(Ph)ighting Phages: How Bacteria Resist Their Parasites

Abstract

Bacteria are under constant attack from bacteriophages (phages), bacterial parasites that are the most abundant biological entity on earth. To resist phage infection, bacteria have evolved an impressive arsenal of anti-phage systems. Recent advances have significantly broadened and deepened our understanding of how bacteria battle phages, spearheaded by new systems like CRISPR-Cas. This review aims to summarize bacterial anti-phage mechanisms, with an emphasis on the most recent developments in the field.

Figure 1.. Stages of a phage’s life cycle that can be targeted by different anti-phage mechanisms.

Upon recognising a surface receptor, a phage injects its DNA into the host cell. Either after injection or after prophage induction, the viral genome is subject to several rounds of replication and gene expression that leads to the assembly and accumulation of new viral particles, which are released upon lysis of the host cell. As indicated, anti-phage mechanisms can interfere with any part of this process.

Figure 2.. Prevention of phage adsorption.

1. Successful binding of the phage to its receptor (green). 2. Sequestration of phage particles by OMVs containing the phage receptor. 3. Prevention of phage adsorption due to receptor post-translational modifications (glycosylation). 4. Prevention of phage adsorption due to receptor occlusion by surface structures (glycan capsule). 5. Receptor modification through interaction with another protein. 6. Receptor mutations that abolish phage binding. 7. Regulation of receptor expression.

Figure 3.. Different CRISPR targeting mechanisms.

See text for details. Purple box: PAM, black circles: crRNAs 5’ end, pink: spacer/protospacer sequences, blue: 5’ crRNA tags inhibiting type III/VI autoimmunity. For types I, II, and V, the DNA double helix is unwound by the main effector complex in a PAM-dependent manner, and DNA is cut by Cas3 (type I) or Cas9/Cas12a (types II/V). Type III and VI recognise the protospacer within a nascent transcript in a PAM-independent manner, this is followed by the cleavage of DNA and/or RNA from the invader. Type III also produces cyclic oligoadenylates (orange hexagons) which allosterically activate the accessory RNase Csm6 (Csx1 for III-B).

Figure 4.. The staphylococcal Stk2 Abi system.

The phage protein pacK triggers autophosphorylation (and activation) of the S. epidermidis Stk2 kinase. Activated Stk2 phosphorylates Stk1 and miscellaneous cellular factors, eventually leading to the abortion of the viral infectious cycle and cell death.

Figure 5.. PICI-mediated interference of phage assembly.

In Gram-positive organisms, PICI expression is inhibited by a transcription repressor. Helper phages produce an antirepressor, leading to the excision of the PICI from the host chromosome. The PICI genome replicates, and expresses proteins that repress late helper phage genes and alter the phage capsid size to be more appropriate for the PICI genome size. This in turn leads to both the preferential packaging of PICI genomes and the prevention of the formation of helper phage virions.