7 research outputs found

    Prevention of Influenza Virus-Induced Immunopathology by TGF-β Produced during Allergic Asthma

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    <div><p>Asthma is believed to be a risk factor for influenza infection, however little experimental evidence exists to directly demonstrate the impact of asthma on susceptibility to influenza infection. Using a mouse model, we now report that asthmatic mice are actually significantly more resistant to a lethal influenza virus challenge. Notably, the observed increased resistance was not attributable to enhanced viral clearance, but instead, was due to reduced lung inflammation. Asthmatic mice exhibited a significantly reduced cytokine storm, as well as reduced total protein levels and cytotoxicity in the airways, indicators of decreased tissue injury. Further, asthmatic mice had significantly increased levels of TGF-β1 and the heightened resistance of asthmatic mice was abrogated in the absence of TGF-β receptor II. We conclude that a transient increase in TGF-β expression following acute asthma can induce protection against influenza-induced immunopathology.</p></div

    Innate immune responses are dispensable for the increased resistance of asthmatic mice.

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    <p>(<b>A</b> and <b>B</b>) OVA-induced allergic inflammation was induced in IFN-α/βR<sup>-/-</sup> mice as described in the legend for <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1005180#ppat.1005180.g001" target="_blank">Fig 1</a>. Non-asthmatic and asthmatic IFN-α/βR<sup>-/-</sup> mice were challenged with CA04 virus and were monitored for survival (A) and weight loss (B) (5–6 mice/group). (<b>C</b> to <b>H</b>) Non-asthmatic and asthmatic mice were depleted of various innate immune cells, infected, and monitored for survival. Mice were treated with RB6-8C5 rat mAb for neutrophil depletion (C and D) (4–6 mice/group), clodronate liposomes (L-CL2MDP) for phagocyte depletion (E and F) (9–14 mice/group), and NK1.1 rat mAb for NK cell depletion (G and H) (6–8 mice/group). Control mice were treated with rat IgG or PBS liposomes (L-PBS). Survival and weight loss were monitored for 20 days. *P<0.05, **P<0.01, ***P<0.001.</p

    Comparable humoral immunity in non-asthmatic and asthmatic mice.

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    <p>(<b>A</b> to <b>D</b>) Non-asthmatic and asthmatic mice were infected with 4LD<sub>50</sub> of CA04 virus. Seven days after primary challenge, BALF were tested for total (A), IgG1 (B), IgG2a (C), and IgG2b (D) antibody binding (4–5 mice/group). (<b>E</b>) Hemagglutination inhibition titers of BALF samples were determined (4–5 mice/group). (<b>F</b>) The numbers of CD19<sup>+</sup> B cells were enumerated in the lung at various time points after CA04 virus infection (4 mice/group). *P<0.05.</p

    Influenza virus induced immunopathology is reduced in asthmatic mice.

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    <p>Non-asthmatic and asthmatic mice were infected i.n. with 4LD<sub>50</sub> of the CA04 virus on day 7 after the last PBS or OVA treatment. The lungs were harvested and homogenized for cytokine quantification at various times following influenza infection. (<b>A</b> to <b>E</b>) Pulmonary cytokine levels were measured by cytometric bead array. (<b>F</b>) Cytotoxicity in BALF was determined by measuring glucose 6-phosphate. (<b>G</b> and <b>H</b>) Total protein levels in BALF were measured using the Pierce BCA Protein Kit following challenge with 4 LD<sub>50</sub> (G) or 400LD<sub>50</sub> (H) of CA04. (<b>I to K</b>) Viral burdens were determined in BALF after challenge with either 4 LD<sub>50</sub> (I) or 400LD<sub>50</sub> (J) of CA04 or 4LD<sub>50</sub> of PR8 (K). Each bar indicates mean ± SD of 3–5 mice/group. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001.</p

    Asthmatic mice are highly resistant to influenza A virus challenge.

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    <p>(<b>A</b>) The general experimental procedure used in this study. Mice were first sensitized to OVA by two i.p. injections, followed by i.n. OVA treatment for 5 consecutive days to induce asthma. Control non-asthmatic mice received PBS only. Asthmatic and non-asthmatic mice were challenged i.n. with PR8 or CA04 influenza A virus at different time points after the last OVA treatment. (<b>B</b> and <b>C</b>) At day 7 after the last PBS or OVA treatment, asthmatic and non-asthmatic mice were infected with either 4, 40 or 400LD<sub>50</sub> of CA04 influenza virus (8 mice/group). Infected mice were monitored for survival (B) and weight loss (C). (<b>D</b> and <b>E</b>) Groups of non-asthmatic and asthmatic mice were challenged with either egg-grown PR8 strain (2x10<sup>3</sup> PFU) (D) or MDCK grown CA04 virus (6x10<sup>4</sup> TCID<sub>50</sub>) (E). Infected mice were monitored for 20 days for survival (5 mice/group). (<b>F</b>) A mouse model of HDM-induced asthma. (<b>G</b> and <b>H</b>) HDM-induced asthmatic and non-asthmatic mice were i.n. challenged with CA04 virus either 1, 2, or 3 weeks following HDM challenge. Weight loss (<b>G</b>) and survival (<b>H</b>) were monitored for 20 days (5 mice/group). *P<0.05; **P<0.01; ***P<0.001.</p

    TGF-β mediates increased resistance in asthmatic mice.

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    <p>(<b>A</b>) TGF-β1 levels in BALF of noninfluenza-infected asthmatic mice (4 mice/group) were determined by ELISA. The dotted line represents background TGF-β1 levels in BALF of non-asthmatic mice. (<b>B</b>) TGF-β1 levels in BALF after CA04 infection were determined by Luminex (3–4 mice/group). (<b>C</b>) Cell surface expression of LAP was measured on day 7 after the last OVA inoculation (4 mice/group). (<b>D</b> and <b>E</b>) Asthmatic mice (5–8 mice/group) infected at different time points after the last OVA treatment were monitored for survival (D) and weight loss (E). (<b>F</b> and <b>G</b>) Survival of <i>TβRII</i><sup><i>f/f</i></sup><i>-Cre</i> and control mice were monitored for survival after infection of either 2x10<sup>3</sup> PFU (F) or 50 PFU (G) of CA04 (4–8 mice/group). (<b>H</b> and <b>I</b>) Total protein levels (H) and viral burdens (I) in BALF were measured on day 3 post-infection (6 mice/group). *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001.</p

    Increased resistance in asthmatic mice is T cell independent.

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    <p>(<b>A</b> to <b>D</b>) Groups of non-asthmatic and asthmatic mice were infected with CA04 virus on day 7 after the last OVA or PBS inoculation. Lungs were isolated on days 3, 5, and 7 post-infection and single cell suspensions were stained for CD4 (A and B), and nucleoprotein (NP)-specific CD8 (C) cells (4 mice/group). A representative dot plot for each group is shown with percentages of NP<sup>+</sup>CD8<sup>+</sup> T cells in the lung (D). (<b>E</b>) BALF Gzm B levels on day 7 post-infection were quantified by ELISA (4–5 mice/group). (<b>F</b>) T cells were depleted by i.p. injection of GK1.5 and 53–6.72 mAb after the last PBS or OVA inoculation. Control mice were treated with rat IgG. Control and T cell-depleted mice were challenged with CA04 virus and monitored for survival (4–8 mice/group). *P<0.05, **P<0.01.</p
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