An expanding arsenal of immune systems that protect bacteria from phages

Abstract

Bacterial anti-phage defense systems are frequently clustered in microbial genomes, forming defense islands. This genomic property enabled the recent discovery of multiple defense systems based on their genomic co-localization with known systems, but the full arsenal of anti-phage mechanisms in bacteria is still unknown. In this study we report the discovery of 21 new defense systems that protect bacteria from phages, based on computational genomic analyses and phage infection experiments. We find multiple systems with protein domains known to be involved in eukaryotic anti-viral immunity, including ISG15-like proteins, dynamin-like proteins, and SEFIR domains, and show that these domains participate in bacterial defense against phages. Additional systems include protein domains predicted to manipulate DNA and RNA molecules, as well as multiple toxin-antitoxin systems shown here to function in anti-phage defense. The systems we discovered are widely distributed in bacterial and archaeal genomes, and in some bacteria form a considerable fraction of the immune arsenal. Our data substantially expand the known inventory of defense systems utilized by bacteria to counteract phage infection.

The defence island repertoire of the Escherichia coli pan-genome

“…Our study, as well as recent studies by others (5, 7, 8, 16, 18, 19), demonstrates that defence systems cluster within specific regions in MGEs, yet the reasons for this clustering are not entirely clear. It is likely that this aggregation of defence systems within mobile elements provides fitness benefits to recipient bacteria living in a phage-rich environment (1).…”

“…These islands typically contain integrase or recombinase genes but lack other known mobility genes. RM, restriction-modification; Gabija, Hachiman and Zorya are defence systems described in (6); AVAST was described in (4); and Olokun, Menshen, and PsyrTA were described in (7). Gene symbols of flanking core genes are indicated for each hotspot.…”

“…Genome assemblies that were highly fragmented and comprised more than 200 contigs were discarded. The following defence systems were identified in the E. coli genome dataset based on cluster annotation, as previously described (7): RM, CRISPR, BREX (11), CBASS (13), DISARM (12), Dnd (39), Druantia, Gabija, Hachiman, Kiwa, Lamassu, Septu, Shedu, Thoeris, Wadjet, Zorya (6), pAgo (40), retrons (14), STK2 (41), Aditi, Azaca, Bunzi, Dazbog, Dodola, Menshen, Olokun, Shango (7), dCTP deaminase (42), DSR1, DSR2, Gao Qat, Gao SIR2-HerA, RADAR (7), PrrC, and Abi proteins (pfams PF07751, PF08843, PF09848, PF10592, PF14253, PF14355).…”

Direct activation of an innate immune system in bacteria by a viral capsid protein

“…Similarly, for CRISPR-Cas systems, the adaptive immune system of some bacteria, guide RNAs enable a cell to specifically target foreign DNA. Dozens of new bacterial defense systems have been discovered in recent years [11][12][13][14][15] , but unlike RM and CRISPR-Cas, many of them must be specifically activated upon phage infection. This is particularly critical for abortive infection (Abi) systems in which a defense system uses a lethal effector to kill an infected cell and prevent propagation of the virus through a population 16 .…”

“…Toxin-antitoxin (TA) systems are prevalent genetic elements in bacteria that are emerging as key components of anti-phage innate immunity 13,14,17,18 , often serving as abortive infection modules that kill infected cells to prevent spread of phages through a population. How TA systems sense and respond to phage infection remains poorly understood.…”