Stumbles PA, Smith M, Bozanich E, Fear V, Wikstrom M, Thomas J, Napoli S, Zosky GR, Larcombe AN, Sly PD, Berry C, von Garnier C, Holt PG and Strickland DH.
The Kids Research Institute Australia, The University of Western Australia, Perth, School of Pathology, Murdoch University, Perth Western Australia.
The respiratory tract (RT) is continually exposed to a plethora of environmental antigens of pathogenic and non-pathogenic nature within inhaled air. To best maintain the crucial normal function of the respiratory tissues the respiratory immune system must constantly screen these antigens for their potential danger to the host and rapidly neutralize the threat, or alternatively must effectively ignore harmless antigens to effectively minimize unnecessary inflammation. A balanced network of antigen presenting cells (APC) play an important role in this process and are capable of regulating tolerance or immunity as required. Respiratory viral infections can pose a serious threat to immunological homeostasis in the RT via the induction of potent inflammatory and cytotoxic responses in local tissues. Disruption to the balance of immunity in the RT can last for a prolonged period following infection, and this may potentially result in modified immune responses to other antigens during this time frame. This includes increasing the risk of allergic sensitization or decreasing resistance to secondary infections. In this study, we have used an experimental mouse model of H1N1 Influenza Type A Virus (IAV) infection in adult and juvenile animals to examine the dynamics and activation states of APC in airway mucosal (AM) and parenchymal lung (PL) tissue of the RT following a time course post IAV. We found marked differences in the selective depletion and reconstitution of dendritic cells (DC) subsets in the AM and PL environments. In adult mice, DC in the AM were shown to have a generally more acute response to infection that resolved by day 7, versus a more delayed response with persistent depletion of PL DC subsets lasting for up to 3 weeks following infection. Tissue-resident macrophages populations in the PL were also significantly altered well after viral clearance, being significantly depleted and remaining in a persistent state of activation. In juvenile mice, persistent changes in PL DC and macrophages were found for up to 5 weeks following IAV infection. These data demonstrate that IAV has differential effects on APC populations in different micro-environmental tissue compartments of the RT, leading to long-term derangement in the numbers and activation states of these cells, which likely disrupt the fine balance of immunological protection in this environment.
Lay summary:
Respiratory viral infections in early life years has been linked to increased risk for a child to develop allergic asthmatic disease. This project investigates how different populations of cells within the respiratory tract immune system are altered during a viral infection. This will help us to understand how it might be possible to prevent allergic asthmatic disease from developing in those children that are at risk following respiratory viral infections during early childhood.
This project is funded by the National Health and Medical Research Council of Australia.