Combatting intracellular pathogens using bacteriophage delivery

Abstract

Intracellular pathogens reside in specialized compartments within the host cells restricting the access of antibiotics. Insufficient intracellular delivery of antibiotics along with several other resistance mechanisms weaken the efficacy of current therapies. An alternative to antibiotic therapy could be bacteriophage (phage) therapy. Although phage therapy has been in practice for a century against various bacterial infections, the efficacy of phages against intracellular bacteria is still being explored. In this review, we will discuss the advancement and challenges in phage therapy, particularly against intracellular bacterial pathogens. Finally, we will highlight the uptake mechanisms and approaches to overcome the challenges to phage therapy against intracellular bacteria.

The Microbiome in Pancreatic Cancer-Implications for Diagnosis and Precision Bacteriophage Therapy for This Low Survival Disease

“…Bacteriophages have been shown to have the capacity to disrupt biofilms ( Lusiak-Szelachowska et al., 2020 ) and eliminate intracellular bacteria ( Goswami et al., 2021 ). One key feature by which bacteria such as P. gingivalis promote their spread and colonisation is through outer membrane vesicles (OMVs) ( Farrugia et al., 2020 ).…”

Biological foundations of successful bacteriophage therapy

“…The first evidence of phages crossing the eukaryotic cell barrier dates back more than 50 years (Monsur et al , 1970 ), and it is known that these viruses can penetrate human cells and even enter their nucleus (Nieth et al , 2015 ; Lehti et al , 2017 ; Nguyen et al , 2017 ; Zhang et al , 2017 ; Sweere et al , 2019 ). Phages may enter the eukaryotic cell non‐specifically by phagocytosis or pinocytosis, or through receptor‐mediated entry by binding specifically to cell surface structures like the neural cell adhesion molecule (NCAM; a major polysialic acid carrier that mimics bacterial receptors) or to cell surface integrins, or by antibody‐mediated uptake when phages are opsonized by circulating immunoglobulins (Bodner et al , 2021 ; Goswami et al , 2021 ) (Fig 5B ).…”

Applications of bacteriophages against intracellular bacteria

“…Recent works discuss possible mechanisms of phage uptake into mammalian cells (Bodner al. 2020;Goswami et al 2021). It was shown that phages utilise pathways of entry via cell-surface receptors (Lehti et al 2017) or through a less specific way, i.e.…”

“…The presence of phages was observed in both non-phagocytic epithelial cells (Guang-Han et al 2016;Zhang et al 2017;Møller-Olsen et al 2018) and macrophages (Broxmeyer et al 2002;Singla et al 2016;Chadha et al 2017). In an extensive literature review, Goswami et al reported studies that attempt to modify either free phages or specific phage carriers based on the Trojan horse principle, in order to improve phage internalisation and loading (Goswami et al 2021). Among the studies using carrier-based delivery systems of particular interest are those in which phages are immobilised in liposomes (Nieth 2015;Singla et al 2016;Chadha et al 2017).…”

“…Among the studies using carrier-based delivery systems of particular interest are those in which phages are immobilised in liposomes (Nieth 2015;Singla et al 2016;Chadha et al 2017). After internalisation in the host cell, most bacterial pathogens reside in subcellular compartments such as phagosomes or endosomes, whose environment they can modify and from which they have developed ways to escape (Goswami et al 2021). So far, little is known about how phages interact directly with hidden bacteria but several studies have shown enhanced bacterial reduction by phages entrapped in liposomal carriers compared to free phages (Broxmeyer et al 2002;Nieth 2015;Singla et al 2016).…”