Publications by authors named "Angus Angermeyer"

11 Publications

  • Page 1 of 1

Temporal shifts in antibiotic resistance elements govern phage-pathogen conflicts.

Science 2021 07;373(6554)

Department of Plant and Microbial Biology, University of California, Berkeley, CA 94720, USA.

Bacteriophage predation selects for diverse antiphage systems that frequently cluster on mobilizable defense islands in bacterial genomes. However, molecular insight into the reciprocal dynamics of phage-bacterial adaptations in nature is lacking, particularly in clinical contexts where there is need to inform phage therapy efforts and to understand how phages drive pathogen evolution. Using time-shift experiments, we uncovered fluctuations in 's resistance to phages in clinical samples. We mapped phage resistance determinants to SXT integrative and conjugative elements (ICEs), which notoriously also confer antibiotic resistance. We found that SXT ICEs, which are widespread in γ-proteobacteria, invariably encode phage defense systems localized to a single hotspot of genetic exchange. We identified mechanisms that allow phage to counter SXT-mediated defense in clinical samples, and document the selection of a novel phage-encoded defense inhibitor. Phage infection stimulates high-frequency SXT ICE conjugation, leading to the concurrent dissemination of phage and antibiotic resistances.
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http://dx.doi.org/10.1126/science.abg2166DOI Listing
July 2021

Bacteriophage ICP1: A Persistent Predator of .

Annu Rev Virol 2021 Jul 27. Epub 2021 Jul 27.

Department of Plant and Microbial Biology, University of California, Berkeley, California 94720, USA; email:

Bacteriophages or phages-viruses of bacteria-are abundant and considered to be highly diverse. Interestingly, a particular group of lytic -specific phages (vibriophages) of the International Centre for Diarrheal Disease Research, Bangladesh cholera phage 1 (ICP1) lineage show high levels of genome conservation over large spans of time and geography, despite a constant coevolutionary arms race with their host. From a collection of 67 sequenced ICP1 isolates, mostly from clinical samples, we find these phages have mosaic genomes consisting of large, conserved modules disrupted by variable sequences that likely evolve mostly through mobile endonuclease-mediated recombination during coinfection. Several variable regions have been associated with adaptations against antiphage elements in ; notably, this includes ICP1's CRISPR-Cas system. The ongoing association of ICP1 and in cholera-endemic regions makes this system a rich source for discovery of novel defense and counterdefense strategies in bacteria-phage conflicts in nature. Expected final online publication date for the , Volume 8 is September 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
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http://dx.doi.org/10.1146/annurev-virology-091919-072020DOI Listing
July 2021

A Family of Viral Satellites Manipulates Invading Virus Gene Expression and Can Affect Cholera Toxin Mobilization.

mSystems 2020 Oct 13;5(5). Epub 2020 Oct 13.

Department of Plant and Microbial Biology, University of California, Berkeley, Berkeley, California, USA

Many viruses possess temporally unfolding gene expression patterns aimed at subverting host defenses, commandeering host metabolism, and ultimately producing a large number of progeny virions. High-throughput omics tools, such as RNA sequencing (RNA-seq), have dramatically enhanced the resolution of expression patterns during infection. Less studied have been viral satellites, mobile genomes that parasitize viruses. By performing RNA-seq on infection time courses, we have obtained the first time-resolved transcriptomes for bacteriophage satellites during lytic infection. Specifically, we have acquired transcriptomes for the lytic phage ICP1 and all five known variants of ICP1's parasite, the hage inducible chromosomal island-ike lements (PLEs). PLEs rely on ICP1 for both DNA replication and mobilization and abolish production of ICP1 progeny in infected cells. We investigated PLEs' impact on ICP1 gene expression and found that PLEs did not broadly restrict or reduce ICP1 gene expression. A major exception occurred in ICP1's capsid morphogenesis operon, which was downregulated by each of the PLE variants. Surprisingly, PLEs were also found to alter the gene expression of CTXΦ, the integrative phage that encodes cholera toxin and is necessary for virulence of toxigenic One PLE, PLE1, upregulated CTXΦ genes involved in replication and integration and boosted CTXΦ mobility following induction of the SOS response. Viral satellites are found in all domains of life and can have profound fitness effects on both the viruses they parasitize and the cells they reside in. In this study, we have acquired the first RNA sequencing (RNA-seq) transcriptomes of viral satellites outside plants, as well as the transcriptome of the phage ICP1, a predominant predator of pandemic Capsid downregulation, previously observed in an unrelated phage satellite, is conserved among hage inducible chromosomal island-ike lements (PLEs), suggesting that viral satellites are under strong selective pressure to reduce the capsid expression of their larger host viruses. Despite conserved manipulation of capsid expression, PLEs exhibit divergent effects on CTXΦ transcription and mobility. Our results demonstrate that PLEs can influence both their hosts' resistance to phage and the mobility of virulence-encoding elements, suggesting that PLEs can play a substantial role in shaping evolution.
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http://dx.doi.org/10.1128/mSystems.00358-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567579PMC
October 2020

Genome replication dynamics of a bacteriophage and its satellite reveal strategies for parasitism and viral restriction.

Nucleic Acids Res 2020 01;48(1):249-263

Department of Plant and Microbial Biology, University of California, Berkeley, Berkeley, CA 94720, USA.

Phage-inducible chromosomal island-like elements (PLEs) are bacteriophage satellites found in Vibrio cholerae. PLEs parasitize the lytic phage ICP1, excising from the bacterial chromosome, replicating, and mobilizing to new host cells following cell lysis. PLEs protect their host cell populations by completely restricting the production of ICP1 progeny. Previously, it was found that ICP1 replication was reduced during PLE(+) infection. Despite robust replication of the PLE genome, relatively few transducing units are produced. We investigated if PLE DNA replication itself is antagonistic to ICP1 replication. Here we identify key constituents of PLE replication and assess their role in interference of ICP1. PLE encodes a RepA_N initiation factor that is sufficient to drive replication from the PLE origin of replication during ICP1 infection. In contrast to previously characterized bacteriophage satellites, expression of the PLE initiation factor was not sufficient for PLE replication in the absence of phage. Replication of PLE was necessary for interference of ICP1 DNA replication, but replication of a minimalized PLE replicon was not sufficient for ICP1 DNA replication interference. Despite restoration of ICP1 DNA replication, non-replicating PLE remained broadly inhibitory against ICP1. These results suggest that PLE DNA replication is one of multiple mechanisms contributing to ICP1 restriction.
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http://dx.doi.org/10.1093/nar/gkz1005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7145576PMC
January 2020

Competition between mobile genetic elements drives optimization of a phage-encoded CRISPR-Cas system: insights from a natural arms race.

Philos Trans R Soc Lond B Biol Sci 2019 05;374(1772):20180089

1 Department of Plant and Microbial Biology, University of California , 111 Koshland Hall, Berkeley, CA 94720 , USA.

CRISPR-Cas systems function as adaptive immune systems by acquiring nucleotide sequences called spacers that mediate sequence-specific defence against competitors. Uniquely, the phage ICP1 encodes a Type I-F CRISPR-Cas system that is deployed to target and overcome PLE, a mobile genetic element with anti-phage activity in Vibrio cholerae. Here, we exploit the arms race between ICP1 and PLE to examine spacer acquisition and interference under laboratory conditions to reconcile findings from wild populations. Natural ICP1 isolates encode multiple spacers directed against PLE, but we find that single spacers do not interfere equally with PLE mobilization. High-throughput sequencing to assay spacer acquisition reveals that ICP1 can also acquire spacers that target the V. cholerae chromosome. We find that targeting the V. cholerae chromosome proximal to PLE is sufficient to block PLE and is dependent on Cas2-3 helicase activity. We propose a model in which indirect chromosomal spacers are able to circumvent PLE by Cas2-3-mediated processive degradation of the V. cholerae chromosome before PLE mobilization. Generally, laboratory-acquired spacers are much more diverse than the subset of spacers maintained by ICP1 in nature, showing how evolutionary pressures can constrain CRISPR-Cas targeting in ways that are often not appreciated through in vitro analyses. This article is part of a discussion meeting issue 'The ecology and evolution of prokaryotic CRISPR-Cas adaptive immune systems'.
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http://dx.doi.org/10.1098/rstb.2018.0089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6452262PMC
May 2019

Analysis of 19 Highly Conserved Bacteriophages Isolated from Environmental and Patient Sources Over a Twelve-Year Period.

Viruses 2018 06 1;10(6). Epub 2018 Jun 1.

Department of Plant and Microbial Biology, University of California Berkeley, Berkeley, CA 94720, USA.

