Bacterial Immunity: An adaptable defense

The response of bacteria to the threat posed by phages depends on their local environment.
  1. Michael A Schelling
  2. Dipali G Sashital  Is a corresponding author
  1. Roy J Carver Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, United States

Many bacteria use a system known as CRISPR-Cas to defend themselves against infection by viruses called phages. This system protects the bacterial cell by taking a short length of DNA from the phage and inserting this 'spacer' into its own genome. If the bacterial cell becomes re-infected, the spacer allows the cell to recognize the phage and stop it from replicating by cutting and destroying its DNA. Bacteria with these spacers survive infections and pass their spacers on to their progeny, creating a population that is resistant to the phage.

Phage populations, however, can also adapt and evade bacterial CRISPR-Cas systems. For example, if a phage develops a random mutation in the region targeted by the spacer, it may become undetectable by CRISPR-Cas, leaving it free to replicate and infect other cells (Barrangou et al., 2007; Deveau et al., 2008). Bacteria can combat these phages by creating multiple spacers that target different regions of the phage genome (van Houte et al., 2016; Figure 1). However, previous studies have shown that bacteria rarely acquire multiple spacers (Heler et al., 2015). Now, in eLife, Nora Pyenson and Luciano Marraffini from the Rockefeller University report that the number of spacers each bacterial cell acquires depends on its local environment (Pyenson and Marraffini, 2020).

Bacteria versus viruses called phages.

To defend themselves against phages, bacteria (colored capsules) acquire a region of a phage genome and insert it into their own genome as a 'spacer'. When growing in a liquid environment (left), individual bacterial cells usually acquire a single spacer that targets just one region of the wild-type (WT) phage (shown in grey). In the figure, each bacterial cell has one of four different spacers (shown in blue, green, orange and pink). However, phages mutate in an effort to bypass these defenses: a mutation in the region of the phage genome corresponding to, say, a blue spacer means that the phage can attack and escape the defense of bacteria with blue spacers (fuzzy green circle), but not bacteria with green, orange or pink spacers (red X inside a circle). When growing on a solid surface (right), if an individual cell acquires, say, a pink spacer, it will go on to form a colony of phage resistant cells (inset). If a phage gains a mutation in the region targeted by the pink spacer, the phage will escape detection. In order to stay protected, some bacterial cells within the colony acquire multiple spacers (multi-colored bacterial cells) and can fight off various mutant phages.

Image credit: Dipali Sashital (CC BY 4.0)

Bacteria grown in liquid culture rarely have multiple spacers. Pyenson and Marraffini hypothesized that this is because bacterial cells move more freely when in this environment and are thus able to work together to defend themselves (Figure 1, left). This limits the need for individual cells to have multiple spacers in order to be protected. To test this theory, Pyenson and Marraffini investigated what happens to infected bacteria that are grown on a solid medium where cell movement is restricted. They found that most cells died, but those that acquired resistance formed separate colonies. Further experiments showed that compared to bacteria grown in liquid culture, bacterial cells in the resistant colonies had often acquired multiple spacers and were able to fight off phages with other mutations (Figure 1, right).

However, it still remained unclear what drives bacteria to acquire multiple spacers. It was previously shown that acquiring an initial spacer can drive the addition of subsequent spacers through a process called priming (Datsenko et al., 2012; Nussenzweig et al., 2019). Pyenson and Marraffini found that a disproportionate number of second spacers were taken from DNA regions located close to the initial spacer, which is a hallmark of priming. This suggests that priming enables immobile bacteria to survive mutated phages that have escaped detection by allowing the bacteria to create multiple spacers.

Cells in these resistant colonies arranged themselves into unusually shaped sectors, with the number and type of spacers present varying between cells in each sector. It seems that when bacteria are immobilized, individual cells within the colony must acquire more spacers to resist infection by the mutated phage (Figure 1, right). The new multi-spacer cells then outgrow the rest of the colony, forming these unusually shaped sectors. These findings suggest that bacteria cooperate and share the spacer load in a liquid environment. On a solid surface, on the other hand, the bacteria are more independent, and if a cell becomes immune to a mutated phage, it will form a new colony sector with its progeny.

In nature, bacteria are often attached to surfaces. For example, some bacteria live at the bottom of bodies of water, and these bacterial communities may be regularly targeted by phages (Tuson and Weibel, 2013). Bacteria also gather on biological surfaces when preparing to invade other organisms. For example, the bacteria Streptococcus preferentially bind and form colonies on mucus membrane surfaces in the human body before infecting epithelial cells (Beachey, 1981). The study by Pyenson and Marraffini reveals how different types of environments may influence the way that bacteria and phages respond to each other and synchronously evolve over time.

