Interactions between Bacteriophage, Bacteria, and the Mammalian Immune System

Abstract

The human body is host to large numbers of bacteriophages (phages)⁻a diverse group of bacterial viruses that infect bacteria. Phage were previously regarded as bystanders that only impacted immunity indirectly via effects on the mammalian microbiome. However, it has become clear that phages also impact immunity directly, in ways that are typically anti-inflammatory. Phages can modulate innate immunity via phagocytosis and cytokine responses, but also impact adaptive immunity via effects on antibody production and effector polarization. Phages may thereby have profound effects on the outcome of bacterial infections by modulating the immune response. In this review we highlight the diverse ways in which phages interact with human cells. We present a computational model for predicting these complex and dynamic interactions. These models predict that the phageome may play important roles in shaping mammalian-bacterial interactions.

Keywords: adaptive immunity; bacteriophage; human host; immunology; innate immunity; phage-human host interaction.

Figure 1

Schematic representation of direct interaction of phages with mammalian cells. (A) Bacteriophage adhering to mucus (BAM). Mucus is produced by the underlying epithelium. Phages of different morphologies (i.e., Myo-, Sipho-, and Podoviridae) can bind variable glycan residues displayed on mucin glycoproteins through variable capsid proteins, such as Ig-like domains. The adherence of phages to this mucus layer creates an antimicrobial layer that reduces bacterial attachment to and colonization of the mucus. This leads, in turn, to a reduction in epithelial cell death. Furthermore, these phages can migrate through theses epithelial cell layers subsequently ending up in the bloodstream. (B) Phage transcytosis. Binding interactions between phages and the membrane through transmembrane mucins, specific receptors, or through non-specific recognition, may allow signal transduction in the epithelial cell. Subsequently the phage particle is taken up by the epithelial cell. The internalized phage particles may be degraded leading to intracellular release of phage particles and DNA. Furthermore, it has been hypothesized that phage particles might cross the eukaryotic cell enabling phages to disseminate to the body. Phages may also gain access to the body via a “leaky gut”, where they bypass the epithelial cell barrier at sites of cellular damage or punctured vasculature. Figure adapted from Barr et al. [63,72].

Figure 2

Interaction of bacteriophages with mammalian immune cells. Independent of the route of administration, phages can enter the bloodstream and tissues and encounter immune cells in the blood. Phages could encounter these immune cells whilst they are bound to their bacterial host and taken up together by either macrophages or dendritic cells. Alternatively, these phages can directly interact with any of these immune cells by either interacting with cell surface molecules or receptors, or taken up using a similar mechanism as observed with phage transcytosis. Once in contact with these immune cells, different pro- (red) or anti-inflammatory (green) cytokines are induced, giving the phage the opportunity to influence the immune response. For example, the induction of IL1RN by the phage blocks the pro-inflammatory signals induced by IL1α and IL1β. Although it is known that phages can induce cytokine response, the precise cells responsible are currently not known. Furthermore, the uptake of phages by antigen presenting cells (APC; e.g., dendritic cells) leads to the activation of B-cells and the production of specific antibodies against the phage.

Figure 3

Antibody induction by phage T4 structural proteins. Individual contribution of T4 head proteins (Hoc, Soc, gp23, gp24, and gp12) to phage immunogenicity. Depending on the administration rote (i.e., oral or intraperitoneal), a difference in antibody response can be observed. When phages are administered orally, strong IgG or low IgA response towards Hoc can be observed, whereas intraperitoneal applications lead to high IgG responses towards Hoc and gp23. Modified Majewska et al. [24]. Permission was obtained for the reproduction of this figure.

Figure 4

Schematic representation of the immune response against phages and bacteria. P–Phage, S–bacteria, I–innate immunity, A–adaptive immune response to phage, B–adaptive immune response to bacteria. Green arrows represent a stimulatory effect, red arrows represent an inhibitory effect. Variables and parameters used in these models are described in Tables S1 and S2. Adapted from Hodyra-Stefaniak et al. [26].

Figure 5

Effects of innate and adaptive immunity on the success or failure of phage antibacterial treatment, numerical simulations. Innate immune response. (A) No relation between innate immunity and phage viability. The survival of the phage is independent of the presence of an innate immune response. (B) Phage susceptibility to the innate immune response. The innate immunity has a negative effect on the phage survival and leads to its removal. Subsequently the bacteria are no longer infected by the phage, and a rise in bacteria is observed. (C) Phage susceptibility to the innate immune response, considering the anti-inflammatory property of the phage. The anti-inflammatory characteristic of the phage leads to a decline in innate immune particles. This has as effect that the bacterial count diminishes, and the phage survives, similar to A. (D) Phage susceptibility to innate immune response accommodated and counteracted by an increased phage dose. The higher phage dose leads to the removal of the pathogen and the survival of the phage. (E) Phage susceptibility to innate immune response accommodated and counteracted by an increased phage dose, considering the anti-inflammatory property of the phage. The effect is the same as in D, but the innate immune response is diminished. Innate and adaptive immune response. (F) Phage susceptibility to the innate immune response and presence of pre-immunization towards the phage. Presence of pre-existing anti-phage antibodies lead to a rapid drop in phage concentration, hence the phage has no effect on the survival of the bacteria. Once an adaptive immune response towards the bacteria is present, bacterial count decreases. (G) Phage susceptibility to the innate immune response and no pre-immunization to the phage exists, considering the anti-inflammatory property of the phage. The anti-inflammatory response of the phage has no direct influence on the phage survival in the presence of an adaptive immune response towards the phage. Overall the response is similar to F. (H) Phage susceptibility to the innate immune response and no pre-immunization to the phage exists. The absence of a specific adaptive immune response towards the phage leads to a decrease in the bacterial population. The combined effect of innate and adaptive immunity towards the phage leads to a drop-in phage particle concentration. (I) Phage susceptibility to the innate immune response and no pre-immunization to the phage exists, considering the anti-inflammatory property of the phage. Once the phage reaches a critical concentration (Pc, the concentration of phages needed to induce an anti-inflammatory response), the innate immune response decreases, and the phage concentration grows until all bacteria are removed. Once an adaptive immune response is present against the phage, the phage concentration diminishes until completely removed. Variables and parameters used in these models are described in Tables S1 and S2.