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Pandoraviruses Are Not Alive

3 December 2020 by Gertrud U. Rey

by Gertrud U. Rey

Viruses are universally defined as “obligate intracellular parasites” because they cannot replicate outside of a host cell and depend on that cell and its various metabolic factors for replicating their genome. Based on this definition, most virologists agree that viruses are not alive. 

When giant viruses were initially discovered, they were found to violate multiple principles of virology. For example, mimiviruses can be parasitized by small viruses called virophages that can only replicate if they confiscate the replication factors of a co-infecting mimivirus. Because the virophage also inactivates the mimivirus during this process, some interpret this scenario as a virus infecting another virus, a previously unheard-of phenomenon. In turn, mimiviruses have defense mechanisms that inhibit virophage replication, a property that is analogous to eukaryotic anti-viral interferon-mediated defenses. Additionally, mimiviruses encode proteins that participate in protein synthesis – another unusual property for a virus.

Some mimiviruses also have a gene that codes for citrate synthase, an enzyme involved in the Krebs cycle. The Krebs cycle is integral to cellular metabolism in living organisms because it ultimately powers the production of adenosine triphosphate (ATP), the cell’s molecular currency of energy. The cycle takes place in the matrix of the mitochondrion (pictured), where it feeds electrons into a string of complexes in the inner mitochondrial membrane known as an electron transport chain. As electrons move down this chain, they release energy, which is used by membrane-resident enzymes to pump protons from the matrix across the membrane into the intermembrane space (pictured as “proton pump”). This produces a concentration gradient, which is a difference in the concentration of protons on one side of the membrane compared to the other. To achieve equilibrium, the protons move back into the matrix through the action of another membrane resident enzyme called ATP synthase, which captures the energy of the protons to produce ATP. In other words, a concentration gradient across a membrane produces an electrical potential and is usually associated with the ability to generate energy in living cells.    

Based on the knowledge that some mimiviruses encode a component of the Krebs cycle, a group in Marseille wanted to determine whether giant viruses can produce their own energy. To do this, they infected a species of amoeba, the natural host of giant viruses, with Pandoravirus massiliensis, a virus with the largest known viral genome encoding many proteins with unknown functions. 

The authors isolated viral particles from P. massiliensis-infected amoebae and treated them with P. massiliensis-specific antibodies and a dye that detects electrical potential. This technique produced fluorescence in the membranes of P. massiliensis particles, indicating the presence of an electrical potential, in contrast to control virus particles isolated from cells infected with cowpoxvirus, which did not fluoresce. To confirm that the observed fluorescence represented a real concentration gradient with potential for electron transport, the authors treated the P. massiliensis particles with CCCP, a chemical that inhibits movement of electrons. This treatment led to diminished membrane fluorescence, suggesting that the observed membrane potential was real. Interestingly, the intensity of the electrical potential could be modified with addition of variable concentrations of acetyl-CoA, a known regulator of the Krebs cycle. 

In an effort to determine how the P. massiliensis genome could play a role in energy metabolism, the authors did a sequence alignment with a database of conserved sequence domains known to be involved in energy metabolism. This revealed that P. massiliensis contains genes for nearly all enzymes in the Krebs cycle, but when these genes were cloned and expressed in bacterial cells, only one of them, isocitrate dehydrogenase, was functional. In agreement with this observation, the authors also found that mature P. massiliensis particles released from amoeba cells did not produce any ATP. Nevertheless, when amoeba cells were infected with P. massiliensis that were pre-treated with CCCP, they produced a lower number of viral particles, suggesting that the observed membrane potential might play a role during infection. 

The authors conclude that these findings “position this virus as a form of life.” I disagree with this conclusion for the following reasons. Although P. massiliensis encodes numerous Krebs cycle enzymes, only one of them seems to be functional. Furthermore, P. massiliensis particles did not produce any ATP, meaning that this virus cannot produce its own energy. Even if it did, it still depends on the host cell for many other replication factors, including those needed to make proteins. As long as a virus requires a cell for replication, it is still a virus, and hence not alive.

