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Persistent and compartmentalised disruption of dendritic cell subpopulations in the lung following influenza A virus infection.

Strickland DH, Fear V, Shenton S, Wikstrom ME, Zosky G, Larcombe AN, Holt PG, Berry C, von Garnier C, Stumbles PA - PLoS ONE (2014)

Bottom Line: A significant depletion in the percentage of AMDC was observed at day 4 post-infection that was associated with a change in steady-state CD11b+ and CD11b- AMDC subset frequencies and significantly elevated CD40 and CD80 expression and that returned to baseline by day 14 post-infection.In contrast, percentages and total numbers of PLDC were significantly elevated at day 14 and remained so until day 21 post-infection.Accompanying this was a change in CD11b+and CD11b- PLDC subset frequencies and significant increase in CD40 and CD80 expression at these time points.

View Article: PubMed Central - PubMed

Affiliation: Telethon Institute for Child Health Research and Centre for Child Health Research, University of Western Australia, Perth, W.A., Australia.

ABSTRACT
Immunological homeostasis in the respiratory tract is thought to require balanced interactions between networks of dendritic cell (DC) subsets in lung microenvironments in order to regulate tolerance or immunity to inhaled antigens and pathogens. Influenza A virus (IAV) poses a serious threat of long-term disruption to this balance through its potent pro-inflammatory activities. In this study, we have used a BALB/c mouse model of A/PR8/34 H1N1 Influenza Type A Virus infection to examine the effects of IAV on respiratory tissue DC subsets during the recovery phase following clearance of the virus. In adult mice, we found differences in the kinetics and activation states of DC residing in the airway mucosa (AMDC) compared to those in the parenchymal lung (PLDC) compartments. A significant depletion in the percentage of AMDC was observed at day 4 post-infection that was associated with a change in steady-state CD11b+ and CD11b- AMDC subset frequencies and significantly elevated CD40 and CD80 expression and that returned to baseline by day 14 post-infection. In contrast, percentages and total numbers of PLDC were significantly elevated at day 14 and remained so until day 21 post-infection. Accompanying this was a change in CD11b+and CD11b- PLDC subset frequencies and significant increase in CD40 and CD80 expression at these time points. Furthermore, mice infected with IAV at 4 weeks of age showed a significant increase in total numbers of PLDC, and increased CD40 expression on both AMDC and PLDC, when analysed as adults 35 days later. These data suggest that the rate of recovery of DC populations following IAV infection differs in the mucosal and parenchymal compartments of the lung and that DC populations can remain disrupted and activated for a prolonged period following viral clearance, into adulthood if infection occurred early in life.

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Clinical features of the adult BALB/c mouse model of A/PR8/34 H1N1 influenza A virus (IAV) infection.Eight week-old female BALB/c mice were inoculated i.n. with 1×102 TCID50 A/PR/8/34 influenza A virus (IAV) in PBS and assessed at the indicated time points over the following 21 days for (A) body weight (B) clinical score and (C) lung tissue viral titres. Data are mean +/− SEM of groups of 20 to 60 mice per time point for weight measurements and clinical score, and 5 mice per time point for lung viral titres. Control mice received equivalent volumes of virus-free DMEM i.n. at day 0. (D) Measurement of airway resistance, tissue damping and tissue elastance at transrespiratory pressure during slow inflation manoeuvres up to 20cm H2O in influenza infected mice (closed circles) and controls (open circles) at day 4 post infection. Influenza infected mice had impairments in Raw, G and H. Asterisks indicate statistical significance of IAV infected as compared to control mice as described in Materials and Methods. Data are means +/− SEM of 4 mice per group. *  =  p<0.05; **  =  p<0.01; ***  =  p<0.001.
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pone-0111520-g001: Clinical features of the adult BALB/c mouse model of A/PR8/34 H1N1 influenza A virus (IAV) infection.Eight week-old female BALB/c mice were inoculated i.n. with 1×102 TCID50 A/PR/8/34 influenza A virus (IAV) in PBS and assessed at the indicated time points over the following 21 days for (A) body weight (B) clinical score and (C) lung tissue viral titres. Data are mean +/− SEM of groups of 20 to 60 mice per time point for weight measurements and clinical score, and 5 mice per time point for lung viral titres. Control mice received equivalent volumes of virus-free DMEM i.n. at day 0. (D) Measurement of airway resistance, tissue damping and tissue elastance at transrespiratory pressure during slow inflation manoeuvres up to 20cm H2O in influenza infected mice (closed circles) and controls (open circles) at day 4 post infection. Influenza infected mice had impairments in Raw, G and H. Asterisks indicate statistical significance of IAV infected as compared to control mice as described in Materials and Methods. Data are means +/− SEM of 4 mice per group. *  =  p<0.05; **  =  p<0.01; ***  =  p<0.001.