CRISPR-Cas systems are exceptionally diverse and use a variety of mechanisms to defend bacteria against infection. Further experiments studying these systems in a variety of environmental contexts will be important to help explain the diverse mechanisms of CRISPR-Cas systems.

References

Article and author information

Author details

  1. Michael A Schelling

    Michael A Schelling is in the Roy J Carver Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, Ames, United States

    Competing interests
    No competing interests declared
  2. Dipali G Sashital

    Dipali G Sashital is in the Roy J Carver Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, Ames, United States

    For correspondence
    sashital@iastate.edu
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7681-6987

Publication history

  1. Version of Record published: March 30, 2020 (version 1)

Copyright

© 2020, Schelling and Sashital

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

  • 6,215
    views
  • 308
    downloads
  • 3
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

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)

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

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

  1. Michael A Schelling
  2. Dipali G Sashital
(2020)
Bacterial Immunity: An adaptable defense
eLife 9:e56122.
https://doi.org/10.7554/eLife.56122

Further reading

    1. Epidemiology and Global Health
    2. Microbiology and Infectious Disease
    Patrick E Brown, Sze Hang Fu ... Ab-C Study Collaborators
    Research Article Updated

    Background:

    Few national-level studies have evaluated the impact of ‘hybrid’ immunity (vaccination coupled with recovery from infection) from the Omicron variants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

    Methods:

    From May 2020 to December 2022, we conducted serial assessments (each of ~4000–9000 adults) examining SARS-CoV-2 antibodies within a mostly representative Canadian cohort drawn from a national online polling platform. Adults, most of whom were vaccinated, reported viral test-confirmed infections and mailed self-collected dried blood spots (DBSs) to a central lab. Samples underwent highly sensitive and specific antibody assays to spike and nucleocapsid protein antigens, the latter triggered only by infection. We estimated cumulative SARS-CoV-2 incidence prior to the Omicron period and during the BA.1/1.1 and BA.2/5 waves. We assessed changes in antibody levels and in age-specific active immunity levels.

    Results:

    Spike levels were higher in infected than in uninfected adults, regardless of vaccination doses. Among adults vaccinated at least thrice and infected more than 6 months earlier, spike levels fell notably and continuously for the 9-month post-vaccination. In contrast, among adults infected within 6 months, spike levels declined gradually. Declines were similar by sex, age group, and ethnicity. Recent vaccination attenuated declines in spike levels from older infections. In a convenience sample, spike antibody and cellular responses were correlated. Near the end of 2022, about 35% of adults above age 60 had their last vaccine dose more than 6 months ago, and about 25% remained uninfected. The cumulative incidence of SARS-CoV-2 infection rose from 13% (95% confidence interval 11–14%) before omicron to 78% (76–80%) by December 2022, equating to 25 million infected adults cumulatively. However, the coronavirus disease 2019 (COVID-19) weekly death rate during the BA.2/5 waves was less than half of that during the BA.1/1.1 wave, implying a protective role for hybrid immunity.

    Conclusions:

    Strategies to maintain population-level hybrid immunity require up-to-date vaccination coverage, including among those recovering from infection. Population-based, self-collected DBSs are a practicable biological surveillance platform.

    Funding:

    Funding was provided by the COVID-19 Immunity Task Force, Canadian Institutes of Health Research, Pfizer Global Medical Grants, and St. Michael’s Hospital Foundation. PJ and ACG are funded by the Canada Research Chairs Program.

    1. Microbiology and Infectious Disease
    Alejandro Prieto, Luïsa Miró ... Antonio Juarez
    Research Article

    Antimicrobial resistance (AMR) poses a significant threat to human health. Although vaccines have been developed to combat AMR, it has proven challenging to associate specific vaccine antigens with AMR. Bacterial plasmids play a crucial role in the transmission of AMR. Our recent research has identified a group of bacterial plasmids (specifically, IncHI plasmids) that encode large molecular mass proteins containing bacterial immunoglobulin-like domains. These proteins are found on the external surface of the bacterial cells, such as in the flagella or conjugative pili. In this study, we show that these proteins are antigenic and can protect mice from infection caused by an AMR Salmonella strain harboring one of these plasmids. Furthermore, we successfully generated nanobodies targeting these proteins, that were shown to interfere with the conjugative transfer of IncHI plasmids. Considering that these proteins are also encoded in other groups of plasmids, such as IncA/C and IncP2, targeting them could be a valuable strategy in combating AMR infections caused by bacteria harboring different groups of AMR plasmids. Since the selected antigens are directly linked to AMR itself, the protective effect extends beyond specific microorganisms to include all those carrying the corresponding resistance plasmids.