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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

Virus replication from primary lung macrophages and dendritic cells cultured ex vivo.BALB/c mice were infected intranasally with 102 PFU of the indicated viruses. Three days post-inoculation, lungs were removed from 2–3 mice per virus group. Cell suspensions were prepared from pooled samples and macrophages (A) and dendritic cells (B) were isolated by CD11b+ ad CD11c+ MACS column purification, respectively. Supernatants from cultures were sampled over time to measure virus production. Virus was titered in duplicate by plaque assay.
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ppat-1000115-g007: Virus replication from primary lung macrophages and dendritic cells cultured ex vivo.BALB/c mice were infected intranasally with 102 PFU of the indicated viruses. Three days post-inoculation, lungs were removed from 2–3 mice per virus group. Cell suspensions were prepared from pooled samples and macrophages (A) and dendritic cells (B) were isolated by CD11b+ ad CD11c+ MACS column purification, respectively. Supernatants from cultures were sampled over time to measure virus production. Virus was titered in duplicate by plaque assay.

Mentions: To determine if innate immune cells are being productively infected in vivo, macrophages and dendritic cells were purified from lungs of infected mice and cultured for infectious virus. Lungs from infected (3 days p.i.) mice were harvested and ex vivo cultures containing either lung macrophages or dendritic cells were sampled for infectious virus over a 65 hour time period. While the seasonal influenza isolate, TX/91 virus was not produced from either macrophages (CD11b+) or dendritic (CD11c+) cells, the 1918 pandemic virus as well as the two human H5N1 isolates were released into the culture supernatant (Figure 7), indicating that these cells are being productively infected in the mouse lung. In CD11b+ (macrophages) cell cultures (Figure 7A), the 1918 and Thai/16 virus infected cells released more infectious virus over time than the LP SP/83 virus infected culture. In CD11c+ (dendritic) cell cultures, the Thai/16 virus infected cultures released more infectious virus than the 1918 and SP/83 virus infected cultures (Figure 7B). These data further demonstrate that mouse lung macrophages and dendritic cells are susceptible to highly pathogenic influenza virus infection in the lung tissue.


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)

Virus replication from primary lung macrophages and dendritic cells cultured ex vivo.BALB/c mice were infected intranasally with 102 PFU of the indicated viruses. Three days post-inoculation, lungs were removed from 2–3 mice per virus group. Cell suspensions were prepared from pooled samples and macrophages (A) and dendritic cells (B) were isolated by CD11b+ ad CD11c+ MACS column purification, respectively. Supernatants from cultures were sampled over time to measure virus production. Virus was titered in duplicate by plaque assay.
© Copyright Policy
Related In: Results  -  Collection

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

ppat-1000115-g007: Virus replication from primary lung macrophages and dendritic cells cultured ex vivo.BALB/c mice were infected intranasally with 102 PFU of the indicated viruses. Three days post-inoculation, lungs were removed from 2–3 mice per virus group. Cell suspensions were prepared from pooled samples and macrophages (A) and dendritic cells (B) were isolated by CD11b+ ad CD11c+ MACS column purification, respectively. Supernatants from cultures were sampled over time to measure virus production. Virus was titered in duplicate by plaque assay.
Mentions: To determine if innate immune cells are being productively infected in vivo, macrophages and dendritic cells were purified from lungs of infected mice and cultured for infectious virus. Lungs from infected (3 days p.i.) mice were harvested and ex vivo cultures containing either lung macrophages or dendritic cells were sampled for infectious virus over a 65 hour time period. While the seasonal influenza isolate, TX/91 virus was not produced from either macrophages (CD11b+) or dendritic (CD11c+) cells, the 1918 pandemic virus as well as the two human H5N1 isolates were released into the culture supernatant (Figure 7), indicating that these cells are being productively infected in the mouse lung. In CD11b+ (macrophages) cell cultures (Figure 7A), the 1918 and Thai/16 virus infected cells released more infectious virus over time than the LP SP/83 virus infected culture. In CD11c+ (dendritic) cell cultures, the Thai/16 virus infected cultures released more infectious virus than the 1918 and SP/83 virus infected cultures (Figure 7B). These data further demonstrate that mouse lung macrophages and dendritic cells are susceptible to highly pathogenic influenza virus infection in the lung tissue.

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