Mentions: An adult BALB/c mouse model of IAV infection was established, using intranasal (i.n.) delivery of an optimised dose of the mouse-adapted A/PR/8/34 (H1N1) type A influenza virus (IAV). Using this protocol, mice developed peak clinical symptoms on d9 to d10 post-infection (p.i.) as evidenced by body weight loss (Fig. 1A) and clinical score (Fig. 1B), with mice recovering to pre-infection clinical score and weight by d14 and d21 p.i. respectively. Lung tissue viral titres were elevated at d3 p.i. and completely resolved by d14 p.i. (Fig. 1C). Lung mechanics were also altered at d4 p.i., with IAV infected mice showing increased airway resistance at functional residual capacity (FRC) (p<0.001), which was maintained throughout inflation up to 20 cmH2O transrespiratory pressure (p<0.001) (Fig. 1D, left panel). Similarly, IAV infected mice had increased tissue damping (0 cm H2O, p<0.01) (Fig. 1D, middle panel) and tissue elastance (0 cm H2O, p  =  0.002; 20 cm H2O, p <0.001) (Fig. 1D, right panel), although at high pressures there was no difference in tissue damping between influenza infected mice and controls.


Persistent and compartmentalised disruption of dendritic cell subpopulations in the lung following influenza A virus infection.

Strickland DH, Fear V, Shenton S, Wikstrom ME, Zosky G, Larcombe AN, Holt PG, Berry C, von Garnier C, Stumbles PA - PLoS ONE (2014)

Clinical features of the adult BALB/c mouse model of A/PR8/34 H1N1 influenza A virus (IAV) infection.Eight week-old female BALB/c mice were inoculated i.n. with 1×102 TCID50 A/PR/8/34 influenza A virus (IAV) in PBS and assessed at the indicated time points over the following 21 days for (A) body weight (B) clinical score and (C) lung tissue viral titres. Data are mean +/− SEM of groups of 20 to 60 mice per time point for weight measurements and clinical score, and 5 mice per time point for lung viral titres. Control mice received equivalent volumes of virus-free DMEM i.n. at day 0. (D) Measurement of airway resistance, tissue damping and tissue elastance at transrespiratory pressure during slow inflation manoeuvres up to 20cm H2O in influenza infected mice (closed circles) and controls (open circles) at day 4 post infection. Influenza infected mice had impairments in Raw, G and H. Asterisks indicate statistical significance of IAV infected as compared to control mice as described in Materials and Methods. Data are means +/− SEM of 4 mice per group. *  =  p<0.05; **  =  p<0.01; ***  =  p<0.001.
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pone-0111520-g001: Clinical features of the adult BALB/c mouse model of A/PR8/34 H1N1 influenza A virus (IAV) infection.Eight week-old female BALB/c mice were inoculated i.n. with 1×102 TCID50 A/PR/8/34 influenza A virus (IAV) in PBS and assessed at the indicated time points over the following 21 days for (A) body weight (B) clinical score and (C) lung tissue viral titres. Data are mean +/− SEM of groups of 20 to 60 mice per time point for weight measurements and clinical score, and 5 mice per time point for lung viral titres. Control mice received equivalent volumes of virus-free DMEM i.n. at day 0. (D) Measurement of airway resistance, tissue damping and tissue elastance at transrespiratory pressure during slow inflation manoeuvres up to 20cm H2O in influenza infected mice (closed circles) and controls (open circles) at day 4 post infection. Influenza infected mice had impairments in Raw, G and H. Asterisks indicate statistical significance of IAV infected as compared to control mice as described in Materials and Methods. Data are means +/− SEM of 4 mice per group. *  =  p<0.05; **  =  p<0.01; ***  =  p<0.001.
Mentions: An adult BALB/c mouse model of IAV infection was established, using intranasal (i.n.) delivery of an optimised dose of the mouse-adapted A/PR/8/34 (H1N1) type A influenza virus (IAV). Using this protocol, mice developed peak clinical symptoms on d9 to d10 post-infection (p.i.) as evidenced by body weight loss (Fig. 1A) and clinical score (Fig. 1B), with mice recovering to pre-infection clinical score and weight by d14 and d21 p.i. respectively. Lung tissue viral titres were elevated at d3 p.i. and completely resolved by d14 p.i. (Fig. 1C). Lung mechanics were also altered at d4 p.i., with IAV infected mice showing increased airway resistance at functional residual capacity (FRC) (p<0.001), which was maintained throughout inflation up to 20 cmH2O transrespiratory pressure (p<0.001) (Fig. 1D, left panel). Similarly, IAV infected mice had increased tissue damping (0 cm H2O, p<0.01) (Fig. 1D, middle panel) and tissue elastance (0 cm H2O, p  =  0.002; 20 cm H2O, p <0.001) (Fig. 1D, right panel), although at high pressures there was no difference in tissue damping between influenza infected mice and controls.

