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.
The emergence of virulent strains of Staphylococcus aureus that are resistant to most antibiotics has become a major public health concern. Virulence and resistance determinants in S. aureus are usually carried on mobile genetic elements, such as S. aureus pathogenicity islands (SaPIs), which are mobilized by bacteriophages and transferred horizontally through the bacterial population. This project aims to understand the mechanism and specificity of the phage-induced mobilization and transfer of SaPIs and their impact on the evolution of bacterial pathogenicity.
|Manning, Keith A; Quiles-Puchalt, Nuria; Penadés, José R et al. (2018) A novel ejection protein from bacteriophage 80? that promotes lytic growth. Virology 525:237-247|
|Kizziah, James L; Manning, Keith A; Dearborn, Altaira D et al. (2017) Cleavage and Structural Transitions during Maturation of Staphylococcus aureus Bacteriophage 80? and SaPI1 Capsids. Viruses 9:|
|Dearborn, Altaira D; Wall, Erin A; Kizziah, James L et al. (2017) Competing scaffolding proteins determine capsid size during mobilization of Staphylococcus aureus pathogenicity islands. Elife 6:|
|Hill, Rosanne L L; Vlach, Jiri; Parker, Laura K et al. (2017) Derepression of SaPIbov1 Is Independent of ?NM1 Type 2 dUTPase Activity and Is Inhibited by dUTP and dUMP. J Mol Biol 429:1570-1580|
|Carpena, Nuria; Manning, Keith A; Dokland, Terje et al. (2016) Convergent evolution of pathogenicity islands in helper cos phage interference. Philos Trans R Soc Lond B Biol Sci 371:|
|Hill, Rosanne L L; Dokland, Terje (2016) The Type 2 dUTPase of Bacteriophage ?NM1 Initiates Mobilization of Staphylococcus aureus Bovine Pathogenicity Island 1. J Mol Biol 428:142-152|
|Wall, Erin A; Caufield, J Harry; Lyons, Charles E et al. (2015) Specific N-terminal cleavage of ribosomal protein L27 in Staphylococcus aureus and related bacteria. Mol Microbiol 95:258-69|
|Dearborn, Altaira D; Laurinmaki, Pasi; Chandramouli, Preethi et al. (2012) Structure and size determination of bacteriophage P2 and P4 procapsids: function of size responsiveness mutations. J Struct Biol 178:215-24|
|Damle, Priyadarshan K; Wall, Erin A; Spilman, Michael S et al. (2012) The roles of SaPI1 proteins gp7 (CpmA) and gp6 (CpmB) in capsid size determination and helper phage interference. Virology 432:277-82|
|Dearborn, Altaira D; Dokland, Terje (2012) Mobilization of pathogenicity islands by Staphylococcus aureus strain Newman bacteriophages. Bacteriophage 2:70-78|
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