Still, these findings are interesting and remind me of bacteriophage ϕKZ, a giant virus discussed in a previous post. After infecting a bacterial cell, ϕKZ assembles a nucleus-like shell, which shields the viral DNA from bacterial immune enzymes. Any discovery that reveals genes in viruses that suggest the potential for cell-like functions raises at least a couple of questions. Are these genes remnants of cellular genes, thereby suggesting that these viruses originated from ancient parasitic cells? Or did these giant viruses acquire the genes over time to gain more independence from host cells? Either way, pandoraviruses are aptly named because their study continues to yield surprising discoveries.

Filed Under: Basic virology, Gertrud Rey Tagged With: acetyl-CoA, amoeba, ATP, citrate synthase, citric acid cycle, concentration gradient, electrical potential, electron transport chain, electrons, energy, giant virus, isocitrate dehydrogenase, Krebs cycle, living cell, living organism, membrane potential, metabolism, mimivirus, mitochondrion, Pandoravirus, Pandoravirus massiliensis, protons, TCA cycle, virophage

TWiV 582: This little virus went to market

12 January 2020 by Vincent Racaniello

TWiV provides updates on the new coronavirus causing respiratory disease in China, the current influenza season, and the epidemic of African swine fever, including determination of the three-dimensional structure of the virus particle.

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Filed Under: This Week in Virology Tagged With: african swine fever virus, capsid, China, coronavirus, cryo-electron micrography, giant virus, Huanan Fish Market, influenza, influenza excess mortality, influenza like illness, influenza vaccine, pig, swine, three dimensional virus structure, viral, virology, virus, viruses, Wuhan pneumonia, zoonosis

Phi Kappa Zeta Builds a Panic Room

2 January 2020 by Gertrud U. Rey

Phikzlikevirus_virionby Gertrud U. Rey

Bacteria use at least a couple of pathways for protecting themselves against viral infection. In return, multiple viral strategies for inhibiting or evading these pathways have evolved.

[Read more…] about Phi Kappa Zeta Builds a Panic Room

Filed Under: Basic virology, Gertrud Rey, Information Tagged With: bacteriophage, crispr, giant virus, infection defense, nucleus-like shell, phage φKZ, viral, virology, virus, viruses

TWiEVO 49: A giant podcast on giant viruses

29 November 2019 by Vincent Racaniello

Rich joins Nels and Vincent for a debriefing on the 4th Ringberg Symposium on Giant Virus Biology in Tegernsee, Germany.

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Filed Under: This Week in Evolution Tagged With: ecology, evolution, giant virus, horizontal gene transfer, natural selection, NCLDV, Nucleocytoplasmic large DNA containing viruses, phycodnavirus, Ringberg, trisymmetron, viral, virology, virophage, virus, viruses

TWiV 575: Endless giant virus forms most beautiful

24 November 2019 by Vincent Racaniello

From the Fourth Symposium on Giant Virus Biology in Germany, Vincent, Rich, and Nels speak with Assaf, Stephen, and Alexandra about their careers and their work on giant viruses that infect ocean hosts: Emiliana huxleyi, Aureococcus anophagefferans, and a choanoflagellate.

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Filed Under: This Week in Virology Tagged With: algal virus, Aureococcus anophagefferans, brown tide, choanoflagellate, Emiliana huxleyi, giant virus, in plaque-MSI, lipidomics, marine carbon cycle, mass spectrometry, metabolic landscape, mimiviridae, mimivirus, NCLDV, plaque assay, rhodopsin photosystem, single-cell genomics, viral, viral evolution, virology, virus, viruses

TWiV 543: Stoned and senile

14 April 2019 by Vincent Racaniello

The TWiV team discusses Medusavirus, isolated from a hot spring in Japan, and induction of neurodegeneration by recurrent herpes simplex virus 1 infection of mice.

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Filed Under: This Week in Virology Tagged With: alzheimer's disease, amoebae, dementia, giant virus, herpes simplex virus 1, histone, horizontal gene transfer, Medusavirus, memory loss, mouse model, NCLDV, neurodegereration, reactivation, viral, virology, virus, viruses

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by Vincent Racaniello

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