Now here’s an astonishing discovery that’s hot off the presses: a virus that infects other viruses! This amazing finding is being published tomorrow in the top-tier peer-reviewed journal, Nature.
I don’t know about you, but when I was in school, I was taught that viruses could only infect other living cells, and further, I was taught that viruses are not living cells. So, logically, one could conclude that viruses cannot infect other viruses. But a new discovery by a group of scientists in France reveals otherwise.
The story began in 2003, when Didier Raoult and his colleagues at the Universitee de la Mediterranee in Marseilles, France, discovered Mimivirus in a water cooling tower in Bradford, UK. That virus is so huge — its linear chromosome is so large that it has the capacity to encode more genes than many bacteria and archaea species, for example — that it challenges the accepted definition of what is a virus. Mimivirus primarily infects the amoeba, Acanthamoeba polyphaga, although antibodies to this virus have been detected in some humans recovering from pneumonia, suggesting that it might have infected humans as well. Mimivirus is known as Acanthamoeba polyphaga mimivirus, or just APVM.
Recently, Raoult and his colleagues were visiting another water cooling tower, this one in Paris, when they found a new strain of mimivirus there. To their surprise, while examining their new find with electron microscopy, it was even larger than the original mimivirus, so they christened it mamavirus. But their surprises did not stop there because they also saw a lot of tiny icosahedral viral particles, a mere 50nm in size, attached to the giant mamavirus (figure 1);
Figure 1 | Different morphological aspects of mamavirus and Sputnik.
a-e, Observations by transmission electron microscopy; f, observation by negative staining electron microscopy. a, Mamavirus virus factory (MVF) with mamavirus particles at different stages of maturation. Clumps of Sputnik particles (arrows) are observed within MVF. b, In some cases, Sputnik is observed within mamavirus capsids. c, Defective particles are produced. d-f, Co-infection with mamavirus and Sputnik results in abnormal morphology of mamavirus particles, such as membrane accumulation at one side (d), membrane accumulation around the particles (e), or open particles (f). Scale bars, 200 nm [larger view].
Thinking this was another virus that infects amoeba, the researchers injected the tiny virions into amoeba. But the tiny virus did not multiply. But amazingly, this virus, which the researchers had named “Sputnik” due to its shape, did multiply when injected amoeba along with either mimivirus or mamavirus (figure 2);
Figure 2 | Sputnik propagation in mamavirus-infected amoebae.
A. castellanii cells were infected with a mixture of mamavirus and Sputnik. Indirect immunofluorescence labelling was performed with rabbit antimimivirus serum (red) and mouse anti-Sputnik serum (green), and nucleic acids were stained with 4,6-diamidino-2-phenylindole (DAPI; blue). a, Numerous Sputnik virions entered the cytoplasm at 30 min after infection. b, At 4 h after infection, the first viral factories were seen as distinct, strongly stained patches. No viral particles could be seen in these cells, indicating an eclipse phase. c, At 6 h after infection, the viral factories expanded and were homogenously and strongly stained with DAPI. Sputnik production was detected at one side of the viral factory, but no mamavirus virions. d-f, At 8 h after infection (d), mamavirus production was observed; this increased extensively at 12 h (e) and 16 h (f) after infection [larger view].
They found that Sputnik co-infection resulted in the production of damaged the mamavirus virions so they were not infective, and also dramatically reduced the probability that infected amoebas would burst open — unlike the normal progression for a mamivirus infection. Thus, it was concluded that Sputnik actually infects mimivirus or mamavirus. Because Sputnik’s behavior is so similar to the effects of bacterial viruses, or bacteriophage, upon bacteria, the researchers refer to this new type of virus as a “virophage”, and suspect it may represent a new virus family.
“Sputnik reproduction seems to impair the production of normal APMV virions significantly, indicating that it is a genuine parasite,” write the scientists. “We have therefore termed this virus a virophage by analogy with bacteriophages; should other similar agents be discovered in the future, virophage could be used as a generic name to denote them.”
Sequence analysis reveals that Sputnik’s circular double-stranded DNA genome consists of only 18,343-base-pair (bp) with 21 predicted protein-coding genes that range in size from 88 to 779 amino-acid residues (figure 3). Compare that to its probable host, APVM (mimivirus), which has more than 900 protein-coding genes.
Figure 3 | The Sputnik chromosome.
The predicted protein coding sequences are indicated on the two DNA strands (first, outer, circle) and coloured according to their corresponding homologues. ORFs with homologues to mamavirus/mimivirus are indicated in blue, ORFs with homologues to other NCLDVs and bacteriophages are shown in green, and the ORF homologous to an archaeal virus gene is shown in red. The virion protein coding sequences are shown in purple and ORFans are shown in grey. Phylogenetic trees are displayed for the predicted protein coding sequences with homologues in nr and/or the GOS data sets along with the 2D-gel identifying the capsid protein. GC skew and G+C content are indicated in the second and third circles, respectively. IPG, immobile pH-gradient buffer [larger view].
Sputnik is also interesting because 13 of its 21 encoded proteins are “ORFans.” ORFs are “Open Reading Frames” meaning that those regions of the genome probably encode a gene product of some sort, so ORFans are genes that have no detectable homologues in the current sequence databases, meaning that we cannot even guess their function based on their similarity to other genes that we’ve already identified and studied.
However, phylogenetic analyses of the remaining eight genes indicate that they have viral/plasmid, bacterial or eukaryotic homologues, or homologues from the environmental Global Ocean Survey (GOS) data. GOS sequence data were retrieved from the world’s oceans by Craig Venter in 2004 and are thought to be comprised mainly of microbial DNA sequences. Thus, the Sputnik genome contains eight genes that are evolutionarily related to at least three distinct sources: a proposed novel family of viruses; either archaeal viruses or plasmids; and third, either mimivirus or mamavirus.
Could Sputnik infect humans, or alternatively, might scientists discover similar virophages that we could use as therapeutics because they infect those viruses that infect humans? The researchers speculate that size plays a role in whether a virus can be infected by a smaller virus such as Sputnik. Unfortunatly, medium-sized viruses such as HIV and avian influenza are too small to be infected, while the extremely large mimivirus and mamavirus can be. It makes me wonder if the extinct large virus, smallpox, might have had its own virophage(s)?
Bernard La Scola, Christelle Desnues, Isabelle Pagnier, Catherine Robert, Lina Barrassi, Ghislain Fournous, Michele Merchat, Marie Suzan-Monti, Patrick Forterre, Eugene Koonin & Didier Raoult. The virophage as a unique parasite of the giant mimivirus Nature DOI:10.1038/nature07218. .