Abstract
Pulmonary infections with Mycobacterium abscessus (M. abscessus) are increasingly prevalent in patients with lung diseases such as cystic fibrosis. M. abscessus exists in two morphotypes, smooth and rough, but the impact of morphotype on virulence is unclear. We developed an immune competent mouse model of pulmonary M. abscessus infection and tested the differences in host inflammatory response between the morphotypes of M. abscessus. Smooth and rough morphotypes of M. abscessus were isolated from the same American Type Culture Collection strain. Wild type and cystic fibrosis mice were intratracheally inoculated with known quantities of M. abscessus suspended in fibrin plugs. At the time of sacrifice lung and splenic tissues and bronchoalveolar lavage fluid were collected and cultured. Bronchoalveolar lavage fluid was analyzed for leukocyte count, differential and cytokine expression. Pulmonary infection with M. abscessus was present at both 3 days and 14 days post-inoculation in all groups at greater levels than systemic infection. Inoculation with M. abscessus rough morphotype resulted in more bronchoalveolar lavage fluid neutrophils compared to smooth morphotype at 14 days post-inoculation in both wild type (p = 0.01) and cystic fibrosis (p<0.01) mice. Spontaneous in vivo conversion from smooth to rough morphotype occurred in 12/57 (21%) of mice. These mice trended towards greater weight loss than mice in which morphotype conversion did not occur. In the described fibrin plug model of M. abscessus infection, pulmonary infection with minimal systemic dissemination is achieved with both smooth and rough morphotypes. In this model M. abscessus rough morphotype causes a greater host inflammatory response than the smooth based on bronchoalveolar lavage fluid neutrophil levels.
Highlights
Nontuberculous mycobacteria (NTM) are environmental organisms ubiquitous in soil and water
While we achieved our goal of establishing a pulmonary infection with little systemic spread in immune competent animals, the burden of pulmonary infection had significantly decreased by 14 days post-inoculation
Infection with the rough morphotype resulted in a great number of Bronchoalveolar lavage fluid (BALF) neutrophils compared to the smooth morphotype at 14 days post-inoculation in both WT and cystic fibrosis (CF) mice
Summary
Nontuberculous mycobacteria (NTM) are environmental organisms ubiquitous in soil and water. Prior mouse models of M abscessus pulmonary infection have demonstrated increased pathogenicity in vivo from the rough compared to the smooth morphotype[10,11]. These prior models, have been limited by the difficulty in establishing a persistent pulmonary infection with minimal systemic spread in immune competent animals. We describe a novel mouse model of M. abscessus infection in which intratracheal inoculation of M. abscessus suspended in thrombin and fibrinogen solutions traps the bacteria in the distal airways in viscous fibrin plugs With this model we tested our hypothesis that the rough morphotype of M. abscessus will cause a greater host inflammatory response than the smooth morphotype. Experiments were conducted in a separate Animal Biohazard Facility within the Biological Resource Center
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