Viral-induced type 2 immunity and immune regulation by farmyard microbes in early life
File(s)
Author(s)
Tian, Kunyuan
Type
Thesis
Abstract
Severe, recurrent respiratory viral infections in early life, such as those caused by respiratory syncytial virus (RSV), or rhinovirus (RV) are associated with recurrent wheezing and asthma in later life. Exposure to farmyard microbes protects against allergen-induced asthma, but the ability to influence viral-induced airways disease and associated immune responses is unknown. Here murine recurrent RSV infection in early life was found to promote pulmonary eosinophilia, mucus hypersecretion and Th2 responses, in particular IL-13+ CD4+ T cells. These pathological features were ameliorated by concomitant inhalation of the inactivated cowshed-derived bacteria, Acinetobacter lwoffii (A.lwoffii ) F78. While short-term exposure to inhaled A.lwoffii , during primary or recurrent RSV infection, resulted in partial protection against Th2- associated pathologies, the protective effect was maximal with continuous A.lwoffii exposure throughout recurrent viral infection. Protection was observed in conjunction with increased circulatory, airway luminal and lung parenchymal neutrophils. Unlike the pro-inflammatory neutrophils induced by RSV infection however transcriptomic and phenotypic analysis revealed A.lwoffii exposure induced a distinct population of neutrophils, characterised by reduced expression of CXCR4, CD11b and CD101, but elevated PD-L1, an immunoregulatory molecule that limits T cell responses. Our findings highlight the increasingly appreciated concept of neutrophil heterogeneity and reveal the potential role of immunoregulatory neutrophils induced by protective microbes in modulating type 2 immune responses to viral infections, and asthma development in early life.
Version
Open Access
Date Issued
2023-08-01
Date Awarded
12/08/2024
License URL
Advisor
Saglani, Sejal
Lloyd, Clare
James, Harker
Sponsor
Asthma + Lung UK (Trust)
Rosetrees Trust (Trust)
Grant Number
AUK-PHD-2016-372
M678
Publisher Department
National Heart and Lung Institute
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)