The enemy of my enemy is my friend
Virophages impede giant virus’ infectivity and help protect host cell populations
By: Sienna Schaeffer
Edited by: Katherine Hill, Isabella Armour, Madeline Nicol
Viruses are paragons of parasitism. They have existed as long as (or longer than1) cellular life and are capable of infecting every organism in existence. Humans are no exception. From influenza to ebola to HIV, viruses represent many of our fiercest medical foes. But are viruses only capable of parasitism? Can they only harm the cells they infect? Recent discoveries in the complex world of viruses have led researchers to theorize that certain viruses, under specific conditions, may actually be able to benefit their host cells by providing a defense system against other viruses. A study performed by Matthias Fischer and Thomas Hackl, published in Nature this past December, provides some of the first evidence that some viruses can actually help their host cells.
The development of the idea that some viruses may be more than just parasites was spurred by the relatively recent discovery of a group of viruses called virophages. Virophages are, simply put, viruses that parasitize other viruses. “Virophage” parallels the term “bacteriophage,” which describes viruses that infect bacteria. The team who discovered virophages initially believed that virophages were distinct from satellite viruses, which are viruses that require a helper virus to replicate. Virophages are currently recognized as a distinct category of satellite viruses due to genetic analysis and the fact that they parasitize a specific group of recently discovered viruses known as the giant viruses2, 3*. Virophages infect a host cell along with another virus and then hinder the other virus’ replication by hijacking the viral factory** that the ‘host’ virus assembles, using it to produce new virophages instead. When the virophage commandeers the viral factory, the host virus can no longer use the factory to reproduce itself. Virophages can also insert their own genes into the host cell’s DNA, an operation that many viruses are capable of, and just leave them there. The inserted genetic material is known as a provirophage.
Fischer and Hackl studied a specific virophage called mavirus and its relationship with its host cell, an amoeba whose scientific name is Cafeteria roenbergensis. The researchers were interested in whether or not a previous infection of the host cell by mavirus could leave the cell’s descendants with an inducible defense system‡ against Cafeteria roenbergensis virus (CroV), a virus that commonly infects the amoeba and serves as mavirus’ ‘host’ virus. Fischer and Hackl predicted that an earlier mavirus infection would produce a line of amoebas with a mavirus provirophage that would be reactivated by CroV during a CroV infection. The reactivation of the provirophage would lead to the production of new mavirus particles that could help protect the cell.
In order to investigate their hypothesis, the researchers created a strain of C. roenbergensis whose genome included the marvirus provirophage (marvirus+ cells) and a strain of provirophage-free C. roenbergensis (marvirus- cells). They then infected mavirus+ cells and mavirus- cells with CroV. The scientists compared the gene expression, DNA replication, and production of new mavirus and CroV particles in the two strains to see if CroV caused marvirus reactivation.
The researchers found that CroV infection caused the mavirus+ cells to produce large amounts of new mavirus particles, which confirmed that CroV is able to induce mavirus replication from a provirophage. Unfortunately, the newly activated maviruses did not protect their original host cells; essentially all of the amoebas infected with CroV died of the infection. However, the idea of the inducible defense system was not dead. When the CroV burst from the original host cell, the reactivated mavirus came with and went on to do what mavirus does best: parasitize CroV. In subsequent infections, mavirus decreased CroV replication by 2–3 orders of magnitude and prevented mature CroV particles from spreading from a lysed host cell. The mavirus provirophage could not save the original cell infected with CroV, but it helped protect the other cells around it. The authors of the paper concluded that the mavirus provirophage acts as the mechanism for an altruistic relationship between amoebas. Some of the amoebas are sacrificed to CroV for the greater good, which allows mavirus to become activated and help protect the population as a whole.
This experiment provides the first evidence that some viruses may have non-parasitic relationships with their host cells. Not only does mavirus not directly parasitize C. roenbergensis, it can actually help protect populations from CroV infection. More work will need to be done to see if this defense system is relevant in the real world for C. roenbergensis populations and other types of protists‡‡. One of the next big steps will be to investigate whether this kind of defense system is widespread amongst protists or if the researchers merely stumbled upon a unique case. If this kind of antiviral defense system is active in natural protist populations, this finding could represent the beginning of significant change in the way that we see viruses.
Footnotes:
*The discovery of the giant viruses in 2003 was a huge shake-up in the virology world. As their name suggests, they are much, much larger than viruses were previously believed to be. In fact, the first giant virus to be discovered was actually ‘discovered’ five years earlier and mistaken for a small parasitic bacterium. For a more indepth discussion of giant virus’ discovery and significance, check out this Radiolab episode: http://www.radiolab.org/story/shrink/
**Viral factory: is basically the area of the cell where the virus sets up shop and recruits necessary cellular machinery to do its dirty work.
‡ Inducible defense system: a defense system that can become activated by certain conditions, such as the presence of another organism or virus.
‡‡ Protists: a group of eukaryotes that are mostly single-celled organisms. This means that (like plants, animals and fungi but unlike bacteria) they have nuclei. The protist label encompasses a wide variety of organisms, from Plasmodium falciparum (causative agent of malaria) to algae. The inducible viral defense system discussed in this article does have a hypothetical link to humans and other animals, but it is tangential. For more information, please see this companion article.
References
Original paper: Fischer, M. G., & Hackl, T. Host genome integration and giant virus-induced reactivation of the virophage mavirus. Nature,540, 288–291. doi:10.1101/068312 (2016)
- Koonin, E. V., Senkevich, T. G., & Dolja, V. V. The ancient Virus World and evolution of cells. Biol Direct,1(29). doi:10.1186/1745–6150–1–29 (2006)
- Krupovic, M., & Cvirkaite-Krupovic, V. Virophages or satellite viruses? Nature Reviews Microbiology,9(11), 762–763. doi:10.1038/nrmicro2676 (2011)
- Krupovic, M., Kuhn, J. H., & Fischer, M. G. A classification system for virophages and satellite viruses. Archives of Virology,161(1), 233–247. doi:10.1007/s00705–015–2622–9 (2015)
