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Title: Alveolar macrophages initiate lung innate immune responses
Author: Makris, Spyridon
ISNI:       0000 0004 7963 7062
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2017
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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.
Supervisor: Johansson, Cecilia ; Culley, Fiona Sponsor: Rosetrees Trust ; Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral