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Review
. 2024 Aug 23;16(9):1348.
doi: 10.3390/v16091348.

Phage against the Machine: The SIE-ence of Superinfection Exclusion

Michael J Bucher  1 , Daniel M Czyż  1
Affiliations
Review

Phage against the Machine: The SIE-ence of Superinfection Exclusion

Michael J Bucher et al. Viruses. .

Abstract

Prophages can alter their bacterial hosts to prevent other phages from infecting the same cell, a mechanism known as superinfection exclusion (SIE). Such alterations are facilitated by phage interactions with critical bacterial components involved in motility, adhesion, biofilm production, conjugation, antimicrobial resistance, and immune evasion. Therefore, the impact of SIE extends beyond the immediate defense against superinfection, influencing the overall fitness and virulence of the bacteria. Evaluating the interactions between phages and their bacterial targets is critical for leading phage therapy candidates like Pseudomonas aeruginosa, a Gram-negative bacterium responsible for persistent and antibiotic-resistant opportunistic infections. However, comprehensive literature on the mechanisms underlying SIE remains scarce. Here, we provide a compilation of well-characterized and potential mechanisms employed by Pseudomonas phages to establish SIE. We hypothesize that the fitness costs imposed by SIE affect bacterial virulence, highlighting the potential role of this mechanism in the management of bacterial infections.

Keywords: Pseudomonas aeruginosa; antimicrobial resistance; bacteriophage; fitness; superinfection exclusion.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Simplified mechanism for Pseudomonas phage Pf4 superinfection exclusion and the proposed associated fitness effects. Superinfection exclusion begins with previous Pf4 infection and integration to the host genome. (1) Host receptor binding: the P. aeruginosa host receptor utilized by Pf4 is the T4P major pilin PilA (purple). After binding, the filamentous phage is pulled through the outer membrane via T4P retraction, mediated by the PilT (orange) ATPase. Next, the filamentous phage is brought through the periplasm and into the inner membrane (IM) via several other proteins not included in the figure. (2) DNA injection and integration: the phage then injects its linear ssDNA into the cytoplasm where it can integrate into the bacterial genome (A) and has its components synthesized utilizing host transcriptional and translational machinery. (3) Protein interaction during superinfection: under conditions of superinfection, the Pf4 phage protein pVIII interacts with (B) PilJ and (C) PilC, components of the T4P. (4) Impact on T4P assembly and virulence: these interactions prevent the complete biosynthesis and assembly of the T4P, likely affecting diverse virulence mechanisms, including (D) superinfection exclusion, (E) loss of twitching motility, (F) reduction in biofilm production, (G) reduced capacity for immune evasion, and (H) tissue invasion.
Figure 2
Figure 2
Overview of phage-induced superinfection exclusion (SIE) mechanisms across different bacterial species. Key mechanisms include the following: (1) O-Antigen serotype switching, where Salmonella, Shigella, Escherichia, and Pseudomonas phages alter the surface antigens of the host bacteria to evade phage recognition. (2) DNA injection inhibition by Salmonella and Escherichia phages prevents the introduction of competing phage DNA into the bacterial cytoplasm. (3) Receptor binding inhibition, a tactic used by Escherichia, Pseudomonas, and Salmonella phages to block or alter the structure of receptor sites, thus preventing attachment of subsequent phages. (4) DNA translocation inhibition, a process where Salmonella, Escherichia, and Pseudomonas phages stop the transport of foreign DNA into the host cell. (5) Cell wall degradation inhibition, employed by Escherichia phages to maintain cell wall integrity against enzymatic degradation by other phages. (6) Membrane depolarization leading to cell death as a defensive measure by Escherichia phages, causing host cell death upon superinfection. (7) Host RNA polymerase (RNAP)/transcription inhibition, a technique used by Escherichia and Pseudomonas phages to interfere with the host’s RNA polymerase, halting host transcription, and propagation of competing phages. The phage components and bacterial targets are represented schematically to depict the interactions and effects of SIE mechanisms.
Figure 3
Figure 3
Sub-therapeutic concentrations of antibiotics can trigger prophage induction and activate superinfection exclusion, leading to compromised bacterial fitness.
See this image and copyright information in PMC

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