Bacteriophage genes that inactivate the CRISPR/Cas bacterial immune system

Bondy-Denomy, Joe; Pawluk, April; Maxwell, Karen L.; Davidson, Alan R.

doi:10.1038/nature11723

Cited by 732 publications

(725 citation statements)

References 32 publications

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“…Alternatively, other molecular regulations employed by bacterial host or phage may be important for CRISPR-mediated resistance and may contribute to the infection outcome. Such regulation mechanisms potentially include transcriptional and/or translational regulation of CRISPR RNA and Cas genes and anti-CRISPR genes encoded by phages (Bondy-Denomy et al, 2013;Pawluk et al, 2014). Interactions between P. acnes and phages may also depend on additional mechanisms involved in phage binding, entry, replication or release.…”

Section: Phage Strainsmentioning

confidence: 99%

The diversity and host interactions of Propionibacterium acnes bacteriophages on human skin

et al. 2015

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The viral population, including bacteriophages, is an important component of the human microbiota, yet is poorly understood. We aim to determine whether bacteriophages modulate the composition of the bacterial populations, thus potentially playing a role in health or disease. We investigated the diversity and host interactions of the bacteriophages of Propionibacterium acnes, a major human skin commensal implicated in acne pathogenesis. By sequencing 48 P. acnes phages isolated from acne patients and healthy individuals and by analyzing the P. acnes phage populations in healthy skin metagenomes, we revealed that P. acnes phage populations in the skin microbial community are often dominated by one strain. We also found phage strains shared among both related and unrelated individuals, suggesting that a pool of common phages exists in the human population and that transmission of phages may occur between individuals. To better understand the bacterium-phage interactions in the skin microbiota, we determined the outcomes of 74 genetically defined Propionibacterium strains challenged by 15 sequenced phages. Depending on the Propionibacterium lineage, phage infection can result in lysis, pseudolysogeny, or resistance. In type II P. acnes strains, we found that encoding matching clustered regularly interspaced short palindromic repeat spacers is insufficient to confer phage resistance. Overall, our findings suggest that the prey-predator relationship between bacteria and phages may have a role in modulating the composition of the microbiota. Our study also suggests that the microbiome structure of an individual may be an important factor in the design of phage-based therapy.

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Section: Phage Strainsmentioning

confidence: 99%

The diversity and host interactions of Propionibacterium acnes bacteriophages on human skin

et al. 2015

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“…We also limited our study to resistance at the target site, even though trans-resistance might be common. Target species may harbor natural variation for Cas9 expression levels or may produce peptides or RNA that silences the CRISPR machinery (Bondy-Denomy et al 2013). The possibility of all these other resistance mechanisms suggests that our estimates for the probability that resistance evolves are likely to be conservative.…”

