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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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Related in: MedlinePlus

Cytokine response from infected human macrophages.Primary macrophages were developed from human peripheral blood monocytes in 6 well plates and infected in vitro (MOI = 0.1) with influenza viruses in duplicate as described (Methods, Table 1). Supernatants were sampled 48 hours post-infection and cytokines measured by Bioplex Protein Array assay (Methods). Macrophages were also treated with bacterial lipopolysaccharide (LPS, 100 ng) and Poly I/C (100 ng) to serve as positive inducers. * p<0.05 between H5N1 and H1N1 viruses.
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ppat-1000115-g005: Cytokine response from infected human macrophages.Primary macrophages were developed from human peripheral blood monocytes in 6 well plates and infected in vitro (MOI = 0.1) with influenza viruses in duplicate as described (Methods, Table 1). Supernatants were sampled 48 hours post-infection and cytokines measured by Bioplex Protein Array assay (Methods). Macrophages were also treated with bacterial lipopolysaccharide (LPS, 100 ng) and Poly I/C (100 ng) to serve as positive inducers. * p<0.05 between H5N1 and H1N1 viruses.

Mentions: Additional experimentation with primary human macrophages revealed that levels of pro-inflammatory cytokines were higher for H5N1-infected cells than either 1918 or TX/91 virus infected cells (48 hrs p.i., MOI = 0.1, Figure 5). Significant differences in cytokine levels were observed between H5N1 and H1N1 virus infected macrophages in all cytokines measured (*p<0.05) except IL-8 where all four viruses elicited similar levels of this chemokine. Interestingly, the 1918 virus elicited similar cytokine responses as to TX/91 inoculated cells in every cytokine measured even though 1918 virus titers at this time point post-infection were 2.5 logs greater than TX/91 infected macrophages (Figure 4B). Thai/16 infected cultures elicited at least a 2 fold greater cytokine response than the SP/83 virus infected cultures in every cytokine measured except IL-8 and MCP-1 chemokines where Thai/16 levels were only slightly higher than SP/83 levels.


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)

Cytokine response from infected human macrophages.Primary macrophages were developed from human peripheral blood monocytes in 6 well plates and infected in vitro (MOI = 0.1) with influenza viruses in duplicate as described (Methods, Table 1). Supernatants were sampled 48 hours post-infection and cytokines measured by Bioplex Protein Array assay (Methods). Macrophages were also treated with bacterial lipopolysaccharide (LPS, 100 ng) and Poly I/C (100 ng) to serve as positive inducers. * p<0.05 between H5N1 and H1N1 viruses.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2483250&req=5

ppat-1000115-g005: Cytokine response from infected human macrophages.Primary macrophages were developed from human peripheral blood monocytes in 6 well plates and infected in vitro (MOI = 0.1) with influenza viruses in duplicate as described (Methods, Table 1). Supernatants were sampled 48 hours post-infection and cytokines measured by Bioplex Protein Array assay (Methods). Macrophages were also treated with bacterial lipopolysaccharide (LPS, 100 ng) and Poly I/C (100 ng) to serve as positive inducers. * p<0.05 between H5N1 and H1N1 viruses.
Mentions: Additional experimentation with primary human macrophages revealed that levels of pro-inflammatory cytokines were higher for H5N1-infected cells than either 1918 or TX/91 virus infected cells (48 hrs p.i., MOI = 0.1, Figure 5). Significant differences in cytokine levels were observed between H5N1 and H1N1 virus infected macrophages in all cytokines measured (*p<0.05) except IL-8 where all four viruses elicited similar levels of this chemokine. Interestingly, the 1918 virus elicited similar cytokine responses as to TX/91 inoculated cells in every cytokine measured even though 1918 virus titers at this time point post-infection were 2.5 logs greater than TX/91 infected macrophages (Figure 4B). Thai/16 infected cultures elicited at least a 2 fold greater cytokine response than the SP/83 virus infected cultures in every cytokine measured except IL-8 and MCP-1 chemokines where Thai/16 levels were only slightly higher than SP/83 levels.

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