The biotype "El Tor" is responsible for all of the current epidemic and endemic cholera outbreaks worldwide. These outbreaks are clonal, and it is hypothesized that they originate from the coastal areas near the Bay of Bengal, where the lytic bacteriophage ICP1 (International Centre for Diarrhoeal Disease Research, Bangladesh cholera phage 1) specifically preys upon these pathogenic outbreak strains. ICP1 has also been the dominant bacteriophage found in cholera patient stools since 2001. However, little is known about the genomic differences between the ICP1 strains that have been collected over time. Here, we elucidate the pan-genome and the phylogeny of the ICP1 strains by aligning, annotating, and analyzing the genomes of 19 distinct isolates that were collected between 2001 and 2012. Our results reveal that the ICP1 isolates are highly conserved and possess a large core-genome as well as a smaller, somewhat flexible accessory-genome. Despite its overall conservation, ICP1 strains have managed to acquire a number of unknown genes, as well as a CRISPR-Cas system which is known to be critical for its ongoing struggle for co-evolutionary dominance over its host. This study describes a foundation on which to construct future molecular and bioinformatic studies of these -associated bacteriophages.
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http://dx.doi.org/10.3390/v10060299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6024749PMC
June 2018

Salt marsh sediment bacterial communities maintain original population structure after transplantation across a latitudinal gradient.

PeerJ 2018 1;6:e4735. Epub 2018 May 1.

Josephine Bay Paul Center, Marine Biological Laboratory, Woods Hole, MA, USA.

Dispersal and environmental selection are two of the most important factors that govern the distributions of microbial communities in nature. While dispersal rates are often inferred by measuring the degree to which community similarity diminishes with increasing geographic distance, determining the extent to which environmental selection impacts the distribution of microbes is more complex. To address this knowledge gap, we performed a large reciprocal transplant experiment to simulate the dispersal of US East Coast salt marsh rhizome-associated microbial sediment communities across a latitudinal gradient and determined if any shifts in microbial community composition occurred as a result of the transplantation. Using bacterial 16S rRNA gene sequencing, we did not observe large-scale changes in community composition over a five-month summer growing season and found that transplanted communities more closely resembled their origin sites than their destination sites. Furthermore, transplanted communities grouped predominantly by region, with two sites from the north and three sites to the south hosting distinct bacterial taxa, suggesting that sediment communities transplanted from north to south tended to retain their northern microbial distributions, and south to north maintained a southern distribution. A small number of potential indicator 16S rRNA gene sequences had distributions that were strongly correlated to both temperature and nitrogen, indicating that some organisms are more sensitive to environmental factors than others. These results provide new insight into the microbial biogeography of salt marsh sediments and suggest that established bacterial communities in frequently-inundated environments may be both highly resistant to invasion and resilient to some environmental shifts. However, the extent to which environmental selection impacts these communities is taxon specific and variable, highlighting the complex interplay between dispersal and environmental selection for microbial communities in nature.
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http://dx.doi.org/10.7717/peerj.4735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5935077PMC
May 2018

Regional Isolation Drives Bacterial Diversification within Cystic Fibrosis Lungs.

Cell Host Microbe 2015 Sep 20;18(3):307-19. Epub 2015 Aug 20.

Department of Microbiology, University of Washington School of Medicine, Seattle, WA 98195, USA; Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA. Electronic address:

Bacterial lineages that chronically infect cystic fibrosis (CF) patients genetically diversify during infection. However, the mechanisms driving diversification are unknown. By dissecting ten CF lung pairs and studying ∼12,000 regional isolates, we were able to investigate whether clonally related Pseudomonas aeruginosa inhabiting different lung regions evolve independently and differ functionally. Phylogenetic analysis of genome sequences showed that regional isolation of P. aeruginosa drives divergent evolution. We investigated the consequences of regional evolution by studying isolates from mildly and severely diseased lung regions and found evolved differences in bacterial nutritional requirements, host defense and antibiotic resistance, and virulence due to hyperactivity of the type 3 secretion system. These findings suggest that bacterial intermixing is limited in CF lungs and that regional selective pressures may markedly differ. The findings also may explain how specialized bacterial variants arise during infection and raise the possibility that pathogen diversification occurs in other chronic infections characterized by spatially heterogeneous conditions.
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http://dx.doi.org/10.1016/j.chom.2015.07.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4589543PMC
September 2015

Decoupled distance-decay patterns between dsrA and 16S rRNA genes among salt marsh sulfate-reducing bacteria.

Environ Microbiol 2016 Jan 8;18(1):75-86. Epub 2015 Apr 8.

