How do bacteria defend themselves against predatory viruses?
Viruses infect a host cell and commandeer their cellular machinery in order to proliferate, bacteria offer such a host. Viruses that infect bacteria are known as bacteriophage, or simply phage. In terms of their importance, it has been estimated that phage could account for ~20–40% of bacterial cell deaths per day . Interactions with phage shape the ecology and evolution of bacterial communities. What’s rather cool, is that we can use this ‘predator-prey’ dynamic beneficially in health care: phage therapy. Using phage to treat bacterial infections could provide a treatment option where antibiotics have failed. However, bacteria can possess a range of defence mechanisms against infection. In the laboratory, bacterial resistance against phage can arise rapidly, but how much of a problem might this become clinically?
The defence responses of bacteria to phage can be likened to an immune system, where both adaptive (e.g. specific) and innate (e.g. nonspecific) responses have been described. 2020 has been an important year for endeavours understanding bacterial immunity, you may have heard of “CRISPR-Cas”? The 2020 Nobel Prize in Chemistry was awarded for the transformation of CRISPR as a gene-editing technology. CRISPR-Cas systems were initially discovered for their role as natural phage defence mechanisms in bacteria, functioning in a manner that can be likened to an adaptive immune response. CRISPR arrays store segments of past infections as small snippets of DNA. When combined with the helpful enzymatic activity of Cas, bacteria are provided with a system to recognise, target and degrade repeat offenders.
CRISPR-Cas systems are arguably the most widely known example of a bacterial defence system to phage, but what else do we find that can combat these tricky cell hijackers?
Phage require entry points to get into bacterial cells. Successful phage infection is initiated with use of these entry points to inject DNA into the cell. Bacteria are able to change, hide or block the surface receptors that phage use to gain entry — and this can effectively function as a first line of defence.
One of these things is not like the other
Several strategies of intracellular innate defences may be on hand if phage DNA injection is successful. Restriction Modification systems are an example of one of these. Host DNA is tagged in a process known as methylation which adds a specific signature to the DNA. This allows it to be identified as ‘self’. Targeting and cleaving of ‘non-self’ DNA can then take place, i.e. the injected phage DNA that is lacking these specific tags.
Bacteria are able to initiate programmed cell death in response to phage infection in a process known as Abortive Infection. This infected cell suicide can effectively be considered a sacrifice. While the cell itself may not survive, it has the potential to protect the neighbouring bacterial population from the replication and release of larger numbers of phage.
Viral infection defending against…. viral infection?
Perhaps more weird and more wonderful still is a phenomenon known as Superinfection Exclusion. Superinfection exclusion describes where the presence of a primary phage infection in the cell is able to block a secondary phage infection. Bacteria can acquire phage encoded protection against additional phage infection.
Looking into 2021 and beyond
The strong selective pressure exerted by phage plays a key role in controlling the number and composition of bacterial populations in most, if not all, ecosystems. The strategies bacteria employ to resist phage infection function to control phage numbers and composition as well. We find that the interaction between bacteria and phage exemplifies a rather beautifully named concept in evolutionary biology; the Red Queen hypothesis. The name is taken from Lewis Carroll’s Through the Looking Glass. In a race against Alice, the Red Queen tells her “It takes all the running you can do, to keep in the same place”. Species must constantly adapt and evolve in order to survive while pitted against ever-evolving opposing species.
Despite considerable advances, we are far from understanding this evolutionary arms race on scale. Yet understanding how these two competitors clash, adapt and evolve is important across a range of applications: from phage therapy to the uses of bacteria beneficially in agriculture, probiotics and fermentation. Bacteria have a dynamic range of defence responses that can function across the breadth of phage infection stages, and we are still discovering completely new players in bacterial phage immunity. Retrons are genetic elements whose natural biological function has remained elusive for quite some time, but new research in 2020 has found an anti-phage function for these mysterious sequences. More specifically, a retron system has experimentally been shown to be involved in an abortive infection pathway in response to phage infection.
Our understanding of bacterial resistance mechanisms and phage infectivity is rapidly evolving itself. Looking to the future, research is being carried out into understanding how our expanse of bacteria-phage laboratory experiments translates into natural population scenarios, and how the dynamics of different phage types affect the resistance mechanisms we see. It’s exciting to consider potential cross-applicability of virus-cell interaction models, and exploration into the similarities between phage and other pathways. Could our understanding of bacteria and phage help build predictions for other virus-cell interaction systems?
Some awesome review articles and reads
Hampton HG, Watson BN, Fineran PC. The arms race between bacteria and their phage foes. Nature. 2020;577(7790):327–36.
Koskella B, Brockhurst MA. Bacteria–phage coevolution as a driver of ecological and evolutionary processes in microbial communities. FEMS microbiology reviews. 2014;38(5):916–31.
Rostøl JT, Marraffini L. (Ph) ighting phages: how bacteria resist their parasites. Cell host & microbe. 2019;25(2):184–94.
Seed KD. Battling phages: how bacteria defend against viral attack. PLoS Pathogens. 2015;11(6):e1004847.
Stern A, Sorek R. The phage‐host arms race: shaping the evolution of microbes. Bioessays. 2011;33(1):43–51.
van Houte S, Buckling A, Westra ER. Evolutionary ecology of prokaryotic immune mechanisms. Microbiology and Molecular Biology Reviews. 2016;80(3):745–63.