Bottom Line: A significant depletion in the percentage of AMDC was observed at day 4 post-infection that was associated with a change in steady-state CD11b+ and CD11b- AMDC subset frequencies and significantly elevated CD40 and CD80 expression and that returned to baseline by day 14 post-infection.In contrast, percentages and total numbers of PLDC were significantly elevated at day 14 and remained so until day 21 post-infection.Accompanying this was a change in CD11b+and CD11b- PLDC subset frequencies and significant increase in CD40 and CD80 expression at these time points.

View Article: PubMed Central - PubMed

Affiliation: Telethon Institute for Child Health Research and Centre for Child Health Research, University of Western Australia, Perth, W.A., Australia.

ABSTRACT
Immunological homeostasis in the respiratory tract is thought to require balanced interactions between networks of dendritic cell (DC) subsets in lung microenvironments in order to regulate tolerance or immunity to inhaled antigens and pathogens. Influenza A virus (IAV) poses a serious threat of long-term disruption to this balance through its potent pro-inflammatory activities. In this study, we have used a BALB/c mouse model of A/PR8/34 H1N1 Influenza Type A Virus infection to examine the effects of IAV on respiratory tissue DC subsets during the recovery phase following clearance of the virus. In adult mice, we found differences in the kinetics and activation states of DC residing in the airway mucosa (AMDC) compared to those in the parenchymal lung (PLDC) compartments. A significant depletion in the percentage of AMDC was observed at day 4 post-infection that was associated with a change in steady-state CD11b+ and CD11b- AMDC subset frequencies and significantly elevated CD40 and CD80 expression and that returned to baseline by day 14 post-infection. In contrast, percentages and total numbers of PLDC were significantly elevated at day 14 and remained so until day 21 post-infection. Accompanying this was a change in CD11b+and CD11b- PLDC subset frequencies and significant increase in CD40 and CD80 expression at these time points. Furthermore, mice infected with IAV at 4 weeks of age showed a significant increase in total numbers of PLDC, and increased CD40 expression on both AMDC and PLDC, when analysed as adults 35 days later. These data suggest that the rate of recovery of DC populations following IAV infection differs in the mucosal and parenchymal compartments of the lung and that DC populations can remain disrupted and activated for a prolonged period following viral clearance, into adulthood if infection occurred early in life.

Show MeSH
Related in: MedlinePlus