The roles of sRNA in the physiology and pathogenesis of Mycobacterium abscessus and other mycobacteria

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Project summary/abstract Mycobacteria cause several human diseases including tuberculosis and leprosy. Mycobacterium abscessus causes serious lung disease particularly in cystic fibrosis patients. M. abscessus infections are especially difficult to treat because the bacteria are intrinsically resistant to many antibiotics. Development of improved therapies requires more information about how M. abscessus regulates its physiology in response to the stressful conditions that it encounters during infection. Regulation of gene expression is a key component of stress responses for most organisms. Small RNAs (sRNAs) have been found to play important roles in gene regulation in a number of other bacterial pathogens. However, little is known about how sRNAs regulate gene expression and contribute to the pathogenesis of mycobacteria, particularly M. abscessus. There is less known about the biology of M. abscessus in general compared to other better-studied mycobacteria, in large part because M. abscessus is difficult to genetically manipulate. We will harness state-of-the-art technologies for both genetic engineering of M. abscessus and the study of sRNAs, in order to address some of the most pressing questions in mycobacterial sRNA biology. We will (1) determine the mechanisms by which the sRNA B11 regulates activity of a secretion system and other virulence-associated phenotypes in M. abscessus, and (2) identify proteins involved in mycobacterial sRNA function and characterize their roles. The proposed studies will provide foundational knowledge needed to facilitate development of more effective treatments for mycobacterial diseases.