Section: Discussionmentioning

confidence: 99%

Evolution of Resistance Against CRISPR/Cas9 Gene Drive

2017

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CRISPR/Cas9 gene drive (CGD) promises to be a highly adaptable approach for spreading genetically engineered alleles throughout a species, even if those alleles impair reproductive success. CGD has been shown to be effective in laboratory crosses of insects, yet it remains unclear to what extent potential resistance mechanisms will affect the dynamics of this process in large natural populations. Here we develop a comprehensive population genetic framework for modeling CGD dynamics, which incorporates potential resistance mechanisms as well as random genetic drift. Using this framework, we calculate the probability that resistance against CGD evolves from standing genetic variation, de novo mutation of wild-type alleles, or cleavage repair by nonhomologous end joining (NHEJ)-a likely by-product of CGD itself. We show that resistance to standard CGD approaches should evolve almost inevitably in most natural populations, unless repair of CGD-induced cleavage via NHEJ can be effectively suppressed, or resistance costs are on par with those of the driver. The key factor determining the probability that resistance evolves is the overall rate at which resistance alleles arise at the population level by mutation or NHEJ. By contrast, the conversion efficiency of the driver, its fitness cost, and its introduction frequency have only minor impact. Our results shed light on strategies that could facilitate the engineering of drivers with lower resistance potential, and motivate the possibility to embrace resistance as a possible mechanism for controlling a CGD approach. This study highlights the need for careful modeling of the population dynamics of CGD prior to the actual release of a driver construct into the wild.KEYWORDS CRISPR/Cas9; gene drive; homing drive; mutagenic chain reaction; whole population replacement T HE prospect of driving genetically modified alleles to fixation in a population has enticed scientists for .40 years (Curtis 1968;Foster et al. 1972). Potential applications are broad and ambitious, including the eradication of vectorborne diseases such as malaria, dengue, and Zika (Burt 2003;Esvelt et al. 2014;Champer et al. 2016). For example, mosquitoes could be genetically altered such that they can no longer transmit Plasmodium parasites. If these altered alleles could then be spread in a wild population, we could effectively eradicate malaria in humans. Similarly, a gene drive could be used to reverse insecticide resistance in an agricultural pest, or to spread a deleterious allele in an invasive species to drive it toward extinction.While various strategies for implementing a gene drive have been discussed since the 1970s, all previously proposed mechanisms have faced significant obstacles. Ongoing efforts to transfer the Medea system from flour beetles to other insects have, thus far, fallen short (Chen et al. 2007;Akbari et al. 2014). Underdominance systems have also been developed (Altrock et al. 2010;Akbari et al. 2013;Reeves et al. 2014), but these are slow-spreading systems that requi...

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“…Indeed, as shown in numerous examples, the CRISPR systems do not completely inhibit the acquisition of all exogenous DNA but are a component of the ongoing coevolution of mobile elements (Croucher et al 2016). Notably, some bacteriophages have evolved genes to counter CRISPR activity and can infect cells with a CRISPR system (Nozawa et al 2011;LopezSanchez et al 2012;Bondy-Denomy et al 2013). Finally, the limited number of complete Parachlamydiaceae genomes available in public databases does not yet allow testing if the rate of gene and genomic island acquisition is lower in Pr.…”

Section: Discussionmentioning

confidence: 99%

CRISPR system acquisition and evolution of an obligate intracellularChlamydia-related bacterium

Bertelli

Cissé

Rusconi

et al. 2015

Preprint

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Recently, a new Chlamydia-related organism, Protochlamydia naegleriophila KNic, was discovered within a Naegleria amoeba. To decipher the mechanisms at play in the modeling of genomes from the Protochlamydia genus, we sequenced the full genome of Pr. naegleriophila, which includes a 2,885,090 bp chromosome and a 145,285 bp megaplasmid. For the first time within the Chlamydiales order, we describe the presence of a clustered regularly interspaced short palindromic repeats (CRISPR) system, the immune system of bacteria, located on the chromosome. It is composed of a small CRISPR locus comprising eight repeats and associated cas-cse genes of the subtype I-E. A CRISPR locus is also present within Chlamydia sp. Diamant, another Pr. naegleriophila strain, suggesting that the CRISPR system was acquired by a common ancestor of Pr. naegleriophila, after its divergence from Pr. amoebophila. Both nucleotide bias and comparative genomics approaches identified probable horizontal gene acquisitions within two and four genomic islands in Pr. naegleriophila KNic and Diamant genomes, respectively. The plasmid encodes an F-type conjugative system highly similar to 1) that found in the Pam100G genomic island of Pr. amoebophila UWE25 chromosome, as well as on the plasmid of Rubidus massiliensis and 2) to the three genes remaining in the chromosome of Parachlamydia acanthamoebae strains. Therefore, this conjugative system was likely acquired on an ancestral plasmid before the divergence of Parachlamydiaceae. Overall, this new complete Pr. naegleriophila genome sequence enables further investigation of the dynamic processes shaping the genomes of the family Parachlamydiaceae and the genus Protochlamydia.

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Bacteriophage genes that inactivate the CRISPR/Cas bacterial immune system

Cited by 732 publications

References 32 publications

The diversity and host interactions of Propionibacterium acnes bacteriophages on human skin

The diversity and host interactions of Propionibacterium acnes bacteriophages on human skin

Evolution of Resistance Against CRISPR/Cas9 Gene Drive

CRISPR system acquisition and evolution of an obligate intracellularChlamydia-related bacterium

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