Racaniello on Picornaviruses, Enteroviruses, Polio, Coxsackie…

Vincent Racaniello has some nice information on these viruses:

And he made a very excellent lecture:

Seth Roberts on Tonsils, Tonsillectomies, Polio and the Immune System

Seth Roberts on Tonsils, Tonsillectomies, Polio and the Immune System:

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Around 1900, America started to have frequent polio epidemics. Starting in 1916, they happened every summer, which came to be called "polio season". Over the years, they got worse. In 1951, thousands of children died, and tens of thousands were crippled. … As both tonsillectomies and polio increased, a horrifying correlation emerged: Children who'd had a tonsillectomy were more likely to get a certain type of polio (infection of the bulbar region of the brain stem) than children who had not had a tonsillectomy. This became common knowledge. Polio Pointers said "don't have mouth or throat operations during a polio outbreak." In 1954, the American Journal of Public Health ran an editorial summarizing the link between tonsillectomy and polio. The main evidence was that within a group of children with polio, the ones with bulbar polio were about three times more likely to have had their tonsils removed than the ones with spinal polio (infection of the spinal cord). This resembles some of the first evidence connecting smoking and lung cancer: Hospital patients with lung cancer were much more likely to be heavy smokers than hospital patients with other diseases. Although Polio Pointers implied that tonsillectomies were unsafe only "during a polio outbreak," this was false. The data implied they were always unsafe: "This higher proportion of bulbar cases in tonsillectomized persons occurs at all ages regardless of the time elapsed since operation," said the editorial. A 1957 paper about the tonsillectomy/polio association cited 19 studies that had observed it. "The association is generally regarded as an underlying causal relationship," said the paper, meaning that the usual explanation was that tonsillectomy increased risk of bulbar polio. The paper found more evidence for this explanation. Researchers considered other explanations for the polio/tonsillectomy association (for example, are tonsillectomies more common among rich children? among sickly children? ) but failed to find supporting evidence. The tonsillectomy/polio connection is probably why tonsillectomies became less popular starting in the 1950s. They declined from extremely common (the most common of any operation) to very common (the most common operation done on children).

By 1960, the tonsillectomy/polio association was firmly established, but its explanation was a mystery. If it reflected cause and effect, why would tonsils protect against infection? Around this time, work by James Gowans and others started to answer this question by figuring out that lymphocytes are the main cells of our immune system. They detect bacteria and viruses and make antibodies against them. T cells, B cells, and natural killer (NK) cells -- all lymphocytes. In one experiment, Gowans and his co-workers drained the lymphocytes from rats. The rats lost the ability to make antibodies. When the researchers put the lymphocytes back into the rats, they regained the ability to make antibodies. That's just an example. Our understanding of what lymphocytes do comes from thousands of experiments.

When the function of lymphocytes became clear, the lymphatic system made much more sense. Lymph washes germs out of tissue and into lymph nodes, where lymphocytes detect and try to kill them. The high density of lymphocytes in the nodes ensures that germs will bump into them and be detected. When lymphocytes detect more germs than usual, they multiply and the nodes enlarge. Tonsils … like lymph nodes are full of lymphocytes. Their shape and placement causes them to sample the bacteria in your mouth, so they protect you against the bacteria in your mouth. Tonsils become swollen and sore during infections because the number of lymphocytes inside has increased -- the lymphocytes are fighting off the infection. These facts about the immune system and the lymphatic system, including the function of lymphocytes, are part of high school biology. …

Removal of your tonsils is removal of part of your immune system. Our understanding of the immune system implies that removal of tonsils reduces ability to fight off infection. We cannot say exactly what tonsils do, just as we cannot say exactly what many parts of the brain do, but our general understanding of the immune system (based on thousands of experiments) implies that removal of any part of it is very dangerous, just as our general understanding of the brain (based on thousands of experiments) implies that removal of any part of it is very dangerous. When a child gets a sore throat, it suggests that his immune system is not doing a good job fighting off infections; a better-functioning system would have killed the germs sooner. Cutting off part of the body that fights infections because of too many infections makes as much sense as getting rid of fire houses because of too many fires. If your outcome measure is narrow, you may conclude that damaging a vital organ is beneficial. For example, prefrontal lobotomies were once claimed to be a a good thing (some people became less disruptive). In rare cases, the benefits of removing part of a vital organ may outweigh the risks. If I were in intractable pain, I might agree to have part of my brain removed. But not because of six sore throats.
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And BTW,  people with adeno- and tonsillectomies seem to have increased risk of obesity and of heart-attacks, among others – hmmm.

If you search tonsillectomy/adverse effects on PubMed, you will get more than 1000 references. There is no sign in the [Cochrane] review that the authors did that search or any other search for bad effects of tonsillectomies. If the authors had looked at the PubMed articles published before their review (about 900), they would have learned that the risks of tonsillectomy include polio, weight gain, vomiting (many articles), taste distortion (here, here, here), Hodgkin's disease (here, here, here, here, here, but here is evidence that disputes the association), Creutzfeld-Jacob disease (e.g., here, here), inflammatory bowel disease and Crohn's disease, rheumatoid arthritis, severe spine infection, neck infection (here, here), speech problems (here, here), hearing loss, ear pain, visual loss (here, here), depression, several other serious problems, and immunological abnormalities (e.g., here, here, here). They would have learned that tonsillectomy "is associated with a relatively high risk of postoperative complications" and that "the actual post-tonsillectomy haemorrhage rate is much higher than that recorded in hospital statistics." (The Cochrane Review says this risk is "small".) They would have learned, if they didn't already know, that "the tonsils have a large immune function."

Gee, thanks!

