A unique mode of nucleic acid immunity performed by a multifunctional bacterial enzyme

Bari, S. M. Nayeemul; Chou-Zheng, Lucy; Howell, Olivia; Hossain, Motaher; Hill, Courtney M.; Boyle, Tori A; Cater, Katie; Dandu, Vidya Sree; Thomas, Alexander; Aslan, Barbaros; Hatoum-Aslan, Asma

doi:10.1016/j.chom.2022.03.001

Cited by 32 publications

(26 citation statements)

References 82 publications

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“…We also found a standalone protein with Fic domain (SoFic), which is known to be a protein AMPylase (capable of ligating AMP onto proteins) (Engel et al, 2012; Harms et al, 2016). One defensive protein in our set encodes a predicted N-terminal nuclease and the domain of unknown function DUF2075 (pfam: PF09848), a domain organization identical to the Nhi anti-phage protein discovered recently in Staphylococcus epidermidis (Bari et al, 2022). Although there is no sequence identity between the S. epidermidis Nhi and the protein we studied here, we denoted our protein Nhi-like, because the similar domain organization suggests a similar function.…”

Section: Resultsmentioning

confidence: 99%

An expanding arsenal of immune systems that protect bacteria from phages

Millman

Melamed

Leavitt

et al. 2022

Preprint

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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.

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Section: Resultsmentioning

confidence: 99%

An expanding arsenal of immune systems that protect bacteria from phages

Millman

Melamed

Leavitt

et al. 2022

Preprint

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“…Such mutations allowed phages to escape the systems Lamassu, Hachiman, ietAS, Retron-Eco8, ShosTA, Borvo, and some AVAST systems (Figure 3, Figure 6). Previous studies on the anti-phage defense systems AbiK (Bouchard and Moineau, 2004;Wang et al, 2011), AbiQ (Samson et al, 2013b), ApbA/B (Yasui et al, 2014), DarTG (LeRoux et al, 2022, Tin (Mosig et al, 1997), and Nhi (Bari et al, 2022) have also reported phage escape via mutation in one of these core replication proteins. Thus, diverse defense systems have evolved to sense or target the core determinants of phage replication.…”

Section: Recurring Themes In Phage Escape From Bacterial Defensementioning

confidence: 99%

“…Although our understanding of bacterial immunity has substantially expanded by these recent discoveries, for the vast majority of the defense systems it is still unknown how they recognize invading phages, and this remains a major unanswered question in the field. Previous studies on individual defense systems, have addressed this question by examining phage mutants that escape defense (Bari et al, 2022;Depardieu et al, 2016;Huiting et al, 2022;Millman et al, 2020;Samson et al, 2013a;Tal et al, 2021Tal et al, , 2022Yasui et al, 2014). Such phages sometimes evade bacterial immunity by mutations in phage components that activate the bacterial defense system; thus escape mutants can generate valuable insights into the mechanism of defense activation (Samson et al, 2013a).…”

Section: Introductionmentioning

confidence: 99%

Discovery of phage determinants that confer sensitivity to bacterial immune systems

Stokar-Avihail

Fedorenko

Garb

et al. 2022

Preprint

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Over the past few years, numerous anti-phage defense systems have been discovered in bacteria. While the mechanism of defense for some of these systems is understood, a major unanswered question is how these systems sense phage infection. To systematically address this question, we isolated 192 phage mutants that escape 19 different defense systems. In many cases, these escaper phages were mutated in the gene sensed by the defense system, enabling us to map the phage determinants that confer sensitivity to bacterial immunity. Our data identify specificity determinants of diverse retron systems and reveal phage-encoded triggers for multiple abortive infection systems. We find general themes in phage sensing and demonstrate that mechanistically diverse systems have converged to sense either the core replication machinery of the phage, phage structural components, or host takeover mechanisms. Combining our data with previous findings, we formulate key principles on how bacterial immune systems sense phage invaders.

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“…VSP- resistant phage M2Φ, producing a slightly different DNA polymerase than that from the VSP- sensitive M1Φ, provides a clue that this defense system could either sense the polymerase directly, or more likely the phage DNA replication intermediates associated with the polymerase. Indeed, a phage defense system called Nhi, carrying both a nuclease and helicase domain, is recently identified to sense phage replication intermediates to direct DNA processing [43]. Regardless of the mechanism, although many versions of VSP-II circulate in the natural isolates of V. cholerae , nearly all VSP-II islands contain the vc0492-490 operon [21, 44], suggesting there is significant pressure to maintain these core genes.…”

Section: Discussionmentioning

confidence: 99%

“…VSPresistant phage M2Φ, producing a slightly different DNA polymerase than that from the VSPsensitive M1Φ, provides a clue that this defense system could either sense the polymerase directly, or more likely the phage DNA replication intermediates associated with the polymerase. Indeed, a phage defense system called Nhi, carrying both a nuclease and helicase domain, is recently identified to sense phage replication intermediates to direct DNA processing [43].…”

Section: Discussionmentioning

confidence: 99%

The Vibrio cholerae Seventh Pandemic islands act in tandem to defend against a circulating phage

O’Hara

Alam

2022

Preprint

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The current circulating pandemic El Tor biotype of Vibrio cholerae has persisted for over sixty years and is characterized by its acquisition of two unique genomic islands called the Vibrio Seventh Pandemic Islands 1 and 2 (VSP-I and VSP-II). However, the functions of most of the genes on VSP-I and VSP-II are unknown and the advantages realized by El Tor through these two islands are not clear. Recent studies have broadly implicated these two mobile genetic elements with phage defense. Still, protection against phage infection through these islands has not been observed directly in any V. cholerae El Tor biotype. Here we report the isolation of a circulating phage from a cholera patient stool sample and demonstrate that propagation of this phage in its native host is inhibited by elements in both VSP-I and VSP-II, providing direct evidence for the role of these genomic islands in phage defense. Moreover, we show that these defense systems are regulated by quorum sensing and active only at certain cell density. Finally, we have isolated a naturally occurring phage variant that is resistant to the defense conferred by the VSP islands, illustrating the countermeasures used by phages to evade these defense mechanisms. Together, this work demonstrates a functional role for the VSPs in V. cholerae and highlights the key regulatory and mechanistic insights that can be gained by studying anti-phage systems in their native contexts.SIGNIFICANCE (AUTHOR SUMMARY)The current pandemic strain of Vibrio cholerae carries two unique genomic islands. How these two islands confer evolutionary advantage to the pathogen is unknown. We show here the identification of a circulating phage that is sensitive to the defense systems present on these two islands and demonstrate how phage variants can evade these defenses. Our studies provide the first direct evidence showing the importance of these genomic islands in defending against phage in their native environments; and in doing so provide novel insight into the mechanisms of these highly conserved defense elements.

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A unique mode of nucleic acid immunity performed by a multifunctional bacterial enzyme

Cited by 32 publications

References 82 publications

An expanding arsenal of immune systems that protect bacteria from phages

An expanding arsenal of immune systems that protect bacteria from phages

Discovery of phage determinants that confer sensitivity to bacterial immune systems

The Vibrio cholerae Seventh Pandemic islands act in tandem to defend against a circulating phage

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