Josephine Bay Paul Center, Marine Biological Laboratory, Woods Hole, MA, 02543, USA.

In many habitats, microorganisms exhibit significant distance-decay patterns as determined by analysis of the 16S rRNA gene and various other genetic elements. However, there have been few studies that examine how the similarities of both taxonomic and functional genes co-vary over geographic distance within a group of ecologically related microbes. Here, we determined the biogeographic patterns of the functional dissimilatory sulfite reductase gene (dsrA) and the 16S rRNA gene in sulfate-reducing bacterial communities of US East Coast salt marsh sediments. Distance-decay, ordination and statistical analyses revealed that the distribution of 16S rRNA genes is strongly influenced by geographic distance and environmental factors, whereas the dsrA gene is not. Together, our results indicate that 16S rRNA genes are likely dispersal limited and under environmental selection, whereas dsrA genes appear randomly distributed and not selected for by any expected environmental variables. Selection, drift, dispersal and mutation are all factors that may help explain the decoupled biogeographic patterns for the two genes. These data suggest that both the taxonomic and functional elements of microbial communities should be considered in future studies of microbial biogeography to aid in our understanding of the diversity, distribution and function of microorganisms in the environment.
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http://dx.doi.org/10.1111/1462-2920.12821DOI Listing
January 2016

Conditions associated with the cystic fibrosis defect promote chronic Pseudomonas aeruginosa infection.

Am J Respir Crit Care Med 2014 Apr;189(7):812-24

1 Department of Medicine, and.

Rationale: Progress has been made in understanding how the cystic fibrosis (CF) basic defect produces lung infection susceptibility. However, it remains unclear why CF exclusively leads to chronic infections that are noninvasive and highly resistant to eradication. Although biofilm formation has been suggested as a mechanism, recent work raises questions about the role of biofilms in CF.

Objectives: To learn how airway conditions attributed to CF transmembrane regulator dysfunction could lead to chronic infection, and to determine if biofilm-inhibiting genetic adaptations that are common in CF isolates affect the capacity of Pseudomonas aeruginosa to develop chronic infection phenotypes.

Methods: We studied P. aeruginosa isolates grown in agar and mucus gels containing sputum from patients with CF and measured their susceptibility to killing by antibiotics and host defenses. We also measured the invasive virulence of P. aeruginosa grown in sputum gels using airway epithelial cells and a murine infection model.

Measurements And Main Results: We found that conditions likely to result from increased mucus density, hyperinflammation, and defective bacterial killing could all cause P. aeruginosa to grow in bacterial aggregates. Aggregated growth markedly increased the resistance of bacteria to killing by host defenses and antibiotics, and reduced their invasiveness. In addition, we found that biofilm-inhibiting mutations do not impede aggregate formation in gel growth environments.

Conclusions: Our findings suggest that conditions associated with several CF pathogenesis hypotheses could cause the noninvasive and resistant infection phenotype, independently of the bacterial functions needed for biofilm formation.
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http://dx.doi.org/10.1164/rccm.201312-2142OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4225830PMC
April 2014

Targeting a bacterial stress response to enhance antibiotic action.

Proc Natl Acad Sci U S A 2009 Aug 12;106(34):14570-5. Epub 2009 Aug 12.

Departments of Genome Sciences and Medicine and Microbiology, University of Washington, Seattle, WA 98195, USA.

This report describes the identification and analysis of a 2-component regulator of Pseudomonas aeruginosa that is a potential aminoglycoside antibiotic combination therapy target. The regulator, AmgRS, was identified in a screen of a comprehensive, defined transposon mutant library for functions whose inactivation increased tobramycin sensitivity. AmgRS mutations enhanced aminoglycoside action against bacteria grown planktonically and in antibiotic tolerant biofilms, against genetically resistant clinical isolates, and in lethal infections of mice. Drugs targeting AmgRS would thus be expected to enhance the clinical efficacy of aminoglycosides. Unexpectedly, the loss of AmgRS reduced virulence in the absence of antibiotics, indicating that its inactivation could protect against infection directly as well as by enhancing aminoglycoside action. Transcription profiling and phenotypic analysis suggested that AmgRS controls an adaptive response to membrane stress, which can be caused by aminoglycoside-induced translational misreading. These results help validate AmgRS as a potential antibiotic combination target for P. aeruginosa and indicate that fundamental stress responses may be a valuable general source of such targets.
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http://dx.doi.org/10.1073/pnas.0903619106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2732827PMC
August 2009
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