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Club Cell Secretory Protein (CC16) is a homodimeric pneumoprotein secreted by club cells and other non-ciliated epithelial cells in the distal airways. Although the complete biological functions and mechanisms of CC16 have not been elucidated, several studies have shown that CC16 has anti-inflammatory and antioxidant properties in the lungs. Studies have shown that low circulating levels of CC16 are correlated to accelerated declines in lung function, increased inflammation, and increased disease severity in asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF) patients. CC16 has also been shown to directly decrease pathogen burden, pulmonary inflammation, and airway hyperresponsiveness during a variety of bacterial and viral lung infections; thereby, further supporting its role in regulating inflammation and immune responses. The airway epithelium is the first line of defense against inhaled pathogens and environmental toxicants; therefore, making it an important mediator of inflammation and immune responses. Airway epithelial cells are important regulators of normal lung homeostasis, which includes lung fluid balance, metabolism, mucociliary clearance of trapped particulates, activation of immune cells during infection or injury, and regulation of smooth muscle function. The four major epithelial cells observed within the lungs are basal, club, ciliated, and goblet cells, all of which perform different functions within the lung. Dysregulation of epithelial cells contributes to the respiratory conditions manifested in pulmonary diseases including asthma, COPD, or CF. In these studies, we provide data showing that CC16 is important for regulating protective properties within the pulmonary epithelium during naïve conditions and during infection with Mycoplasma pneumoniae (Mp). During early life Mp infection, we show that CC16 protects the lungs by decreasing airway hyperresponsiveness, remodeling, inflammation, and Mp burden within the lung i

The Neisseriaceae family is a group of Gram-negative bacteria that forms part of the microbiota of humans and animals. Within the genus Neisseria, there are only two pathogens, N. gonorrhoeae and N. meningitidis (Nme) which infect only humans and cause disease. Others are either commensals of humans or animals including wild mice, dogs, cats, cows, and non-human primates. Pathogenic Neisseria also behave like commensals in that they are able to colonize the mucosal surfaces asymptomatically. Commensal Neisseria are little studied and there is no small animal model for studying commensal Neisseria-host interactions in a natural setting. There are small animal models for studying pathogenic Neisseria infection, but due to their strict tropism for humans, they are heterologous systems which require treatment of hormones, antibiotics, and invasive procedures. Recent work in the So laboratory has circumvented the tropism issue. Former postdoctoral researcher Nate Weyand isolated Neisseria musculi (Nmus) from wild mice, and showed Nmus is genetically related to human Neisseria – including genes encoding many host interaction factors such as Type IV pilus and capsule. I expanded this study and my investigations showed that Nmus colonize laboratory mice. This work, described in chapter 2, led to a natural mouse model that now allows studies on asymptomatic colonization from the standpoint of the bacterium and the host. Using the natural mouse model of commensal Neisseria colorization and persistence, I showed that host genetics, host immune status, and bacterial host interaction factors are essential determinants for Neisseria colonization and persistence. Type IV pilus fiber and Type IV pilus retraction null mutants are defective in establishing colonization. This natural mouse model of commensal Neisseria colonization and persistence will allow us to identify new neisserial and host genes that are important for asymptomatic colonization and/ or persistence. I also showed