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Alveolar macrophages initiate lung innate immune responses

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Title: Alveolar macrophages initiate lung innate immune responses
Authors: Makris, Spyridon
Item Type: Thesis or dissertation
Abstract: Alveolar macrophages (AMs) are one of the first cells to respond to inhaled pathogens. The RIG-I-like receptors (RLRs) are critical for recognition of respiratory syncytial virus (RSV), a common cause of lower respiratory tract infections. Upon detection of the virus, RLRs signal via MAVS to induce the synthesis of pro-inflammatory mediators, including type-I-interferons (IFNs), which trigger and shape antiviral responses and protect cells from infection. AMs are among the first immune cells to encounter RSV and the main producers of type I IFNs. The ability of AMs to restrict viral replication places AMs as ideal sensors of RSV infections and important initiators of immune responses in the lung. Whether IFNs act to prevent AMs from serving as vehicles for viral replication remains unclear. To answer this question, AMs from MAVS (Mavs-/-) or type I IFN receptor (Ifnar1-/-) deficient mice were exposed to RSV ex vivo and in vivo. Wildtype (wt) AMs but not Mavs-/- or Ifnar1-/- AMs produced inflammatory mediators in response to RSV. Furthermore, Mavs-/- and Ifnar1-/- AMs accumulated more RSV proteins compared to wt, however the infection was abortive, demonstrating that induction of pro-inflammatory mediators from AMs upon RSV infection, but not the viral restriction, depends on RLR-MAVS and IFNAR signalling. Infants are vulnerable to severe RSV infection, which may require hospitalisation, and which is associated with asthma and wheezing in adolescence. Upon RSV infection, neonatal mice lack an enhanced innate response compared to adults. In order to understand this characteristic and examine potential adjuvants that can boost an immune response, neonates were exposed to various pattern recognition receptor ligands agonists (R848, imiquimod, CpG, poly(I:C) and LPS). When compared to adults, the neonates responded strongly to R848 and not to the other stimuli, highlighting the importance of TLR7 signalling in neonates. Improving the understanding of this response and the cell types responsible can open avenues to using ligands as potential vaccine adjuvants to RSV.
Content Version: Open Access
Issue Date: Feb-2017
Date Awarded: Jun-2017
URI: http://hdl.handle.net/10044/1/70116
DOI: https://doi.org/10.25560/70116
Supervisor: Johansson, Cecilia
Culley, Fiona
Sponsor/Funder: Rosetrees Trust
Medical Research Council (Great Britain)
Funder's Grant Number: M370
G0800311
Department: National Heart & Lung Institute
Publisher: Imperial College London
Qualification Level: Doctoral
Qualification Name: Doctor of Philosophy (PhD)
Appears in Collections:National Heart and Lung Institute PhD theses



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