Bacteriophages as Potential Clinical Immune Modulators

Abstract

Bacteriophages (phages for short) are bacteria-specific viruses that have been drawing attention when it comes to countering the ever-growing antibiotic bacterial resistance, and are being seen as one of the most promising technologies against multi-antibiotic-resistant bacteria. Although bacteriophages are commonly regarded only as anti-bacterial objects unable to directly interact with eukaryotic cell metabolism, an increasing quantity of evidence has indicated that bacteriophages can directly affect cells bacteria in both in vitro and in vivo applications, influencing the behavior of tissues and immune systems. In sight of this new range of applications, several authors have expressed enthusiasm in phage therapy as direct modulators of eukaryotic cells for clinical usage, highlighting the need for further investigations covering the pharmacology of these new "eukaryotic-viruses", as even harmful interactions with eukaryotic cells were detected after phage therapy. The present review aims to cover and highlight mechanisms through which bacteriophages may interact with immune cells, analyzing potential clinical applications and obstacles presented in the use of bacteriophages as anti-inflammatory tools.

Keywords: anti-inflammatory; bacteriophages; immune modulation; immunology; inflammation.

Figure 1

Known, speculated and undiscovered mechanisms behind bacteriophage anti-inflammatory activity. ① Blocking of β3-integrin-NF-κB and CD40L-β3-integrin pathways by KGD-presenting bacteriophages. ② NF-κB inhibition by a TLR-Myd88 pathway. ③ Unknown mechanisms behind a bacteriophage’s anti-inflammatory effects, namely TLR4 decrease, TLR10 increase, decrease in pro-inflammatory cytokines and chemokines TNF-α, CXCL12a, IL-6, IL-8, CXCL5 and CXCL1; increase in the anti-inflammatory cytokines and chemokines IL-10 and SOCS-3; increase in the IL-1 downregulator IL1RN. ④ Inhibition of NF-κB translation by phage-mediated IFN-1 production though the stimulation of TLR3/TRIF by the virus RNA, transcribed inside the cell.

Figure 2

Necessary considerations for the use of bacteriophages as clinical immune modulators for a more effective therapy. ① Conditions between the inoculation by nasal (1-a), oral (1-b) or intravenous route (1-c) and the specific profile of the patient. ② Requirements between the phage-product and the targeted inflamed tissue. (2-a) Specific tropism and effective dosage to the targeted tissue. (2-b) Stability against enzymatic/environmental hazards that may compromise the phage integrity. ③ Immunological consequences of an improper product’s pharmacokinetics. (3-a) Generated adaptive immunity against the phage product. (3-b) Hindrance of the therapy and prevention of future therapies with the same phage product due to the presence of anti-phage antibodies. (3-c) Pro-inflammatory signal due to the recognition of the phage product as an invading body resulting from anti-phage antibody activation.