To enjoy beautiful environments, we may need to defend ourselves from resident pests, from midge flies on Scottish slopes to…
To enjoy beautiful environments, we may need to defend ourselves from resident pests, from midge flies on Scottish slopes to tropical jungle mosquitoes. If pests are many and different, a broad spectrum defense strategy, such as spraying an insecticide, can be the best. Bacteria can also use general defense to fight their viral predators, in addition to having a plethora of more specific defenses aimed at certain viruses. Writing in Nature Kronheim et al. . 1 reports their analysis of an antiviral defense system that can protect more than one bacterial species. These results can have major consequences for our understanding of how bacteria and viruses interact.
Virus that infects bacteria is known as bacteriophage, or just subjects, and they have key roles in bacterial development, population dynamics and physiology. Fages are considered to be the most abundant and different biological entities on earth 2 and it is important to consider them when they try to get a complete understanding of the bacterial world. But despite their significance, there are huge gaps in our knowledge. In many cases, information about the subject values (the types of bacteria that a particular subject can infect) is limited. Some aspects of how bacteria defend themselves against professional attacks are also mysterious.
Most bacterial species make many and different metabolites (small molecular metabolites) that can provide widespread protection from fungal and other types of bacteria. On the other hand, most of the well-understood anti-trade defense in bacterial proteins, which often offer protection only at the level of the individual cell that makes the protein instead of providing protection to a bacterial population. Such a common bacterial defense is the modification of the microbial cell surface to prevent phage binding. Another strategy known as the CRISPR-Cas Defense System 3 is due to an infected bacterium that recognizes and captures sequences from the virus genome, and uses them to promote a response that kills viruses containing a copy of the captured sequences. Some bacteria take the approach of adding methyl groups to their DNA and degradation of all non-methylated, and therefore foreign, DNA. Many other fascinating examples of these “single-cell” defense strategies are 5 .
Widespread antiviral defense mechanisms in bacteria occur but are less known. For example, bacteria can throw blisters from their outer membranes to “mop up” phages 6 . The lack of examples in this category probably reflects the limited scope of earlier research rather than a lack of such systems in itself. Bacteria and phages have coevolved over approximately 3.9 billion years 7 so it seems reasonable to speculate that non-specific mechanisms can play a key role in the bacterial defense. Presumably, such broad-based systems may have a longer evolutionary history than the more specific types of defense, and may have shaped the development of the subsequent targeted strategies.
Kronheim and colleagues began to investigate how bacteria could target phage by testing the ability of a total of 4,960 molecules from a drug discovery library to prevent a phage called lambda from infecting the model bacterium Escherichia coli . This revealed 1
1 molecules that can limit the success of phage infection. Nine of these can embed DNA and are called DNA intercalators. Of the 11 molecules, 4 belong to a group called the anthracyclines. These include the naturally occurring compounds daunorubicin and doxorubicin, which are used as cancer drugs. The dual ability of these molecules to target cancer cells and phages raises the question of whether they act by recognizing modified DNA.
Antimagazine effects of daunorubicin and doxorubicin were first discovered more than 50 years ago 8  –10 . Nevertheless, it is strange that insights 8–10 that bacteria can produce DNA intercalators directed against phages did not appear. Research 11–14 from the 1940s and 1950s also showed that several other antibiotics could prevent phage infection. However, these observations were not interpreted as an indication that the molecules were components of a natural bacterial anti-defense strategy.
Kronheim et al. . tried to determine how the molecules they identified seem to block phage infection. They showed that viral entry into the cell, viral DNA replication, viral protein synthesis and virus assembly are not inhibited by the addition of daunorubicin. However, they found that daunorubicin may block one step immediately after viral infection and prior to replication. There will undoubtedly be future studies to determine the mechanism of molecular action at this stage. The most credible hypothesis suggested by the authors is that daunorubicin blocks the circularization of linear viral DNA. If so, viral DNA that remains in a linear form may be impaired by the host bacterium or phage infection may be suppressed because the viral DNA can not interact with the proteins needed for its transcription.
Bacteria of the genus Streptomyces are particularly prominent metabolite producers and the source of many antibiotics. Kronheim and colleagues give an important demonstration that Streptomyces species can produce daunorubicin and doxorubicin, which shows that bacteria can create their own metabolite-based anti-phage system. The authors showed that Streptomyces produces many anthracycline-like compounds, some of which prevent infection of bacteria through specific phages, while others prevent infection by a number of phages. The authors tested samples of small molecule extracts from Streptomyces species and found that 30% of the extracts inhibited phage infection but did not affect bacterial growth, suggesting that bacterial DNA is not susceptible to the disruption of the molecules that prevent phage infection.
The authors’ findings indicate that Streptomyces bacteria release anthracyclines that can diffuse from the bacterial cell in the external environment, indicate adjacent bacterial cells and inhibit phage infection. This was confirmed by adding the medium of several days old cultures of Streptomyces to fresh cultures of Streptomyces to which phages were added. Remarkably, they showed that when doxorubicin-containing microbial media from cultures of Streptomyces peucetius bacteria were added to cultures of Streptomyces coelicolor bacteria, it was protected from phage infection by S. coelicolor 1).
The defense mechanism disclosed by Kronheim and colleagues contrasts with the best known bacterial antiviral mechanisms in two ways. First, it uses metabolites rather than proteins. Secondly, the mechanism not only protects the cell that produces the anti-phage molecule, but also adjacent bacterial cells of the same and even different bacterial species. This proposes a broad spectrum metabolite-based defense system that works in a manner that is related to a “phagicidal”, whereby one type of molecule can defend different bacterial species against many different types of subjects.
By expanding the concept of professionalism from the individual cell to the masses, Kronheim and colleagues study suggests that trade defense is not so targeted at specific subjects as previously thought. Their work raises many questions. How important is this mechanism, and how are these metabolites done? Are they continuously manufactured or manufactured only in response to pharyngeal infection? It would be interesting to learn how many different types of metabolites are capable of targeting phages, how specific metabolites are, and the extent to which such molecules can provide protection over different bacterial species.
Fager has developed ways to overcome most bacterial defenses and can cooperate to avoid CRISPR-Cas defense
15 16 so it seems likely that some phages may have developed ways to fight these bacterial defense molecules. To investigate if this is the case should provide some interesting insights. The term professionicides is likely to spark searches for other types of antifungal metabolites, which may lead to the discovery of antiviral metabolites targeting other types of subjects, such as those that have their genetic information in the form of RNA rather than DNA.
Kronheim and colleagues work also adds to the growing evidence that reveals the complexity of interactions between phages and bacteria. It follows other paradigm shifting observations in this field of research, as the report that signals between phages can affect whether the virus enters a dormant state or replicates 17 . Based on Kronheim and colleagues work, it is time to consider the idea that metabolites can move from bacteria to bacteria to block phage infection. When further systems are being studied, this should help calculate the extent of this communication and illustrate how bacteria and their viral predators shape the world in which we live.