Bringing Structure to Biology
Agents of Disease and Cure
Through the image for June in our 2019 calendar we would like to present you the most abundant creature in the world, which is not alive, nor even dead but is responsible for billions of (bacterial) deaths across millennia – the bacteriophage.
Bacteriophages are everywhere. They can be found wherever bacteria exist; in the soil, deep within the earth's crust, inside plants and animals, and even in the oceans. They also live inside us as part of our own microbiota. Usually they cause us no problems, but some bacteria can only cause disease if they are themselves infected by a bacteriophage.
A bacteriophage is a virus that attacks and kills bacteria, using the bacterium to replicate its genome. They come in many shapes and sizes, but the one in our image is of the myovirus family, often what we imagine when we think of a bacteriophage. When a bacteriophage such as this finds its host (usually a specific bacterial species and/or some of its very close relatives) it connects its tail fibres with receptors on the bacterial surface and uses a sort of syringe mechanism to puncture the bacterium’s surface. Then it injects its genetic information into the bacterial cytoplasm. This genetic information is copied and bacteriophage genes are expressed to make proteins, some of which assemble to form capsids (heads). The capsids are stuffed with new genetic material to make lots of new bacteriophages.
While, at the time of writing, there's no structure of a whole myovirus in the PDB, but there are structures of capsids, and parts of tail fibres and the baseplate to which the fibres are attached. The capsid and baseplate from T4 bacteriophage, which infects E.coli, are shown below.
Bacteriophage capsids are often icosahedral, having 20 faces and 30 edges. The size of the capsid, and the number of proteins which build it up, vary enormously between species of bacteriophage. A few examples are shown below.
A selection of viral capids. In the centre is T4, PDB entry 5vf3, and surrounding it, clockwise from the top:Caulobacter bacteriophage 5, PDB entry 2w4z. Phi6, PDB entry 5muu. Bacteriophage MS2, PDB entry 2wbh. Haloarcula hispanica virus SH1, PDB entry 6qt9. Bacteriophage alpha3, PDB entry 1m06. Bordetella phage BPP-1, PDB entry 3j4u. PDB entry 2bpa. and Bateriophage PM2, PDB entry 2w0c.
To lyse, or not to lyse?
Some bacteriophages can only reproduce via a lytic lifecycle, in which, as well as replicating, they produce an enzyme endolysin. Endolysin makes holes in the cell wall, which leads to the bacterium bursting. Cell bursting (cell lysis) releases hundreds of new bacteriophages which can infect and kill other bacterial host cells nearby. Other bacteriophages can alternate between a lytic lifecycle and a lysogenic lifecycle. In a lysogenic cycle the bacteriophage doesn’t kill the host immediately but is instead copied along with the host genetic information each time the cell divides. Under the right conditions, the viral incorporated genome can be activated, switching to the lytic cycle and producing hundreds of new bacteriophage.
Bacteriophages were discovered more than a decade before penicillin and were successfully used to treat dysentery and cholera. Despite this success, using bacteriophages for therapeutic purposes was overshadowed by the later discovery of antibiotics, which we’ve been using for about a hundred years. During that time (mainly because of over-use and misuse) bacteria have evolved to become resistant to antibiotics. The United Nations estimates that by the year 2050 more people will die from antibiotic resistant infections than currently die from cancer. There are already bacterial strains (known as superbugs) that are resistant to the majority of antibiotics commonly used today. If you are infected by one of those organisms, the prognosis is bleak and you just hope that your immune system is able to control the infection. But let’s forget these horror scenarios for a while and let’s focus on the potential of bacteriophages to be used as a cure.
Bacteriophages in a post-antibiotic world
Following the increased incidence of bacterial resistance to antibiotics over recent decades, bacteriophages have surfaced again as potential alternative or complementary therapies to control bacterial infections. The desire to use bacteriophages as human therapeutics has led to deeper exploration in western countries. Currently there are no bacteriophage therapy products approved for human use in the EU or United States, although there are states (Georgia, Poland) where the use of naturally-occurring bacteriophages in medicine has a contentious history. Some types of bacteriophages have been approved and are used in the food industry to kill virulent foodborne pathogens. Despite this, very little is known about the interactions between bacteriophage, bacteria, and the human a bacterium might be infecting. Research is still needed to see how safe and effective bacteriophages are. Most importantly, the immune response that a bacteriophage might illicit needs to be understood. And who knows, maybe one day they’ll move to be our first line of defence against “superbugs”.
About the Artwork
The bacteriophage was sketched by K. Prince from Impington Village College in Cambridge. It's shaped called to mind characters in the game Minecraft. Thanks to his cute, grumpy ‘face’ the drawing has become one of our favourites.