1. Genetics and Genomics
  2. Microbiology and Infectious Disease
Download icon

Bacterial Warfare: Toxins, mutations and adaptations

  1. Maarten De Jong
  2. Neal M Alto  Is a corresponding author
  1. Department of Microbiology, University of Texas Southwestern Medical Center, United States
Insight
  • Cited 0
  • Views 940
  • Annotations
Cite this article as: eLife 2021;10:e66676 doi: 10.7554/eLife.66676

Abstract

The toxins that some bacteria secrete to kill off rival species can also generate mutations that help toxin-resistant populations adapt to new environments.

Main text

Bacterial communities are often comprised of numerous different species which either co-exist in harmony or compete with each other for resources. To gain an upper hand on the competition, some bacteria have developed a form of needle-like machinery called a type VI secretion system (or T6SS for short) that injects toxic proteins directly into their rivals (Basler et al., 2012; Hood et al., 2010; Klein et al., 2020; Russell et al., 2011). It is generally thought that the toxins secreted by T6SS decapacitate the target organism by impairing important processes such as cell wall synthesis, ATP production and DNA replication (Ahmad et al., 2019; Jurėnas and Journet, 2020; Whitney et al., 2015). While these toxins are clearly involved in anti-bacterial warfare, it is unclear whether T6SS can also facilitate symbiotic relationships within bacterial communities.

Recently, a collaboration between groups led by Joseph Mougous (University of Washington) and David Liu (Harvard University and the Broad Institute) discovered that the T6SS of Burkholderia cenocepacia secretes a toxin called DddA that catalyzes the removal of an amino group from cytosine, converting it to uracil (Mok et al., 2020). In most cells, these enzymes – known as cytosine deaminases – are important for maintaining the levels of nucleotide precursors in cells (Neuhard, 1968). While most cytosine deaminases catalyze this reaction in single-stranded DNA, DddA is the first enzyme found to convert cytosine to uracil in double-stranded DNA. However, uracil is normally only found in RNA, where it pairs with another nucleotide base called adenosine: in DNA, adenosine pairs with thymine, whereas cytosine pairs with guanine in both DNA and RNA (Figure 1).

The DddA toxin from B. cenocepacia affects other bacterial species in different ways.

DddA is a toxin that removes an amino group from cytosine (C; green), converting it into uracil (U; yellow) in chromosomal DNA (top). In some bacterial species uracil is then removed by the DNA repair machinery (left), which can lead to double-stranded DNA breaks and ultimately cell death. In bacteria resistant to the toxic effects of DddA, DNA breaks do not occur (right): instead, uracil is converted into thymine (T; orange), which causes guanine (G; red) to convert to adenosine (A; blue). This results in genetic variation within the targeted population, further diversifying the community of bacteria.

Now, in eLife, Mougous and colleagues – including Marcos de Moraes as first author – report that as well as destroying bacteria, DddA also provides a selective advantage for some bacteria in the community (de Moraes et al., 2021). The team (who are based at the University of Washington) found that when the bacterium B. cenocepacia injects DddA, uracil accumulates in the DNA of the targeted bacteria. Since uracil is normally only found in RNA, its presence triggers a repair mechanism that attempts to remove it from the DNA. However, this repair mechanism can lead to a break in one strand of the DNA, and if there are too many breaks in close proximity, they can lead to double-stranded breaks which stop DNA replication and result in bacterial cell death (Figure 1; D'souza and Harrison, 2003; Wallace, 2014). Indeed, de Moraes et al. found that the DddA delivered by B. cenocepacia suppresses the viability of several other bacterial species, including Pseudomona aeruginosa and Burkholderia thailandensis.

Although DddA causes double-stranded DNA breaks and cell death in most bacterial species, some disease-causing bacteria – including Eschericia coli and Salmonella enterica – are able to resist its detrimental effects. To better understand this observation, de Moraes et al. examined the long-term effects of DddA on these bacteria. They found that rather than excising the uracil that had replaced cytosine, the DNA replication machinery in the infected bacteria converts the uracil into a different nucleotide, thymine. As thymine pairs with adenosine in DNA, C-G pairs throughout the genome get replaced with T-A pairs (Figure 1).

An unanticipated consequence of this exchange was that the bacteria not killed by DddA acquired resistance to the antibiotic rifampicin. Further experiments revealed that other deaminase toxins similar to DddA were also able to introduce mutations in single-stranded DNA, suggesting this may be a widespread mechanism within bacterial populations (de Moraes et al., 2021).

