Bacterial defences interact synergistically by disrupting phage cooperation

Abstract

The constant arms race between bacteria and their phages has resulted in a large diversity of bacterial defence systems, with many bacteria carrying several systems. In response, phages often carry counter-defence genes. If and how bacterial defence mechanisms interact to protect against phages with counter-defence genes remains unclear. Here, we report the existence of a novel defence system, coined MADS (Methylation Associated Defence System), which is located in a strongly conserved genomic defence hotspot in Pseudomonas aeruginosa and distributed across Gram-positive and Gram-negative bacteria. We find that the natural co-existence of MADS and a Type IE CRISPR-Cas adaptive immune system in the genome of P. aeruginosa SMC4386 provides synergistic levels of protection against phage DMS3, which carries an anti-CRISPR (acr) gene. Previous work has demonstrated that Acr-phages need to cooperate to overcome CRISPR immunity, with a first sacrificial phage causing host immunosuppression to enable successful secondary phage infections. Modelling and experiments show that the co-existence of MADS and CRISPR-Cas provides strong and durable protection against Acr-phages by disrupting their cooperation and limiting the spread of mutants that overcome MADS. These data reveal that combining bacterial defences can robustly neutralise phage with counter-defence genes, even if each defence on its own can be readily by-passed, which is key to understanding how selection acts on defence combinations and their coevolutionary consequences.

My host’s enemy is my enemy: plasmids carrying CRISPR-Cas as a defence against phages

“…Given that CRISPR-Cas can be essential for bacterial survival during a phage attack, it is expected to be located on the chromosome. However, bacteria typically carry several defence mechanisms against phages [ 3 ], and some of those defence mechanisms can work synergistically [ 44 , 45 ]. Consequently, CRISPR-Cas may not always be essential but moderately beneficial for bacterial survival and therefore it could be located on a plasmid.…”

My host’s enemy is my enemy: plasmids carrying CRISPR-Cas as a defence against phages

“…Given that CRISPR-Cas can be essential for bacterial survival during a phage attack, it is expected to be located on the chromosome. However, bacteria typically carry several defense mechanisms against phages [3] and some of those defence mechanisms can work synergistically [44, 45]. Consequently, CRISPR-Cas may not always be essential but moderately beneficial for bacterial survival and therefore it could be located on a plasmid.…”

Molecular basis of foreign DNA recognition by BREX anti-phage immunity system

“…A range of DNA-targeting systems rely on epigenetic DNA modifications, such as DNA methylation, as a marker of self 10 ; a classic example being restrictionmodification (R-M) systems present in ~83% of sequenced prokaryotic genomes 11 . A multitude of recently described immunity systems, such as Dnd 12 , Ssp 13 , Dpd 14 , DISARM 15 , MADS 16 , and BREX 17,18 also encode DNA modification proteins. The mechanisms of phage defense by these systems are not fully determined and likely are more sophisticated than direct nucleolytic cleavage of non-modified invading DNA 19,20 .…”