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Title: Immunology of the neonatal lung and the long term consequences of neonatal respiratory virus infection for pulmonary innate immunity
Author: Lambert, Laura
ISNI:       0000 0004 6495 5957
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2015
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Early life is a period of increased vulnerability to infection, particularly of the respiratory tract. The neonatal adaptive immune system is immature, with a bias towards Th2/Th17 responses and against Th1. Very little is understood about the innate response in early life, especially at mucosal surfaces such as the lung. To address this, Toll-like receptor (TLR) ligands were administered intranasally to neonatal and adult mice. In neonates, pulmonary neutrophilic influx was barely detectable, and expression of inflammatory chemokines greatly attenuated. Administration of exogenous CXCL1 elicited a strong neutrophilic response, indicating that diminished chemokine production is a limiting factor for cellular inflammation in early life. An unbiased microarray approach revealed that whilst expression of immune-related genes was mostly suppressed in the naïve neonatal lung, antimicrobial peptides such as cathelicidin were over-expressed. These novel findings challenge the perception that the infant immune system is simply an ‘immature’ version of the adult system, with implications for development of vaccines and adjuvants for this vulnerable population. An important respiratory pathogen of infants is respiratory syncytial virus (RSV), which can cause bronchiolitis, and in clinical studies is linked with lung dysfunction such as asthma and wheezing later in life. However, the mechanisms by which early life RSV infection could cause these delayed sequelae are unknown, and the effect on the innate immune response has not been explored. The long-term consequences of early life RSV infection were investigated using a murine model. Following neonatal RSV infection, allergen challenge resulted in an exaggerated inflammatory response in the adult murine lung, indicating that pulmonary innate immunity was dysregulated. Further, expression of various immune response, apoptosis-related and circadian rhythm genes was found to be altered. These data provide new evidence that infantile RSV has a causative effect on later lung dysfunction and identify gene targets for further investigation.
Supervisor: Culley, Fiona J. Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral