Comparative Pathology in Ferrets Infected with H1N1 Influenza A Viruses Isolated from Different Hosts

The generation of a heterosubtypic memory T cell response is important for cross-protective immunity against unrelated strains of influenza virus. One way to facilitate the generation of the memory T cell population is to control the activity of immune modulatory agents. The enzyme, indoleamine 2,3-dioxygenase (IDO), is upregulated during influenza infection by the interferon response where IDO activity depletes tryptophan required in T cell response. In this study, IDO activity was pharmacologically inhibited with 1-methyl-tryptophan (1MT) during the primary response to influenza virus infection and the effect on the memory T cell response was evaluated. 1MT treatment improved the memory T cell response to influenza virus challenge by increasing interferon gamma expression by CD4 and CD8 T cells, and numbers of lung virus-specific CD8 + T cells, and increased the Th1 response as well as modifying the immunodominance hierarchy to increase the number of subdominant epitope specific CD8 + T cells, a feature which may be linked to decreased regulatory T cell function. These changes also accompanied evidence of accelerated lung tissue repair upon virus challenge. These findings suggest that modulation of IDO activity could be exploited in influenza vaccine development to enhance memory T cell responses and reduce disease burden.

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“…Virus titer was measured by TCID50 (49). Briefly, extracted lungs were homogenized using a tissue-lyser (Eppendorf, Hamburg, Germany).…”

Section: Influenza Virus Titer By Tcid50mentioning

confidence: 99%

Indoleamine 2,3-Dioxygenase (IDO) Activity During the Primary Immune Response to Influenza Infection Modifies the Memory T Cell Response to Influenza Challenge

et al. 2014

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“…Classical swine influenza virus isolates have been shown to be particularly pathogenic in mice and in ferrets (16,29). Here, we used the sw30 virus, which is highly lethal in mice.…”

Section: Figmentioning

confidence: 99%

“…We also wanted to investigate whether the in vitro neutralization activity translates to in vivo activity in a mouse model. We tested the prophylactic neutralizing activity of MAb 6F12 against several strains of H1 viruses: the mouse-adapted laboratory strain PR8, the classical swine influenza sw30, which resembles the 1918 pandemic H1N1 strain (29), the prepandemic seasonal strain SI06, and finally, a mouse-adapted 2009 pandemic strain, namely, NL09 (15).…”

Section: Selection and Characterization Of A Mab 6f12 Escape Mutantmentioning

confidence: 99%

A Pan-H1 Anti-Hemagglutinin Monoclonal Antibody with Potent Broad-Spectrum EfficacyIn Vivo

Tan

Krammer

Eggink

et al. 2012

J Virol

156

202

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Seasonal epidemics caused by antigenic variations in influenza A virus remain a public health concern and an economic burden. The isolation and characterization of broadly neutralizing anti-hemagglutinin monoclonal antibodies (MAb) have highlighted the presence of highly conserved epitopes in divergent influenza A viruses. Here, we describe the generation and characterization of a mouse monoclonal antibody designed to target the conserved regions of the hemagglutinin of influenza A H1 viruses, a subtype that has caused pandemics in the human population in both the 20th and 21st centuries. By sequentially immunizing mice with plasmid DNA encoding the hemagglutinin of antigenically different H1 influenza A viruses (A/South Carolina/1/1918, A/USSR/92/1977, and A/California/4/2009), we isolated and identified MAb 6F12. Similar to other broadly neutralizing MAb previously described, MAb 6F12 has no hemagglutination inhibition activity against influenza A viruses and targets the stalk region of hemagglutinins. As designed, it has neutralizing activity against a divergent panel of H1 viruses in vitro , representing 79 years of antigenic drift. Most notably, MAb 6F12 prevented gross weight loss against divergent H1 viruses in passive transfer experiments in mice, both in pre- and postexposure prophylaxis regimens. The broad but specific activity of MAb 6F12 highlights the potent efficacy of monoclonal antibodies directed against a single subtype of influenza A virus.

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“…In negative control animals (non-inoculated) the median number (range) of mononuclear cells is 0. 30 10 9 /L (0.13-0.37) in the blood and 17 (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22) in the alveolar lumina, for neutrophils 4.33 (3.07-7.28) in the blood and 0.5 (0-2) in the alveolar lumina. doi:10.1371/journal.pone.0042343.g009 Table 5.…”

Section: Discussionmentioning

confidence: 99%

Comparison of Temporal and Spatial Dynamics of Seasonal H3N2, Pandemic H1N1 and Highly Pathogenic avian influenza H5N1 Virus Infections in Ferrets

Brand

Stittelaar

Amerongen

et al. 2013

Journal of Comparative Pathology

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Humans may be infected by different influenza A viruses-seasonal, pandemic, and zoonotic-which differ in presentation from mild upper respiratory tract disease to severe and sometimes fatal pneumonia with extra-respiratory spread. Differences in spatial and temporal dynamics of these infections are poorly understood. Therefore, we inoculated ferrets with seasonal H3N2, pandemic H1N1 (pH1N1), and highly pathogenic avian H5N1 influenza virus and performed detailed virological and pathological analyses at time points from 0.5 to 14 days post inoculation (dpi), as well as describing clinical signs and hematological parameters. H3N2 infection was restricted to the nose and peaked at 1 dpi. pH1N1 infection also peaked at 1 dpi, but occurred at similar levels throughout the respiratory tract. H5N1 infection occurred predominantly in the alveoli, where it peaked for a longer period, from 1 to 3 dpi. The associated lesions followed the same spatial distribution as virus infection, but their severity peaked between 1 and 6 days later. Neutrophil and monocyte counts in peripheral blood correlated with inflammatory cell influx in the alveoli. Of the different parameters used to measure lower respiratory tract disease, relative lung weight and affected lung tissue allowed the best quantitative distinction between the virus groups. There was extra-respiratory spread to more tissues-including the central nervous system-for H5N1 infection than for pH1N1 infection, and to none for H3N2 infection. This study shows that seasonal, pandemic, and zoonotic influenza viruses differ strongly in the spatial and temporal dynamics of infection in the respiratory tract and extra-respiratory tissues of ferrets.

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Comparative Pathology in Ferrets Infected with H1N1 Influenza A Viruses Isolated from Different Hosts

Cited by 28 publications

References 36 publications

Indoleamine 2,3-Dioxygenase (IDO) Activity During the Primary Immune Response to Influenza Infection Modifies the Memory T Cell Response to Influenza Challenge

Indoleamine 2,3-Dioxygenase (IDO) Activity During the Primary Immune Response to Influenza Infection Modifies the Memory T Cell Response to Influenza Challenge

A Pan-H1 Anti-Hemagglutinin Monoclonal Antibody with Potent Broad-Spectrum EfficacyIn Vivo

Comparison of Temporal and Spatial Dynamics of Seasonal H3N2, Pandemic H1N1 and Highly Pathogenic avian influenza H5N1 Virus Infections in Ferrets

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