Neutrophils and Non-tuberculous Mycobacteria

Abstract

Recent work suggested that neutrophils may play a role in controlling Non-Tuberculous Mycobacterial (NTM) infection. These cells, however, also contribute to host disease, such as bronchiectasis. This thesis has investigated neutrophil responses to non-tuberculous mycobacterial infection in three distinct adult human populations: people with antibody deficiency (Common Variable Immune Deficiency, CVID) or X-linked Agammaglobulinemia (XLA), people with NTM pulmonary disease (NTM-PD), and a healthy comparator group. The CVID/XLA cohort was chosen because of their infrequent acquisition of NTM infection despite bronchiectasis. I evaluated neutrophil activation, surface markers expression, and their phagocytic ability for labelled M. abscessus and M. avium in addition to mycobacterial growth over a 4-day incubation for both species in a whole blood assay. These experiments revealed significant differences in neutrophil activation and immaturity between patient groups and healthy individuals, and greater phagocytosis with a more marked activation response to M. abscessus than M. avium. Additionally, I assessed opsonization in serum and sputum across groups, finding superior serum opsonic capacity in CVID/XLA patients. I explored the broader immune response to NTM by assessing cytokines, chemokines, growth factors, neutrophil-derived proteins, and antibodies in various samples, revealing that CVID/XLA patients exhibit notable inflammation, marked by elevated cytokine levels, yet differ in neutrophilic inflammatory markers compared to NTM-PD patients. In adults with NTM-PD, I examined the relationship between neutrophil markers, humoral immune response indicators, and health status with radiological lung disease severity. Results indicated a significant positive correlation between serum neutrophil markers and bronchiectasis severity CT scan scores. Additionally, transcriptomic analysis identified distinct gene expression patterns associated with bronchiectasis severity and neutrophil-related markers in NTM-PD patients. My work has potentially important clinical implications including the identification of biomarkers to monitor disease severity and options for host-directed therapy.