Mycobacterium abscessus (Mabs), a nontuberculous mycobacterium (NTM), is an important emerging pathogen which causes treatment-refractory, progressive lung disease in patients with abnormal airways characterized by bronchiectasis. Progressive Mabs lung infection has thus far only been modeled in immunodeficient mice. We hypothesize that Mabs infection in immunocompetent mice with bronchiectatic lung airways will mimic human disease. Development of this mouse infection model during this pilot project will create the opportunity for studies of disease pathogenesis and antimicrobial efficacy uniquely applicable to humans:
Specific Aim 1 : To determine whether bronchiectatic lung airways are sufficient for Mabs to persist and invade mouse lungs in spite of an intact cell-mediated immune response we will assess Mabs lung airway colonization and infection in a mouse model which mimics the genetic defect leading to bronchiectasis in humans.
Specific Aim 2 : To determine whether antimicrobial efficacy against Mabs infecting mouse lung is affected by the presence of bronchiectatic airways we will assess the activity of azithromycin used to treat Mabs lung infection in humans in a mouse model which mimics the genetic defect leading to bronchiectasis in humans. Health Relatedness: Although Mabs does not typically cause illness in otherwise healthy, immunocompetent individuals, it can establish itself in the lungs of immunocompetent patients with abnormal lung airways, and cause progressive lung disease. Delineating the bacterial factors involved in Mabs lung airway colonization and invasion, and establishing an infection model in mice with abnormal airways will be major advances in understanding this paradox. Identification of therapeutic targets for interrupting disease pathogenesis will be the end result. Research Design and Methods: A mouse model utilizing a unique conditional mutant which develops bronchiectasis will be used to model Mabs growth and persistence in abnormal lung airways.
Mycobacterium abscessus is an emerging infection causing lung disease in patients with abnormal lung airways due to various causes. This proposal seeks to understand why abnormal lung airways predispose to M. abscessus infection so that novel therapies can be developed to treat infection caused by this organism.
