Alveolar macrophages initiate lung innate immune responses
File(s)
Author(s)
Makris, Spyridon
Type
Thesis
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.
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.
Version
Open Access
Date Issued
2017-02
Date Awarded
2017-06
Copyright Statement
Attribution NoDerivatives 4.0 International Licence (CC BY-ND)
Advisor
Johansson, Cecilia
Culley, Fiona
Sponsor
Rosetrees Trust
Medical Research Council (Great Britain)
Grant Number
M370
G0800311
Publisher Department
National Heart & Lung Institute
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)