PLoS One. 2014 Nov 14;9(11):e111520.

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

 

Strickland DH1, Fear V1, Shenton S2, Wikstrom ME1, Zosky G3, Larcombe AN1, Holt PG4, Berry C5, von Garnier C6, Stumbles PA2.
  • 1Telethon Institute for Child Health Research and Centre for Child Health Research, University of Western Australia, Perth, W.A., Australia.
  • 2Telethon Institute for Child Health Research and Centre for Child Health Research, University of Western Australia, Perth, W.A., Australia; School of Veterinary and Life Sciences, Murdoch University, Perth, W.A., Australia.
  • 3Telethon Institute for Child Health Research and Centre for Child Health Research, University of Western Australia, Perth, W.A., Australia; School of Medicine, University of Tasmania, Hobart, Tasmania, Australia.
  • 4Telethon Institute for Child Health Research and Centre for Child Health Research, University of Western Australia, Perth, W.A., Australia; Queensland Children’s Medical Research Institute, University of Queensland, Brisbane, Qld., Australia.
  • 5School of Veterinary and Life Sciences, Murdoch University, Perth, W.A., Australia.
  • 6Telethon Institute for Child Health Research and Centre for Child Health Research, University of Western Australia, Perth, W.A., Australia; Pulmonary Medicine, Bern University Hospital and Department of Clinical Research, Berne University, Berne, Switzerland.

 

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.

PMID: 25398128

 

Supplement

Why we did the study: Influenza A virus (IAV) is a common and serious respiratory pathogen, with early-life infections having a potentially deleterious consequences for lung development and establishment of respiratory immunological homeostasis in later life. The virus initially infects and then damages airway epithelial cells (AEC), resulting in intense local and systemic inflammatory responses. Airway mucosal dendritic cells (AMDC) reside in the epithelium and submucosa of the mucosal surfaces of the large and small conducting airways, where they are in intimate contact with AEC (see Figure 1). AMDC provide a “front line” surveillance of inhaled materials and direct the nature of the immune response (if any) that should develop. For example, for inhaled pathogens a rapid immune response must develop to avoid damage to the host, however for harmless proteins such as allergens an immune response can be more damaging than beneficial. We have previously shown that AMDC are important regulators of airway immunity, determining the balance between promoting (immunity) or dampening (regulation) the T cell responses to inhaled allergens, pathogens or particles (see Figure 2). AMDC are thought to rely on interactions with AEC to regulate their function and retention within the airway mucosa, and thus any damage to AEC could potentially disrupt the fine immune regulatory balance provided by subsets of AMDC.

 

Microsoft Word - Document2

 

Our hypothesis: While the immediate effects of IAV infection on DC subsets has been previously described, our hypothesis was that damage to AEC following IAV infection would lead to long-term disruption to AMDC homeostasis due to the damage to the potential for prolonged damage to the airway epithelium as a result of the intense inflammatory response, even after the virus has been cleared. We further hypothesised that the damage would be more pronounced in juvenile mice and could persist into adulthood, which would have potential issues for immune regulation to inhaled allergens in adult mice after juvenile IAV exposure.

Microsoft Word - Document2How we did it and what we found: In this study we used a mouse model of human IAV infection using the mouse adapted A/PR8/34 H1N1 influenza a virus. We developed infection models for both adult mice and mice that had just been weaned (juvenile) and showed that juvenile mice develop clinical symptoms and recover from a non-lethal IAV infection over a similar time course as to adults. Using flow cytometry of mouse tracheal cells, we then showed changes in the numbers, ratios and activation status of AMDC subsets (CD11bhi and CD11blo) that persisted for up to 3 weeks after infection in adult mice, well after viral clearance from the lungs. In juvenile mice, a similar disruption was observed, however in this case were able to observe the disruptions for up to 5 weeks after IAV infection, at a time when the mice had reached what would typically be considered the equivalent of human adulthood.

What does it mean? Early-life IAV infections are a significant health issue, being linked to the development and exacerbation of serious adult lung diseases such as allergic asthma. Although the immunological impacts of IAV infections have been extensively studied, most studies have primarily focussed on adult short-term resolution responses, and have generally not examined the longer-term disruption to mucosal populations of AMDC, especially following juvenile infection. Our data could have a direct clinical impact, as a better understanding of the impact of early-life IAV infection on the developing lung immune system may lead to early interventions after viral infection to re-establish AMDC networks and immune homeostasis so as to avert the potential onset of respiratory inflammatory diseases such as allergic asthma in later life.

 

 

 

 

 

 

 

 

 

 

References:

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  8. von Garnier, C., L. Filgueira, M. Wikstrom, M. Smith, J. A. Thomas, D. H. Strickland, P. G. Holt, and P. A. Stumbles. 2005. Anatomical location determines the distribution and function of dendritic cells and other APCs in the respiratory tract. J immunol 175: 1609-1618.
  9. Stumbles, P. A., D. H. Strickland, C. L. Pimm, S. F. Proksch, A. M. Marsh, A. S. McWilliam, A. Bosco, I. Tobagus, J. A. Thomas, S. Napoli, A. E. Proudfoot, T. N. Wells, and P. G. Holt. 2001. Regulation of dendritic cell recruitment into resting and inflamed airway epithelium: use of alternative chemokine receptors as a function of inducing stimulus. J immunol 167: 228-234.
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