ARRA: Pathogenesis of Moraxella catarrhalis in chronic obstuctive pulmonary disease

Moraxella catarrhalis is an exclusively human pathogen that is a common cause of exacerbations of chronic obstructive pulmonary disease (COPD) in adults and otitis media in children. COPD is the fourth most common cause of death in the US. The course of COPD is characterized by intermittent exacerbations or worsening of disease. Exacerbations cause enormous morbidity, including emergency room visits, hospital admissions, respiratory failure and are associated with substantial mortality. Approximately 50% of exacerbations are caused by bacterial infection and M. catarrhalis is the second most common bacterial pathogen, estimated to cause 2 to 4 exacerbations annually in the US. Little is known about the pathogenesis of bacterial infection in COPD, especially M. catarrhalis infection in COPD. Understanding such mechanisms is critical and has the potential lead to the development of novel strategies for treatment and prevention of exacerbations and/or chronic infection in COPD, including antimicrobial agents, immunomodulators and vaccines. This proposal will take complementary approaches to identify and characterize virulence molecules that are important in infection in COPD. A genomics approach will be used in aim 1 to identify COPD-associated genes. In Aim 2, global gene expression and proteomic expression profiling using state of the art methods will be used to identify genes and proteins expressed by a prototype COPD strain grown in conditions that simulate those in the human respiratory tract. In aim 3, the role in pathogenesis of genes and gene products identified in Aims 1 and 2 will be elucidated by generating knockout mutants and studying them in a series of model systems of M. catarrhalis infection. This work will advance the field by elucidating molecular mechanisms of pathogenesis of bacterial infection in COPD, an area where little is known, particularly in the case of M. catarrhalis. The proposal also advances the field through the development of novel methods to elucidate mechanisms of pathogenesis of exclusively human pathogens. Identifying molecules that mediate survival and infection in the human respiratory tract such as anti-oxidant activity, nutritional uptake or intracellular growth will provide excellent opportunities for the development of interventions such as inhaled topical agents to eradicate airway infection or immunomodulators to block bacterial antigen induced airway inflammation.