Phages and Bacterial Diseases
Genes carried by phages cause the serious symptoms associated with many human diseases, including cholera, botulism, toxic-shock syndrome and diphtheria. Recent human microbiome studies have also revealed that phage populations in diseased individuals are dramatically different than in healthy individuals, and are highly enriched for genes encoding antibiotic resistance and a wide variety of virulence factors. Although phages undoubtedly play key roles in the progression and outcome of bacterial diseases, their influence has not been systematically investigated. We are using the human pathogen Pseudomonas aeruginosa, which causes severe infections in Cystic Fibrosis patients and burn victims, as a model to comprehensively probe the effects of phage-encoded genes on the physiology and pathogenicity of this bacteria.
We are identifying and characterizing phage-encoded genes that increase bacterial virulence. This group of genes, which are not required for the life cycle of the phage itself, are known as "morons" as they add more on the phage genome when they are present. Phage morons have been shown to help bacteria invade healthy human tissue, evade the immune system, protect against antibiotic treatment, or lead to the production of toxins. In many human infections, the expression of phage morons can set the course between life and death.
We have developed a unique platform for studying morons, including a large and diverse collection of P. aeruginosa phages, a strong bioinformatic pipeline, a diverse array of assays to measure clinically important phenotypes, and a large number of longitudinally collected patient strains. The long term goal of this work is to predict the outcome of CF lung infections based on the complement of phage morons that are present in the infecting bacterial strain. Since prophages are readily able to move from one bacterial strain to another, this produces a situation in which the bacterial strains within a patient can become a "moving target", constantly changing their properties as prophage move in and out. Thus, our ability to treat chronic infections with full effectiveness will rely on understanding the activities of morons and their roles in bacterial pathogenesis.
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