Patients with structural lung conditions, such as cystic fibrosis and bronchiectasis are highly susceptible to infections with Mycobacterium abscessus. These pathogens are detected in the sputum of ~13% of cystic fibrosis patients in the US. In addition to those with underlying lung conditions, immune competent post-menopausal Caucasian women are also selectively susceptible to pulmonary M. abscessus infections. Despite increasing prevalence of this disease, very little is known about the pathogenesis of pulmonary infections with M. abscessus. This proposal?s aim is to fill critical gaps in our understanding of pulmonary M. abscessus infection. Recent studies have demonstrated that the peptidoglycan, the exoskeleton of the bacterial cell, of M. abscessus is unique in the final step of its synthesis compared to other gram negative and gram positive bacteria. Furthermore, this distinction is due to the activities of non-classical transpeptidases. I will study the relevance of these novel transpeptidases to the physiology of M. abscessus peptidoglycan and their contribution during acute and chronic stages of pulmonary infection. Investigating M. abscessus in vivo is critical, however current published accounts of mouse models often lack a sustained chronic infection analogous to what would occur in cystic fibrosis or bronchiectasis patients. They also lack demonstrated progression to pathology. I have developed a mouse model which fulfills both of these criteria, generating not only a chronic M. abscessus pulmonary infection, but also leading to gross pathological findings that mimic those observed in humans. The studies outlined in this proposal will provide new insights into aspects of M. abscessus cell wall metabolism and physiology during infection that could lead to novel therapeutic development and novel chemotherapy regimens of existing antibiotics.
In patients with underlying structural lung conditions such as cystic fibrosis and bronchiectasis, Mycobacterium abscessus causes chronic and often untreatable infections that can be life threatening. Emerging evidence shows that M. abscessus uses unique sets of enzymes to synthesize its cell wall peptidoglycan. Here, we will study the contributions of these unique enzymes to cell physiology, their vulnerabilities to antibiotic treatment, and pathogenesis of pulmonary infections using a mouse model that develops focused granulomas similar to that in humans.
