Structural basis for mobilization of S. aureus pathogenicity islands

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PROJECT SUMMARY Staphylococcus aureus is an opportunistic bacterial pathogen involved in severe infections in humans. Most virulence determinants in S. aureus are carried on mobile genetic elements (MGEs), such as plasmids, bacteriophages and genomic islands. Transduction by bacteriophages (phages) represents the main mechanism by which MGEs are transmitted horizontally in S. aureus. Among these MGEs are the S. aureus pathogenicity islands (SaPIs), which carry genes encoding superantigen toxins and other virulence factors. SaPIs are normally stably integrated into the host genome, but become mobilized at high frequency by specific helper phages, resulting in packaging of the SaPI genomes into transducing particles made from helper-encoded structural proteins. SaPIs have evolved the ability to sense the presence of a lytic phage, exploit phage functions and interfere with phage multiplication, in order to promote their own dissemination. SaPIs this play important roles in S. aureus evolution and pathogenicity. The overall aim of the current project is to understand the structural basis for SaPI mobilization, helper-SaPI specificity, and the factors involved in their spread and establishment. Our specific aims are: (1) Determine the mechanism of SaPI-induced capsid size redirection; (2) Understand the function of the phage baseplate in infection and host specificity; (3) Elucidate the role of minor capsid protein gp44 in the lytic/lysogenic switch. These three aims focus on different aspects of the mobilization process and will be studied by a combination of genetic, biochemical and structural methods. All three aims are based on a solid premise set by our previous studies and extensive preliminary data. Upon completion of these aims, we will have gained new insights into the process of capsid assembly and size redirection, the infection and transfer process, the mechanisms by which SaPIs and their virulence factors are transmitted and established in the bacterial population.