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Updated: Jan 30, 2026
Arbovirus Infections As Screening Tools for the Identification of Viral Immunomodulators and Host Antiviral Factors
Published on: September 13, 2018
A prophage-encoded abortive infection protein preserves host and prophage spread
Molly R Sargen1, Sadie P Antine1,2, Grzegorz J Grabe3
1Department of Microbiology, Harvard Medical School, Boston, MA, USA.
Abstract:
Most bacterial pathogens are polylysogens, harbouring multiple vertically transmitted prophages1-3. These prophages enhance bacterial pathogenicity and survival by encoding virulence factors and anti-phage defence systems while retaining the capacity for horizontal transfer. Thus, prophage-encoded anti-phage defences must block propagation of external phages without inhibiting the spread of the prophages that encode them. Here we identify HepS-an abortive infection system encoded on the Gifsy-1 prophage constituted of a single HEPN domain protein-which restricts phages of the Siphoviridae family. We demonstrate that in its native host context of Salmonella enterica serovar Typhimurium, HepS both senses phage infection and enacts abortive infection. Structures of HepS reveal a tetrameric nuclease complex that undergoes allosteric activation upon recognition of Siphoviridae tail tip proteins during production of new phage particles. Once activated, HepS cleaves specific transfer RNA anticodon loops and arrests phage replication. Gifsy-1, a Siphoviridae itself, evades self-targeting by expressing a tail tip variant that does not trigger HepS, as do co-resident Siphoviridae prophages Gifsy-2 and Gifsy-3. This evasion permits Gifsy-1 to spread despite encoding HepS. These findings reveal a mechanism by which a prophage defends the host while maintaining its propagation abilities.
Insights
Bacterial prophages use HepS, an abortive infection system, to restrict new phages without harming themselves. This system targets specific tRNA anticodon loops, halting phage replication and protecting the host bacterium.
Area of Science:
- Microbiology
- Molecular Biology
- Virology
Background:
- Bacterial pathogens often harbor multiple prophages, which can enhance virulence and survival.
- Prophages encode anti-phage defense systems to protect against external phage infection.
- These defense systems must allow the prophage to propagate while restricting other phages.
Purpose of the Study:
- To identify and characterize a novel prophage-encoded anti-phage defense system.
- To understand the mechanism of action and regulation of this system.
- To elucidate how the prophage evades self-targeting by its own defense system.
Main Methods:
- Identification of the HepS abortive infection system from the Gifsy-1 prophage.
- Structural analysis of the HepS protein complex.
- Biochemical assays to determine HepS activity and substrate specificity.
- In vivo studies in Salmonella enterica serovar Typhimurium to assess HepS function and evasion mechanisms.
Main Results:
- HepS, a single HEPN domain protein, restricts Siphoviridae phages.
- HepS functions as a tetrameric nuclease activated by Siphoviridae tail tip proteins.
- Activated HepS cleaves tRNA anticodon loops, arresting phage replication.
- Gifsy-1 and related prophages evade HepS by expressing altered tail tip proteins.
Conclusions:
- HepS is a prophage-encoded abortive infection system that defends the bacterial host against specific phages.
- Prophages utilize tail tip variants to evade self-targeting by HepS, ensuring their own propagation.
- This study reveals a sophisticated mechanism for balancing host defense and prophage survival.
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