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UBC Theses and Dissertations

Pathogen-induced inflammation in immunocompromised conditions McDonald, Allison


Primary immunodeficiencies arise from genetic anomalies and can cause aberrant inflammation, tissue destruction, and uncontrolled infections. Defects in immunity often first present as cases of recurrent or severe infections with unusual pathogens. Patients with chronic granulomatous disease (CGD) have mutations in the NADPH oxidase that prevent the formation of reactive oxygen species (ROS) critical for effective immunity. We investigated the phagocyte response to Burkholderia cenocepacia, which causes severe lung infections in patients with CGD. B. cenocepacia survived within ROS-deficient neutrophils and induced rapid cell death that was not observed by infection with other bacteria, including other CGD pathogens. Increased cell death was associated with enhanced caspase-3 activation and phosphatidylserine surface exposure compared to healthy neutrophils, both hallmarks of apoptotic programmed cell death. Caspase activation was required to induce increased neutrophil death in the absence of ROS. B. cenocepacia-induced apoptotic neutrophils were pro-inflammatory to macrophages, especially in the absence of ROS, inducing the secretion of IL-6, IL-8, and TNF-α but not the anti-inflammatory cytokines IL-10 or TGF-β from human macrophages. Surprisingly, macrophages enhanced the growth of B. cenocepacia by providing a nutrient-rich intracellular replication niche that allowed the bacteria to escape from normal neutrophil killing. We also report here two sisters with an underlying immunodeficiency who presented with fatal neurodegeneration triggered by infections. Whole exome sequencing identified mutations in perforin1, involved in the granule-mediated cytotoxicity pathway for eliminating infected host cells. Perforin1 mutations are associated with familial hemophagocytic lymphohistiocytosis (FHL). In contrast to FHL, these girls did not have hematopathology or elevated cytokine overproduction. However, 3 years after disease onset, the proband had markedly deficient cytokine production, including IL-1β production following stimulation with a panel of bacterial ligands. These observations extend the spectrum of disease associated with perforin mutations to immune-mediated neurodegeneration triggered by infection. Studies that investigate how opportunistic pathogens cause disease aim to decrease morbidity and mortality in immunocompromised patients and also provide the opportunity to better understand the molecular mechanisms that allow healthy individuals to combat disease.

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