The Ensminger laboratory studies when, where, and how bacteria have learned to cause human disease. To answer these big questions, we study bacteriophages, anti-phage defences, toxin-antitoxin systems, effectors, and metaeffectors.

LEGIONELLA PHAGES

Shaping human disease.

The growing consensus over the first 50 years of Legionella research has been that these bacteria largely avoid phage infections. Our discovery of the first infectious Legionella phage (LME-1) shows this not to be the case. Instead, the apparent absence of prophages in our strains should have been a big red flag–we now know that the main feature that makes “clinical strains” a high risk to human health derives from resistance to phage attachment. In other words, environmental encounters between Legionella and phages underpin the frequency and severity of Legionnaires’ disease in humans. Understanding the Legionella-phage arms race is essential to determining how these bacteria pose such a significant risk to human health.

METAEFFECTORS

Effect the unexpected.

A central pillar of molecular pathogenesis is that translocated bacterial effectors modulate host proteins. We use high-throughput yeast robotics, protein-protein interaction mapping, and protein modeling to systematically identify "metaeffectors" – effectors that target other effectors rather than host proteins. Having established these methodologies in Legionella pneumophila, we are now extending our work to other pathogens. We are also using what we have learned from metaeffectors, as natural inhibitors of effector function, to design synthetic inhibitors of protein function.

TOXIN-ANTITOXINS

Microbial persistence

In the lab, bacteria are often studied in nutrient-rich environments under maximal growth rates. The reality is that microbial life is typically characterized by punctuated, suboptimal conditions of growth. One mechanism by which bacteria regulate their growth is through toxin-antitoxin systems. Despite their name, these “toxins” are not delivered to other cells but rather limit the replication of the cells that encode for them. By studying Legionella TA systems, we have made several unexpected discoveries, most notably a remarkable phenotype in which mutant bacteria confer stress resistance to neighbouring cells in a contact-dependent manner. These observations highlight fundamental gaps in our knowledge of bacterial cell-to-cell communication that we are well-positioned to mechanistically explore.