Bacteriophage trigger antiviral immunity and prevent clearance of bacterial infection

Abstract

Bacteriophage are abundant at sites of bacterial infection, but their effects on mammalian hosts are unclear. We have identified pathogenic roles for filamentous Pf bacteriophage produced by Pseudomonas aeruginosa (Pa) in suppression of immunity against bacterial infection. Pf promote Pa wound infection in mice and are associated with chronic human Pa wound infections. Murine and human leukocytes endocytose Pf, and internalization of this single-stranded DNA virus results in phage RNA production. This triggers Toll-like receptor 3 (TLR3)- and TIR domain-containing adapter-inducing interferon-β (TRIF)-dependent type I interferon production, inhibition of tumor necrosis factor (TNF), and the suppression of phagocytosis. Conversely, immunization of mice against Pf prevents Pa wound infection. Thus, Pf triggers maladaptive innate viral pattern-recognition responses, which impair bacterial clearance. Vaccination against phage virions represents a potential strategy to prevent bacterial infection.

5 challenges in understanding the role of the virome in health and disease

“…For phages, presuming they act by modulating the bacterial community, the animal model must harbor the relevant bacterial host species, and thus the bacterial microbiome may need to be manipulated as well. Notably, some recent studies have suggested that phages may also interact directly with eukaryotic host cells [28,29]. Overall, significant effort and resources must be expended to establish robust animal-infection models suitable to define the role of the virome.…”

Impact of Historic Migrations and Evolutionary Processes on Human Immunity

“…This is the case of parasites that infect other parasites, such as bacteriophage viruses, that can influence the outcome of bacterial infections. For example, in a cohort of individuals with chronic wounds, a report showed that the phage Pf, which coexists with Pseudomonas aeruginosa in infected wounds, triggered the production of type I IFN, the inhibition of tumor necrosis factor (TNF) production, and the suppression of phagocytosis in human primary monocytes and mouse bone marrow-derived macrophages, dampening the antibacterial response and promoting the bacterial infection [60]. However, bacteriophages can also provide protection to the human host by directly attacking pathogenic bacteria and by upregulating in human PBMCs the expression of proinflammatory genes such as IL1A, IL1B, IL6, TNFA, CXCL1, and CXCL5, as shown for several S. aureus and P. aeruginosa phages, including PNM, LUZ19, 14-1, and GE-vB_Pae-Kakheti25 [61].…”

Review article: bacteriophages in gastroenterology—from biology to clinical applications

“…Close follow‐up of the effect of phage therapeutic products in the human host is essential. Recent data suggest that phages may be able to produce mRNA within human cells, thereby modulating the immune response of the human host by decreasing tumour necrosis factor production and preventing bacterial clearance …”

“…29,30 by decreasing tumour necrosis factor production and preventing bacterial clearance. 54 Bacterial resistance to phages is a result of bacterial adaptation to the selective pressure of phage infections. In natural environments, antibiotic and phage resistance phenotypes are thought to evolve independently.…”