Paul Has Measles is a free children's book about viruses and vaccines available in 16 languages (link). Paul Stays Home is a free children's book about COVID-19 (link).

By David Tuller, DrPH

Mahana set to announce FDA approval for ineffective IBS program

Earlier this year, I spent a lot of time blogging about the unethical and dishonest manner in which a San Francisco start-up called Mahana Therapeutics was promoting an eight-week web-based program of cognitive behavior therapy for patients suffering from irritable bowel syndrome. The company had recently licensed this product from King’s College London and was seeking marketing approval in the US and the UK.

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TWiV reviews the difficulties in predicting species susceptibility to SARS-CoV-2 infection by only examining the ACE2 protein, and the olfactory mucosa as a portal of entry into the central nervous system in COVID-19 patients.

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Daniel Griffin provides his weekly clinical report on COVID-19, including analysis of vitamin D levels in patients, information on Moderna and Pfizer vaccines, distribution plans suggested by ACIP, and more.

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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.

By David Tuller, DrPH

Earlier this week, I blogged about a story in The Observer that provided an inaccurate description of what it called chronic fatigue syndrome. For much of the piece, the writer, Eleanor Morgan, offered a sympathetic portrait of people, including herself, experiencing prolonged symptoms after an acute bout of Covid-19. A lot of what she presented was informative and likely helpful for others in that situation.

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By David Tuller, DrPH

News organizations continue to misrepresent ME (and its various iterations) in their coverage of what has come to be called long-Covid. A current UK example is Sunday’s Observer article by writer Eleanor Morgan, who is experiencing prolonged symptoms since falling ill last spring. (It’s on The Guardian site; the two organizations are linked in some way.) Here’s Morgan’s bio on the website for the literary journal Granta, to which she has also contributed: “Eleanor Morgan is a writer based in London. Her latest book, Hormonal: A Conversation About Women’s Bodies, Mental Health and Why We Need to Be Heard (Virago) is out now. She is also training as a psychologist.”

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TWiV 685: Pandemicky

The TWiVers analyze efficacy of the AstraZeneca/Oxford adenovirus vectored vaccine, SARS-CoV-2 did not infect miners who became ill 8 years ago after cleaning bat guano from a cave in Yunnan Province, and induction of antigen-specific germinal center responses and production of neutralizing antibody by SARS-CoV-2 mRNA vaccine but not purified protein.

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Daniel Griffin provides a clinical report on COVID-19, and Shane Crotty explains a study of antibodies, B cells and T cells in patients which suggests that immunological memory to SARS-CoV-2 might be long-lived.

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By David Tuller, DrPH

On November 12, I received my latest letter from BMJ’s so-called research integrity office about the pile of potential research misconduct otherwise known as the pediatric study of cognitive behavior therapy and music therapy as a treatment for chronic fatigue after acute EBV. This study was published in April by BMJ Paediatrics Open and immediately came under sharp and justified criticism–including from me.

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By David Tuller, DrPH

I have written multiple posts this year about a Norwegian study of cognitive behavior therapy plus music therapy as a treatment for chronic fatigue after acute EBV infection (aka mononucleosis and glandular fever). The study, published in April by BMJ Paediatrics Open, was rife with methodological and ethical flaws. It should not have been accepted in the first place.

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