"PA-X exhibits remarkable sequence conservation across strains, although it does come in two forms, with many strains of the recently introduced swine-origin IAV (SOIV) possessing a stop codon that truncates PA-X by 20 residues. This situation is eerily similar to PB1-F2, the first IAV gene product shown to be generated from a non-spliced alterative reading frame (encoding 87 to 90 amino acids in PB1) (7). PB1-F2 exhibits similar length polymorphism [typically, SOIVs encode an 11-residue fragment, and recent classical H1N1 viruses express a 57-residue form (8)]. Further, like PB1-F2 (8), PA-X is a viral accessory protein (i.e., dispensable for replication, but rather modulates host immune response).

Jagger et al. show that eliminating PA-X expression in the highly pathogenic 1918 IAV (whose associated pandemic caused perhaps 50 million deaths worldwide) enhances viral pathogenicity while inducing many changes in host gene expression, as determined by global transcriptional profiling. This may reflect, at least in part, the direct and cascading effects of host mRNA degradation by PA-X, although it is probable that PA-X, like many viral accessory proteins, is highly multifunctional. Although IAV pathogenesis is complex, it seems that PA-X diminishes viral damage by reducing the expression of select proinflammatory cytokines.

Intriguingly, PA-X and PB1-F2 exert opposite effects on pathogenesis, because PB1-F2 enhances morbidity and mortality (albeit in a viral strain– and host-dependent manner) (9). Presumably, the two proteins work together to optimally modulate host immunity. It will be interesting to examine the effect of PA-X on secondary bacterial pneumonia, whose severity is enhanced by PB1-F2 in mouse-model infections (10).

How do PA-X and PB1-F2 contribute to viral transmission between hosts, given that transmission is the ultimate selective factor in viral evolution? IAV’s high mutation rate ensures that genes that do not confer increased fitness quickly succumb to loss-of-function mutations."


Frameshifting to PA-X Influenza
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3777247/

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"Another bacteria to have gone through the genetic analysis is Bordetella pertussis, the bacteria responsible for whooping cough. Originally thought to have passed to humans via a similar species found in domestic animals, the molecular evidence once again suggests that it has been around since before animals were first domesticated. Instead it may have evolved from the bacteria B. bronchiseptica which was present around 2.5 million years ago with a preference for infecting hominids. This makes a rather neat little story of a bacteria adapting to fit the changing hominids as they became human and evolving specifically to fit the human niche."

"Trying to combine SNP analysis results with the molecular clock dating of pseudogenes creates some interesting paradoxes, such as pseudogenes within M. leprae that arose over 9 million years ago, when modern humans have only existed since approximately 250,000 years ago!"
(Perhaps it infected an ancestor of our 9 million years ago? We test human viruses on mice; 9 million years ago gorillas differentiated from chimps. We share nearly all viruses with primates...)

"What is clear however is that not all diseases can be blamed on cities and animal domestication, and that some bacteria were infecting humans back when Homo sapiens was still an exciting new species to be."
(If you don't know what it is, you don't know what it isn't. No conclusion can be made.)

S. Gould
Ancient Diseases of Human Ancestors
https://blogs.scientificamerican.com/lab-rat/ancient-diseases-of-human-ancestors/

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"Michael Specter’s article accurately describes the current H5N1 avian-flu controversy (“The Deadliest Virus,” March 12th). The debate has come about as the result of the enormous growth in biodefense research after the 2001 anthrax scares. Since then, the number of American high-containment laboratories for developing defenses against dangerous pathogens has increased from several hundred to more than a thousand, at a cost of billions of dollars annually in federal funds. This young enterprise, which supports many university, government, and commercial ventures, has expanded too quickly, and has failed to standardize its biosecurity and biosafety measures or its project-review mechanisms. Especially disconcerting is the emergence of two apparently adversarial camps: bioterrorism experts who forecast imminent attacks, and scientists who feel that the benefits of research outweigh potential security risks. Public safety and national security are at stake, but who is in charge?"
Jeanne Guillemin
Senior Adviser
M.I.T. Security Studies Program
Cambridge, Mass. https://www.newyorker.com/magazine/2012/04/02/flu-fears