The rapid dissemination of pathogenic species that are resistant to antibiotics is becoming an increasingly daunting healthcare issue. One of the most promising of currently available options is the therapeutic application of bacterial viruses (phages). Phage therapy however is limited by the narrow host specificity of phages and our incomplete understanding about phage-human interaction. The aim of my doctoral research was to gain deeper insight about these two factors.
The first part of my work was to generate hybrid transducing phage particles with altered host specificity using genome engineering. We successfully tailored the host range of T7 hybrid particles by exchanging and modifying phage tail fiber regions of said particles. As the genetic background of the harmless laboratory strains highly differs from that of the pathogenic ones, we aimed to develop a method that could be applied to clinically relevant strains as well. Thus, we generated and identified mutant hybrid phage transducing particles which were able to effectively deliver large amounts of DNA into both a panel of clinically relevant bacterial species besides laboratory strains. During the second half of my doctoral research I focused on the study of phages able to endure the human gastrointestinal ecosystem, as such phages can feature characteristics that are therapeutically valuable assets. My goal was to study the genetics of phages able to adhere upon gut epithelial cell surfaces. We showed that Ig-like domains (mainly so-called BACON and PKD domains) are overwhelmingly prevalent in adherent phages. Our findings also revealed that the attachment site of such phages can be both the mucus and the glycocalyx layer. In the light of the above, we propose the ‘Riverbed’ model as the culmination of our results assuming the existence and instrumental role of the phages in the homeostasis of the human gut.