Regulation of Phagocyte Immunity: Genes, Age and Microbes

Abstract

Background: Phagocytes have diverse roles including the ingestion and clearance of microbes, foreign particulate matter and dead cells. The study of patients with phagocyte dysfunction, either because of young age or inborn errors of immunity, could help design novel immunomodulatory treatments. However, such insights have been limited by a lack of access to the relevant clinical samples. Methods: Phagocytes from three groups of infants and children with clinical features of phagocyte dysfunction, obtained by novel sample collection methods, were studied by in vitro functional and transcriptomic testing. Results: Analysis of the clinical phenotype combined with functional testing of patient phagocytes demonstrated: i) primary alveolar macrophages isolated from healthy infants exhibited poorer control of Mycobacterium tuberculosis replication, as well as reduced expression of genes involved in lysosomal function and mycobactericidal activity, as well as genes encoding chemokines, which may explain the observed clinical vulnerability of infants to severe tuberculosis; ii) impaired control of mycobacterial replication by monocyte-derived macrophages of children with deletion of genes involved in cholesterol metabolism (LIPA and CH25H) is associated with clinical susceptibility to infection caused by Bacillus Calmette–Guérin vaccination; and iii) neutrophils from children with glucose-6-phosphatase catalytic subunit 3 deficiency exhibited increased inflammatory responses, which drives inflammatory bowel disease and can be corrected by haematopoietic stem cell transplant. Conclusion: Age-dependent and genetic factors make clinically important contributions to phagocyte immunity.

Date of Award	31 Dec 2018
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Peter Arkwright (Supervisor) & Tracy Hussell (Supervisor)