Battling Phages: How Bacteria Defend against Viral Attack

Bacteriophages (phages) are accomplished, bacteria-specific, viral predators with far-reaching impact: from the food and biotechnology industries [1] to global nutrient cycling [2] to human health and disease [3]; wherever bacteria thrive, it seems, so do predatory phages. In order to survive the constant onslaught of phage, bacteria have evolved mechanistically diverse defense strategies that act at every stage of the phage life cycle (Fig 1) [4,5]. Phages rapidly co-evolve to overcome these barriers, resulting in a constant, and often surprising, molecular arms race [6]. In this review, I highlight the spectrum of “innate” strategies used by bacteria to evade phage predation, with particular attention paid to more recent findings in the field. For a discussion of the CRISPR-Cas adaptive immune system, readers are directed to several recent reviews [4–6]. Fig 1 An overview of bacterial defense systems against phage. Preventing Phage Attachment A successful phage infection starts with adsorption of the virus to a specific bacterial surface receptor. Phage receptors, typically protein, polysaccharide, or lipopolysaccharide (LPS), must not only be present on the surface of the cell, but must be accessible and in a permissive spatial distribution. Therefore, strategies to prevent phage adsorption include modifying receptor structure through mutation and concealing receptors with an additional physical barrier [4,5]. A decrease in receptor availability can be mediated by phase variation in which receptor expression is subject to heritable, reversible switching, allowing for population heterogeneity in an effort to ensure survival. Bordetella bronchiseptica varies between the Bvg+ phase, which is required for pulmonary colonization, and the Bvg- phase. In the Bvg+ phase, the bacteria express numerous virulence and colonization factors, including the adhesin pertactin. Phages that use pertactin as a receptor have been identified [7]. Not surprisingly, these are temperate phages associated with clinical isolates of B. bronchiseptica. Similarly, Vibrio cholerae O1 serogroup strains rely on expression of the LPS O1 antigen for efficient colonization of the intestinal tract. Prevalent phages associated with V. cholerae in clinical samples, although in a virulent, not temperate, relationship, depend on wild-type levels of O1 antigen expression. The O1 antigen is subject to phase variation, and these phase variants are protected from phage infection and attenuated for virulence [8]. Although the classical view of phase variation is often that its purpose is to facilitate evasion of the host immune system [9], phages also apply powerful selective forces on bacterial surface molecules, and the high levels of variation observed with many of these molecules may be driven by either, or both, forces. The expression of surface receptors can also be modulated by competing phages. The availability of the Pseudomonas aeruginosa type IV pilus (TFP), which is important in pathogenesis and biofilm formation, can be modulated by lysogenic conversion. Phage D3112 encodes a protein called Tip that binds to a TFP ATPase and prevents its localization, resulting in a loss of surface piliation and protection from other phages that depend on TFP for infection [10]. In some cases, phage receptors may be hidden behind a physical barrier, such as a capsule or other extracellular polymer. The K1 capsule of Escherichia coli has been shown to directly interfere with phage T7 attachment to its LPS receptor [11]. In addition to hiding receptors to prevent phage attachment, bacteria may produce decoys. Phage T4 levels can be reduced by the presence of outer membrane vesicles (OMVs), leading to the suggestion that shedding of OMVs into the environment may act as a decoy to prevent phage adsorption that would otherwise lead to a productive infection [12].