Diverse enzymatic activities mediate antiviral immunity in prokaryotes

Abstract

Bacteria and archaea are frequently attacked by viruses and other mobile genetic elements and rely on dedicated antiviral defense systems, such as restriction endonucleases and CRISPR, to survive. The enormous diversity of viruses suggests that more types of defense systems exist than are currently known. By systematic defense gene prediction and heterologous reconstitution, here we discover 29 widespread antiviral gene cassettes, collectively present in 32% of all sequenced bacterial and archaeal genomes, that mediate protection against specific bacteriophages. These systems incorporate enzymatic activities not previously implicated in antiviral defense, including RNA editing and retron satellite DNA synthesis. In addition, we computationally predict a diverse set of other putative defense genes that remain to be characterized. These results highlight an immense array of molecular functions that microbes use against viruses.

Prophage-encoded hotspots of bacterial immune systems

“…A series of remarkable discoveries stemmed from the observation that bacterial defense systems tend to cluster in genomic regions termed defense islands (15,16). The systematic investigation of genes found in association with known defense genes has considerably expanded our knowledge of bacterial immunity (17,18). Despite these remarkable findings, it is believed that many defense systems remain to be discovered.…”

Phage lysis‐lysogeny switches and programmed cell death: Danse macabre

“…[ 88 ] Systematic searches of bacterial genomes for anti‐phage defense systems have revealed a staggering diversity of previously unknown ones of which most can be predicted to function via the Abi strategy, and many are likely to employ cyclic oligonucleotides as signals similar to CBASS. [ 85,89 ] Furthermore, type III CRISPR‐Cas systems contain a built‐in CBASS‐like mechanism that induces dormancy or PCD upon infection by a specific virus containing a cognate protospacer. [ 90 ] Most likely, the diversity of Abi‐like systems in bacteria and archaea is far greater than currently explored, and collectively, these systems comprise a major component of the network of microbial “pan‐immunity.” [ 91 ]…”

Growing away from monocultures – interdependent growth conditions for studying antibacterial and antiphage systems

“…These immunity gene clusters were identified by comparative genomics given their chromosomal localization and the proteins' homology to previously characterized T6SS immunity factors. Within the past 2 years, a plethora of new antiphage defence systems have also been identified (Doron et al ., 2018; Gao et al ., 2020). While powerful DNA editing tools such as restriction/modification (R/M) and CRISPR/Cas systems, used by bacteria against invasion by foreign DNA, are well‐studied, it is likely that we have only touched the tip of the iceberg.…”

“…In contrast to adaptive immunity (i.e., CRISPR/Cas), these newly discovered innate immunity‐like systems often encode for conditionally abortive phage infection as a mechanism of defence. Indeed, reconstitution of several gene operons in bacterial chassis (e.g., E. coli or Bacillus subtilis ) protected the host bacterium against certain classes of phages (Doron et al ., 2018; Gao et al ., 2020). Notably, these inhibited the phage propagation at the population level rather than through protection of the single bacterium.…”

“…These mechanisms could have applications as genome editing tools, similar to the ‘CRISPR revolution’, for which Charpentier and Doudna won the 2020 Nobel Prize in Chemistry. Towards this, a recent study described enzymatic activities that were not previously known to be associated with phage defence mechanisms that include RNA editing capabilities and retron satellite DNA synthesis (Gao et al ., 2020). These new findings highlight the potential of these and additional, yet to be discovered, systems as genome editing tools in the future.…”