Use of a Regression Model to Study Host-Genomic Determinants of Phage Susceptibility in MRSA

Abstract

Staphylococcus aureus is a major agent of nosocomial infections. Especially in methicillin-resistant strains, conventional treatment options are limited and expensive, which has fueled a growing interest in phage therapy approaches. We have tested the susceptibility of 207 clinical S. aureus strains to 12 (nine monovalent) different therapeutic phage preparations and subsequently employed linear regression models to estimate the influence of individual host gene families on resistance to phages. Specifically, we used a two-step regression model setup with a preselection step based on gene family enrichment. We show that our models are robust and capture the data’s underlying signal by comparing their performance to that of models build on randomized data. In doing so, we have identified 167 gene families that govern phage resistance in our strain set and performed functional analysis on them. This revealed genes of possible prophage or mobile genetic element origin, along with genes involved in restriction-modification and transcription regulators, though the majority were genes of unknown function. This study is a step in the direction of understanding the intricate host-phage relationship in this important pathogen with the outlook to targeted phage therapy applications.

Determinants of Phage Host Range in Staphylococcus Species

“…More phage resistance systems likely remain undiscovered. A genome-wide association study of 207 clinical MRSA strains and 12 phage preparations identified 167 gene families putatively associated with phage-bacterium interactions (131). While these families included restriction-modification genes, transcriptional regulators, and genes of prophage and SaPI origin, most were accessory gene families of unknown function.…”

Genes influencing phage host range in Staphylococcus aureus on a species-wide scale

“…In addition, although many S. aureus phages are reported to have wide host ranges (28)(29)(30)(31)(32)(33)(34), and even early studies suggested staphylococcal phage therapies to be highly effective (35), experiments conducted thus far have failed to explain the genetic bases of host range or resistance development in a species-wide manner. Only one previous study has associated genetic factors (gene families) with phage resistance using a hypothesis-free method (36). This work used a two-step linear regression model to associate some 167 gene families, mostly of unknown function, with resistance assessed in 207 clinical MRSA strains and 12 phage preparations.…”

Phage Therapy: What Have We Learned?

“…Differential phage susceptibility determinants that are encoded by various strains of the same species include genes encoding phage receptors or pathways of their synthesis and phage-compatible restriction-modification systems [ 149 , 150 , 151 , 152 , 153 , 154 , 155 ]. Additionally, bacteria encode phage defence mechanisms, but these mechanisms protect the bacterium by itself either from infection with certain phages or from phage propagation, or induce apoptosis to protect the population from spread of the infection [ 156 , 157 , 158 , 159 , 160 , 161 , 162 , 163 ]. The differential phage susceptibility determinants are exchangeable between strains of a given species.…”