/83 virus reached it's highest titers on day 7 p.i.. Lung virus titers were significantly higher (*p<0.05) in the 1918 and Thai/16 virus groups compared to TX/91 and SP/83 infected mice at all time points measured.


H5N1 and 1918 pandemic influenza virus infection results in early and excessive infiltration of macrophages and neutrophils in the lungs of mice.

Perrone LA, Plowden JK, García-Sastre A, Katz JM, Tumpey TM - PLoS Pathog. (2008)

Lung virus titers.Female BALB/c mice were infected intranasally with 102 PFU of influenza viruses and lungs were harvested for virus titration at various times post-inoculation. Lungs were homogenized in 1 ml of PBS and virus titers determined by plaque assay (+ TPCK trypsin 1 µg/ml) on MDCK cells in duplicate (n = 3 mice per time point). * p<0.05 between 1918 and Thai/16 infected lungs and TX/91 and SP/83 infected lungs.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2483250&req=5

ppat-1000115-g001: Lung virus titers.Female BALB/c mice were infected intranasally with 102 PFU of influenza viruses and lungs were harvested for virus titration at various times post-inoculation. Lungs were homogenized in 1 ml of PBS and virus titers determined by plaque assay (+ TPCK trypsin 1 µg/ml) on MDCK cells in duplicate (n = 3 mice per time point). * p<0.05 between 1918 and Thai/16 infected lungs and TX/91 and SP/83 infected lungs.
Mentions: Female BALB/c mice were infected intranasally with either highly pathogenic (HP) or low-pathogenic (LP) influenza viruses (Table 1, Methods) based on known LD50's and phenotypes of disease in mouse [21] and ferret [18],[22] models. As shown in Figure 1, the 1918 (H1N1) and A/Thailand/16/2004 (Thai/16, H5N1) viruses replicated to high titers that were at least 5-fold higher than the respective LP viruses, A/Texas/36/91 (TX/91, H1N1) and A/Thailand/SP/83/2004 (SP/83, H5N1) as early as 1 day post-infection (p.i.) and sustained higher levels of replication than the LP viruses throughout the course of infection. 1918 and TX/91 virus infected lungs reached peak titers on day 3 p.i. and remained elevated for the duration of the study. The HP Thai/16 virus reached peak titers later than the 1918 virus at day 5 pi. while the less mouse-virulent SP/83 virus reached it's highest titers on day 7 p.i.. Lung virus titers were significantly higher (*p<0.05) in the 1918 and Thai/16 virus groups compared to TX/91 and SP/83 infected mice at all time points measured.

Bottom Line: Fatal human respiratory disease associated with the 1918 pandemic influenza virus and potentially pandemic H5N1 viruses is characterized by severe lung pathology, including pulmonary edema and extensive inflammatory infiltrate.Interestingly, while these similarities were observed, the HP H5N1 virus consistently elicited significantly higher levels of pro-inflammatory cytokines in whole lungs and primary human macrophages, revealing a potentially critical difference in the pathogenesis of H5N1 infections.These results together indicate that infection with HP influenza viruses such as H5N1 and the 1918 pandemic virus leads to a rapid cell recruitment of macrophages and neutrophils into the lungs, suggesting that these cells play a role in acute lung inflammation associated with HP influenza virus infection.

View Article: PubMed Central - PubMed

Affiliation: Immunology and Pathogenesis Branch, Influenza Division, National Center for Immunization and Respiratory Diseases, Collaborating Centers for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America.

ABSTRACT
Fatal human respiratory disease associated with the 1918 pandemic influenza virus and potentially pandemic H5N1 viruses is characterized by severe lung pathology, including pulmonary edema and extensive inflammatory infiltrate. Here, we quantified the cellular immune response to infection in the mouse lung by flow cytometry and demonstrate that mice infected with highly pathogenic (HP) H1N1 and H5N1 influenza viruses exhibit significantly high numbers of macrophages and neutrophils in the lungs compared to mice infected with low pathogenic (LP) viruses. Mice infected with the 1918 pandemic virus and a recent H5N1 human isolate show considerable similarities in overall lung cellularity, lung immune cell sub-population composition, and cellular immune temporal dynamics. Interestingly, while these similarities were observed, the HP H5N1 virus consistently elicited significantly higher levels of pro-inflammatory cytokines in whole lungs and primary human macrophages, revealing a potentially critical difference in the pathogenesis of H5N1 infections. Primary mouse and human macrophages and dendritic cells were also susceptible to 1918 and H5N1 influenza virus infection in vitro. These results together indicate that infection with HP influenza viruses such as H5N1 and the 1918 pandemic virus leads to a rapid cell recruitment of macrophages and neutrophils into the lungs, suggesting that these cells play a role in acute lung inflammation associated with HP influenza virus infection.

Show MeSH
Related in: MedlinePlus