Bacterial Immunity: An adaptable defense
The response of bacteria to the threat posed by phages depends on their local environment.
- 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).
Figure 1
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
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Bacterial adherence: adhesin-receptor interactions mediating the attachment of bacteria to mucosal surfaceJournal of Infectious Diseases 143:325–345.https://doi.org/10.1093/infdis/143.3.325
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Phage response to CRISPR-encoded resistance in Streptococcus thermophilusJournal of Bacteriology 190:1390–1400.https://doi.org/10.1128/JB.01412-07
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- Version of Record published: March 30, 2020 (version 1)
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© 2020, Schelling and Sashital
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Bacterial Immunity: An adaptable defense
eLife 9:e56122.
https://doi.org/10.7554/eLife.56122
Further reading
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- Microbiology and Infectious Disease
- Structural Biology and Molecular Biophysics
African trypanosomes replicate within infected mammals where they are exposed to the complement system. This system centres around complement C3, which is present in a soluble form in serum but becomes covalently deposited onto the surfaces of pathogens after proteolytic cleavage to C3b. Membrane-associated C3b triggers different complement-mediated effectors which promote pathogen clearance. To counter complement-mediated clearance, African trypanosomes have a cell surface receptor, ISG65, which binds to C3b and which decreases the rate of trypanosome clearance in an infection model. However, the mechanism by which ISG65 reduces C3b function has not been determined. We reveal through cryogenic electron microscopy that ISG65 has two distinct binding sites for C3b, only one of which is available in C3 and C3d. We show that ISG65 does not block the formation of C3b or the function of the C3 convertase which catalyses the surface deposition of C3b. However, we show that ISG65 forms a specific conjugate with C3b, perhaps acting as a decoy. ISG65 also occludes the binding sites for complement receptors 2 and 3, which may disrupt recruitment of immune cells, including B cells, phagocytes, and granulocytes. This suggests that ISG65 protects trypanosomes by combining multiple approaches to dampen the complement cascade.
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- Medicine
- Microbiology and Infectious Disease
Background:
End-stage renal disease (ESRD) patients experience immune compromise characterized by complex alterations of both innate and adaptive immunity, and results in higher susceptibility to infection and lower response to vaccination. This immune compromise, coupled with greater risk of exposure to infectious disease at hemodialysis (HD) centers, underscores the need for examination of the immune response to the COVID-19 mRNA-based vaccines.
Methods:
The immune response to the COVID-19 BNT162b2 mRNA vaccine was assessed in 20 HD patients and cohort-matched controls. RNA sequencing of peripheral blood mononuclear cells was performed longitudinally before and after each vaccination dose for a total of six time points per subject. Anti-spike antibody levels were quantified prior to the first vaccination dose (V1D0) and 7 d after the second dose (V2D7) using anti-spike IgG titers and antibody neutralization assays. Anti-spike IgG titers were additionally quantified 6 mo after initial vaccination. Clinical history and lab values in HD patients were obtained to identify predictors of vaccination response.
Results:
Transcriptomic analyses demonstrated differing time courses of immune responses, with prolonged myeloid cell activity in HD at 1 wk after the first vaccination dose. HD also demonstrated decreased metabolic activity and decreased antigen presentation compared to controls after the second vaccination dose. Anti-spike IgG titers and neutralizing function were substantially elevated in both controls and HD at V2D7, with a small but significant reduction in titers in HD groups (p<0.05). Anti-spike IgG remained elevated above baseline at 6 mo in both subject groups. Anti-spike IgG titers at V2D7 were highly predictive of 6-month titer levels. Transcriptomic biomarkers after the second vaccination dose and clinical biomarkers including ferritin levels were found to be predictive of antibody development.
Conclusions:
Overall, we demonstrate differing time courses of immune responses to the BTN162b2 mRNA COVID-19 vaccination in maintenance HD subjects comparable to healthy controls and identify transcriptomic and clinical predictors of anti-spike IgG titers in HD. Analyzing vaccination as an in vivo perturbation, our results warrant further characterization of the immune dysregulation of ESRD.
Funding:
F30HD102093, F30HL151182, T32HL144909, R01HL138628. This research has been funded by the University of Illinois at Chicago Center for Clinical and Translational Science (CCTS) award UL1TR002003.
