Achilles Heel: Type VII Toxin/Antitoxin System Hha/TomB Facilitates Phage Infection by Regulating Cryptic Prophage Lytic Genes

Toxin/antitoxin systems (TAs) are stress-response loci most-closely linked to stabilizing mobile genetic elements such as plasmids and inhibiting phage infection. In contrast to the phage inhibition paradigm, here we demonstrate that the type VII TA system, Hha/TomB, facilitates rather than inhibits Escherichia coli infection with 12 BASEL lytic phages (seven Tequatrovirus phages and five Vequintavirus members), including phage 48 (a Vequintavirus), which we chose to focus on due to its clear phenotype. Toxin Hha regulates cryptic prophage lytic genes, and antitoxin TomB masks Hha toxin activity by oxidizing a conserved Hha cysteine residue. We find here that the mechanism by which Hha increases infection is via activation of cryptic prophage lytic genes. Therefore, this is one of the first reports of phages and a type VII TA system as well as the first report of a TA system that is not advantageous for phage inhibition but instead may be an Achilles heel that is manipulated by lytic phages.