Browsing by Author "McCoy, Kathy D."
Now showing 1 - 3 of 3
Results Per Page
Sort Options
Item Open Access Enhanced Induction of Epithelial-Derived IL-17C Following Bacteria and Rhinovirus Exposure(2019-05-15) Jamieson, Kyla Carol; Proud, David; Jenne, Craig N.; Hirota, Simon Andrew; Yipp, Bryan G.; McCoy, Kathy D.; Peebles, Ray StokesUp to 80% of Chronic Obstructive Pulmonary Disease (COPD) exacerbations are associated with bacterial and/or viral pathogens, with bacteria-virus co-infections detected in up to 25% of exacerbations. These co-infections are associated with increased symptoms, increased systemic inflammation, longer hospital stays, and increased risk of hospital re-admission. Human rhinovirus (HRV) is the most common viral pathogens detected, while non-typeable Haemophilus influenzae (NTHI) and Pseudomonas aeruginosa (PAO) are among the most common bacterial pathogens identified. The airway epithelium is the first line of defence against these pathogens and responds by releasing proinflammatory cytokines and anti-microbial peptides. Interleukin (IL)-17C is a novel pro-inflammatory cytokine that is typically released from epithelial cells in response to bacteria, viral, or fungal pathogens, and in response to pro-inflammatory cytokines such as TNFα and IL-1β. In this thesis, we performed the first study to assess the involvement and functional role of IL-17C in bacteria-rhinovirus co-infections in human bronchial epithelial cells (HBECs). Bacteria-rhinovirus co-exposure for 24 hours induced significant, and synergistic, IL-17C gene expression and protein release. Synergistic IL-17C release was dependent on viral replication recognition sensors, RIG-I and MDA5, as well as NF-κB and p38 signalling. In an autocrine/paracrine manner, IL-17C acted on the airway epithelium to induce CXCL1, CXCL2, TFRC, and NFKBIZ gene expression, to induce CXCL1 protein release, and to promote HBEC-induced neutrophil recruitment. To assess how IL-17C is involved in the clinical context of COPD, HBECs were obtained via bronchial brushings from non-smokers, smokers with normal lung function, and patients with physician-diagnosed COPD and these cells were exposed to NTHI and HRV-1A concurrently. Interestingly, in response to concurrent NTHI and HRV-1A exposure, HBECs from COPD patients released significantly more IL-17C than cells from either non-smokers or healthy smokers, and HBECs from healthy smokers released significantly less IL-17C than non-smokers. Further, acute cigarette smoke extract exposure significantly reduced microbial-induced IL-17C release from cells from normal subjects. Using a morphologically-relevant well-differentiated HBEC model, IL-17C was predominantly released basolaterally, from apical cells, in response to HRV in a dose-, time-, and replication-dependent manner. High doses of NTHI could also induce basolateral IL-17C, however synergy was no longer achieved with NTHI+HRV-1A co-infections. Similar to monolayer culture, IL-17C acted on basal cells to induce significant basolateral release of CXCL1, providing physiological relevance for subsequent neutrophil recruitment. These results suggest that IL-17C acts to induce CXCL1 release and promote neutrophil recruitment to the site of bacteria or rhinovirus respiratory infections, however, this response is exaggerated in epithelial cells from COPD patients.Item Embargo Investigating the Role of Maternal Microbiota and Antibodies in Development of the Neonatal Immune System(2023-05-02) Czyz, Sonia; McCoy, Kathy D.; Kubes, Paul; Ousman, ShalinaMicrobial colonization in early life plays a critical role in the development and education of the host’s immune system. However, the precise mechanisms underlying microbial-immune interactions during the early life period are still under investigated. Postnatal colonization of the body with microbes was assumed to be the main stimulus for neonatal immune development. However, our group previously demonstrated that the maternal microbiota during gestation shapes the immune system of the offspring, both in utero and postnatally. This thesis aims to examine the underlying mechanisms by which the maternal microbiota drives neonatal immune development and the functional consequence of the maternal microbiota on offspring resistance to systemic infection. To disassociate the effects of the maternal microbiota from microbial signals coming from colonization after birth, a model of ‘gestational-only colonization’ was utilized. Firstly, the neonatal Fc receptor (FcRn) was found to be required for gestational-only colonization to induce ILC3 populations in the neonatal gut. Mechanistically, this suggests that the FcRn is necessary for transportation of maternal IgG-bound microbial products and metabolites to the offspring. Secondly, transfer of maternal anti-E. coli IgG induced ILC3 populations in the neonate, even when it was associated with products and metabolites generated by another bacterial species. This suggests that bacterial molecules may bind IgG in a non-specific manner and that this is sufficient to transfer the associated molecules to induce offspring immune cell changes. Lastly, we found gestational-only colonization led to reduced bacterial load in multiple offspring systemic organs after intravenous challenge with the pathogen S. aureus. Despite this, gestational-only colonization was not sufficient to protect the neonate from bacterial sepsis. Overall, this thesis revealed how maternal microbial products and metabolites are handled at the maternal-offspring interface in early life to educate the neonatal immune system and impact health outcomes in systemic infection.Item Open Access The role of intestinal fungi on microbiome ecology, host immune development, and susceptibility to airway inflammation(2023-12-04) van Tilburg Bernardes, Erik; Arrieta, Marie-Claire; Proud, David; McCoy, Kathy D.; McDonald, Braedon A.Early-life microbiome alterations can lead to immune dysregulation and increase susceptibility to asthma. Bacterial changes often precede asthma development in humans and have been causally linked to heightened airway inflammation in mice. Prospective infant studies have also identified fungal microbiome (mycobiome) alterations associated with asthma risk. However, it remains unknown if fungi contribute to the pathogenesis of atopy and asthma. My Ph.D. thesis project aimed to determine the causal role of early-life fungal colonization in immune development and susceptibility to allergic airway inflammation. We determined the role of intestinal fungi on microbiome structure, function, and host immune development in gnotobiotic mice colonized with defined communities of 12 bacteria and/or five fungi. Gut fungi exerted significant ecological pressures to the coexisting bacterial microbiome, and vice versa. Early-life fungal colonization also induced robust host systemic immune changes and influenced the immune phenotype of lung’s inflammatory response to ovalbumin allergen. Antibiotic use also impacts the gut microbiome, leading to an increased risk of asthma. However, the impact of antibiotics on the infant mycobiome is unknown. To investigate mycobiome changes associated with antibiotic treatment we conducted an observational, prospective clinical study of 47 infants (under 6 months of age) who received antibiotics. Antibiotic use decreased bacterial and increased fecal fungal DNA and induced the expansion of Malassezia spp. in infants. To evaluate the effect of colonization with Malassezia spp. on immune development and airway inflammation, we assessed early-life immune readouts and susceptibility to a house-dust mite (HDM) model in mice colonized with or without Malassezia restricta. M. restricta colonization increased intestinal immune responses deemed critical in atopy development, and elevated airway inflammation in HDM-challenged mice. Further evaluation in eosinophil-deficient mice revealed that the observed immune response is partially dependent on this cell type. This translational work demonstrates that fungi are integral components of the intestinal microbiome, causally implicated in host immune development and susceptibility to airway inflammation. Fungal overgrowth and expansion of Malassezia spp. are previously overlooked collateral effects of infant antibiotic use, which may offer a potential strategy to prevent or mitigate pediatric asthma and related conditions.