Determinants of infection of Mycobacterium abscessus by therapeutically useful phages

Nontuberculous mycobacteria (NTM), including Mycobacterium abscessus, are emerging opportunistic pathogens that are intrinsically resistant to many antibiotics. In response, there is considerable interest in using mycobacteriophages (phages) as therapeutic alternatives to treat NTM infections, and over 20 patients have been treated with phages on a compassionate use basis. These case studies show considerable promise, but the breadth of this treatment is limited because bacterial strains vary in their phage susceptibility profiles, and many strains are not infected by any phages tested. This venture into clinical use has underscored how little we know about the basic interactions between phages and mycobacteria; for example, the host recognition receptors used by the majority of mycobacteriophages are unknown. The Wetzel Lab is eager to address these gaps in knowledge to reveal new molecular mechanisms of virus-host cell interactions. Understanding these interactions will also inform efforts to expand phage-based therapies and other novel treatments against NTM infections.

A PhD student is sought to identify and characterize mycobacteria factors required for M. abscessus infection of diverse, therapeutically useful phages. This project will involve generating mutagenesis libraries of M. abscessus and challenging them with phage to identify factors required for phage infection. The student will identify which step of phage infection is interrupted in resistant bacteria and determine the breadth of phage resistance. The student may also characterize phage-resistant M. abscessus mutants and/or engineer phage genomes as needed. The student will perform molecular and bacterial cell culture/infection-based assays. Experience in high throughput DNA sequencing approaches/analysis is preferred.