The phages of staphylococci: critical catalysts in health and disease

Abstract

The phages that infect Staphylococcus species are dominant residents of the skin microbiome that play critical roles in health and disease. While temperate phages, which can integrate into the host genome, have the potential to promote staphylococcal pathogenesis, the strictly lytic variety are powerful antimicrobials that are being exploited for therapeutic applications. This article reviews recent insights into the diversity of staphylococcal phages and newly described mechanisms by which they influence host pathogenicity. The latest efforts to harness these viruses to eradicate staphylococcal infections are also highlighted. Decades of research has focused on the temperate phages of Staphylococcus aureus as model systems, thus underscoring the need to broaden basic research efforts to include diverse phages that infect other clinically relevant Staphylococcus species.

Keywords: SaPI; Staphylococcus; pathogenesis; phage; phage therapy; transduction.

Figure 1.

Primary pathways of phage replication (top) and transduction (bottom). (A) The lytic and lysogenic pathways of phage replication are shown. The first step in both pathways involves the attachment of phage receptor binding proteins to specific receptor(s) on the host cell surface and subsequent ejection of phage DNA (cyan). Obligately lytic/virulent phages are obliged to follow the lytic life cycle, in which phage DNA and proteins are replicated and synthesized, respectively (rolling-circle DNA replication is shown as an example). The DNA is packaged, phage particles are assembled, and the host cell is finally lysed to allow for phage escape. Lysogenic/temperate phages have the capacity to choose whether to enter into the lytic cycle or lysogenic cycle following DNA ejection. During the lysogenic cycle, the phage genome is integrated into the host chromosome (magenta), at which point the phage becomes a prophage, and the cell becomes a lysogen. The prophage genome is then replicated passively along with the host genome, until a stressor or other environmental signal triggers phage entry into the lytic cycle, a process known as induction. Inset shows the morphologies of the most commonly-encountered phages--myovirus (left), podovirus (center), and siphovirus (right). (B) The three major pathways of transduction are shown using a lysogenic staphylococcal phage as an example. Following prophage induction, the phage packaging (pac) site (black triangle) serves as a primary recognition sequence for the phage packaging machinery and enables the high-frequency production of infective lytic particles containing phage genomes (cyan). During generalized transduction (left), the occasional packaging of host-derived DNA bearing pac site homologs (pseudo-pac sites, green triangles) results in the infrequent production of transducing particles containing host-derived DNA (magenta). During specialized transduction (middle pathway), imprecise excision of the prophage genome leads to packaging of a DNA hybrid containing the phage genome along with host genes adjacent to the phage integration site. Lateral transduction (right) occurs in specific staphylococcal prophages in which DNA replication begins prior to excision—this process results in the high frequency packaging of both phage DNA and host DNA encoded hundreds of kilobases from the prophage integration site. (C) The pathway for SaPI (Staphylococcus aureus Pathogenicity Island) transduction is shown. Upon induction of the helper prophage (cyan), both prophage and SaPI (green) excise and replicate. A SaPI-specific packaging site (orange triangle) directs the high frequency packaging of SaPI DNA into transducing particles composed of phage structural proteins. Some SaPIs encode proteins that alter the capsid architecture, resulting in the production of transducing particles with unusually small capsids.

Figure 2.

Transmission electron microscope images of S. epidermidis phages representing the morphological diversity of all known staphylococcal phages. Herelleviridae (formerly Myoviridae) members possess myovirus morphology, with rigid, retractable tails with inner and outer sheathes. Siphoviridae phages have siphovirus morphology with flexible, non-contractile tails. Podoviridae members possess podovirus morphology, with short, non-contractile tails. Phages were isolated from municipal wastewater in Tuscaloosa, AL. Scale bar = 100 nm.