It is generally thought that DNA mutations that arise during natural selection are caused by errors during chromosome replication or by exogenous factors such as chemicals and ionizing stress (Schroeder et al., 2018). Some bacteria rapidly adapt by importing fragments of foreign DNA from the environment and integrating them into their genome. This mechanism has been proposed to increase the genetic variation of populations, which provides a selective advantage to bacteria living in challenging environments or competing with other species (Dubnau and Blokesch, 2019; Mell and Redfield, 2014). The findings of de Moreas et al. suggest a similar mechanism in which the mutations produced by deaminase toxins help to diversify the population, creating new variants that can rapidly adapt to environmental changes.

There are several exciting avenues of research resulting from these findings. First, it is unclear why some bacteria are susceptible to DddA intoxication, whereas others are resistant. Defining these resistance mechanisms could help reveal the biological scenarios in which T6SS helps communities of bacteria adapt to their environment. Second, it will be interesting to determine how DddA toxins alter the composition of bacterial communities: DddA intoxication could eliminate competing species, while the genetic variations induced in resistant species may help enhance the long-term fitness of the community. Lastly, new insights into these topics may increase our understanding of human diseases where pathogenic bacteria come into contact with communities of microbes in the body, such as inflammatory bowel disease and cystic fibrosis, which could ultimately lead to better treatments (Buffie and Pamer, 2013; Spiewak et al., 2019).

References

Article and author information

Author details

  1. Maarten De Jong

    Maarten De Jong is in the Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, United States

    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2278-286X
  2. Neal M Alto

    Neal M Alto Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, United States

    For correspondence
    neal.alto@utsouthwestern.edu
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7602-3853

Publication history

  1. Version of Record published: February 23, 2021 (version 1)

Copyright

© 2021, De Jong and Alto

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 940
    Page views
  • 97
    Downloads
  • 0
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Genetics and Genomics
    2. Microbiology and Infectious Disease
    Jessamyn I Perlmutter et al.
    Research Article

    Wolbachia are the most widespread bacterial endosymbionts in animals. Within arthropods, these maternally-transmitted bacteria can selfishly hijack host reproductive processes to increase the relative fitness of their transmitting females. One such form of reproductive parasitism called male killing, or the selective killing of infected males, is recapitulated to degrees by transgenic expression of the WO-mediated killing (wmk) gene. Here, we characterize the genotype-phenotype landscape of wmk-induced male killing in D. melanogaster using transgenic expression. While phylogenetically distant wmk homologs induce no sex-ratio bias, closely-related homologs exhibit complex phenotypes spanning no death, male death, or death of all hosts. We demonstrate that alternative start codons, synonymous codons, and notably a single synonymous nucleotide in wmk can ablate killing. These findings reveal previously unrecognized features of transgenic wmk-induced killing and establish new hypotheses for the impacts of post-transcriptional processes in male killing variation. We conclude that synonymous sequence changes are not necessarily silent in nested endosymbiotic interactions with life-or-death consequences.

    1. Genetics and Genomics
    Kevin R Costello et al.
    Research Article

    Transposable elements (TEs) are mobile genetic elements that make up a large fraction of mammalian genomes. While select TEs have been co-opted in host genomes to have function, the majority of these elements are epigenetically silenced by DNA methylation in somatic cells. However, some TEs in mice, including the Intracisternal A-particle (IAP) subfamily of retrotransposons, have been shown to display interindividual variation in DNA methylation. Recent work has revealed that IAP sequence differences and strain-specific KRAB zinc finger proteins (KZFPs) may influence the methylation state of these IAPs. However, the mechanisms underlying the establishment and maintenance of interindividual variability in DNA methylation still remain unclear. Here we report that sequence content and genomic context influence the likelihood that IAPs become variably methylated. IAPs that differ from consensus IAP sequences have altered KZFP recruitment that can lead to decreased KAP1 recruitment when in proximity of constitutively expressed genes. These variably methylated loci have a high CpG density, similar to CpG islands, and can be bound by ZF-CxxC proteins, providing a potential mechanism to maintain this permissive chromatin environment and protect from DNA methylation. These observations indicate that variably methylated IAPs escape silencing through both attenuation of KZFP binding and recognition by ZF-CxxC proteins to maintain a hypomethylated state.