Bacteria armed with Ssp defenses can distinguish self from invading phage by modifying host DNA and selectively cutting foreign DNA. In this system, sequence-specific phosphorothioate (PT) modifications are installed in the host genome through SspABCD, while unmodified foreign DNA is targeted for cleavage by SspFGH or SspE. The resulting “PT self-pattern” acts as a molecular signature that immune enzymes can recognize.
Now, a new study reports a viral countermeasure: PptA, a phage-encoded protein containing a [4Fe–4S] iron–sulfur cluster. Rather than creating PT modifications from scratch, PptA hijacks host cellular machinery by partnering with cognate IscS homologues—host cysteine desulfurase enzymes that normally contribute sulfur chemistry required for other metabolic and cofactor assembly pathways.
The investigators combined biochemical experiments with structural analysis to define how sulfur is transferred at the molecular level inside the IscS–PptA complex. Their model supports a streamlined PT installation route, in which the phage protein leverages the catalytic capabilities of the IscS homologues to drive the formation of PT modifications on DNA.
A key finding is that infection triggers not just the presence of PptA, but its robust expression, which is required to reach PT incorporation levels sufficient to reshape the phage genome. In other words, the virus depends on active remodeling of its DNA chemistry to achieve immune evasion, not merely on passive inheritance of pre-modified sequences.
With PT patterns now resembling those found in the bacterial chromosome, the phage DNA can escape recognition and subsequent cleavage by the SspFGH/SspE pathway. The study frames this as molecular mimicry: the phage “masquerades as self” by co-opting the PT blueprint that Ssp surveillance expects to see only on host DNA.
The authors further demonstrate functional consequences at the phage level. They show that PptA can reprogram the Ssp-sensitive λ phage into an immune-evasive variant, converting a virus that would normally be eliminated into one capable of persisting despite Ssp-based restriction.
Overall, the work reveals a co-evolutionary strategy in which phages overcome PT-centered bacterial immunity through direct capture and repurposing of host sulfur transfer chemistry. By clarifying the intermolecular mechanics of sulfur delivery within an IscS–PptA complex, the findings also suggest a new engineering path for therapeutic phages.
Such phages could be designed to carry protein factors like PptA (or functional analogs) that install host-like PT modifications, enabling treatment candidates to bypass a widespread bacterial defense system that otherwise limits phage efficacy.
Subject of Research:
Phage evasion of bacterial Ssp phosphorothioate DNA immunity via hijacking host IscS-based sulfur transfer machinery
Article Title:
Phage hijacks host phosphorothioate DNA modification machinery to circumvent bacterial Ssp defences.
Article References:
Wang, Y., Yang, H., Jiang, L. et al. Phage hijacks host phosphorothioate DNA modification machinery to circumvent bacterial Ssp defences. Nat Microbiol (2026). https://doi.org/10.1038/s41564-026-02387-3
Image Credits: AI Generated
DOI: https://doi.org/10.1038/s41564-026-02387-3
Keywords:
Tags: bacterial DNA phosphorothioate modificationbacterial-phage interactionshost sulfur transfer pathwaysiron–sulfur clusters in phage proteinsIscS homologues in bacterial DNA modificationmolecular basis of bacterial immunityphage evasion mechanismsphage hijacking of bacterial machineryphosphorothioate DNA modificationsPptA phage-encoded proteinSsp bacterial defense systemviral countermeasures against bacterial defenses