The other day, I noted a contrast between certain parts of the developed world (namely, Europe) where, thanks to fears of the MMR vaccine stoked by Andrew Wakefield and the credulous and sensationalistic British press, MMR uptake rates have fallen and, predictably, measles incidence has skyrocketed, and the rest of the world, where polio is now on the verge of being eradicated, thanks to vaccination campaigns. It's evidence that the antivaccine movement, inspired by Andrew Wakefield and promoted by antivaccine groups like Generation Rescue, the National Vaccine Information Center, the Australian Vaccination Network, and Safeminds, has harmful consequences to public health. Of course, it's entirely predictable that, where vaccination rates fall, vaccine-preventable diseases will tend to make a comeback. Indeed, it was antivaccine fear mongering based on religion and suspicion of Westerners that delayed progress in the eradication of polio, progress that is only now getting back on track.

Other vaccine-preventable diseases are also making a comeback, unfortunately, as I found out when I read Trine Tsouderos' excellent article in the Sunday paper entitled Whooping cough returns as vaccine use drops, changes. The situation is a little more complex than that for the resurgence of measles due to catastrophic declines in MMR uptake in the U.K. and parts of continental Europe, but once again it's a situation where less vaccination equals more disease.

Now was your little anti-vaxx irrational confirmation bias worth that? Gee, thanks.

Vincent Racaniello on poliovirus vaccine litigation

Vincent Racaniello on poliovirus vaccine litigation – a must read in its entirety:

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Second, a single monkey with a 3-3 neurovirulence score appears to have played an important role in this case, but that ignores the fact that there are almost always wide variations that result in “outliers” whenever biological assays are involved.  We have studied poliovirus infection of mice in my laboratory, for example, and outliers are common – the one mouse in twenty that becomes ill or dies, while the others remain well. Other investigators have shown that poliovirus recovered from the spinal cord of an outlier monkey – one with a 3-3 neurovirulence score – does not produce these results when re-injected in a different group of monkeys. The monkey with a 3-3 score observed in the government’s test of one monopool of type 3 poliovirus vaccine is clearly an outlier. The other 14 monkeys in the intraspinal test had very low scores, and Lederle’s neurovirulence test did not produce a monkey with a 3-3 score. I conclude that the neurovirulence test on this type 3 monopool clearly did not exceed that of the reference virus – there is no scientifically valid justification for arguing otherwise.

If you don’t believe in outliers, there is another way to look at this issue: does a monkey with a 3-3 score in the neurovirulence test mean that the lot of vaccine is more likely to cause paralysis in humans? We cannot carry out such an experiment prospectively, but we can do the next best thing – compare the results of the monkey neurovirulence test with the rate of vaccine-associated poliomyelitis. In the entire history of the monkey neurovirulence test – from 1962-1999 – some monopools of vaccine periodically had one or two monkeys with a 3-3 neurovirulence score, and others did not. Nevertheless, the rate of vaccine-associated paralytic disease remained remarkably constant over this time: 5-10 cases per year. There were no spikes in the years when the “3-3″ vaccines were in distribution. The conclusion is clear: no lot of vaccine is associated with an increase in the number of paralytic cases in any year.

Why do the Sabin vaccine strains cause paralytic disease in some recipients and contacts? Albert Sabin derived these vaccine strains by serially passing neurovirulent isolates in different cell types, empirically identifying viral mutants with a reduced capacity to cause disease. There are few mutations responsible for the reduced neurovirulence of the Sabin strains – 5 for type 1, and 2 each for the type 1 and type 2 strains. These mutations rapidly revert during multiplication of the vaccine viruses in the human gut, and that occurs in every recipient of the vaccine. Within several days, the recipient sheds viruses that no longer bear the mutations that Sabin so painstakingly selected. These excreted revertants, when tested in monkeys, are more neurovirulent than the vaccine that was fed to the recipient.
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Oral polio vaccine has an inherent risk that public health authorities deemed to be acceptable, given the extraordinary benefits of the vaccine. However, in a sense, the ~400 individuals who contracted vaccine-associated polio from 1962-1999 paid a price for the greater good of the population. For this reason alone they deserved compensation, which is what they now receive under the National Childhood Vaccine Injury Act. Compensation for these individuals is given without the need to castigate life-saving vaccines likes OPV.

Polio Vaccine

There are two types of polio vaccine, both of which were developed in the 1950s. The first, developed by Jonas Salk, is a formalin-killed preparation of normal wild type polio virus. This is grown in monkey kidney cells and the vaccine is given by injection. It elicits good humoral (IgG) immunity and prevents transport of the virus to the neurons where it would otherwise cause paralytic polio. This vaccine is the only one used in some Scandinavian countries where it completely wiped out the disease.

A second vaccine was developed by Albert Sabin. This is a live attenuated vaccine that was produced empirically by serial passage of the virus in cell culture. This resulted in the selection of a mutated virus that grew well in culture and, indeed, in the human gut where the wild type virus grows. It cannot, however, migrate to the neurones. It replicates a normal infection since the virus actually grows in the vaccinee and it elicits both humoral and cell-mediated immunity. It is given orally, a route that is taken by the virus in a normal infection since the virus is passed from human to human by the oral-fecal route. This became the preferred vaccine in the United States, United Kingdom and many other countries because of it ease of administration (often on a sugar lump), the fact that the vaccine virus replicates in the gut and only one administration is needed to get good immunity (though repeated administration was usually used). In addition, the immunity that results from the Sabin vaccine lasts much longer that that by the Salk vaccine, making fewer boosters necessary. Since it elicits mucosal immunity (IgA) in the gut, the Sabin vaccine has the potential to wipe out wild type virus whereas the Salk vaccine only stops the wild type virus getting to the neurons.

The attenuated Sabin vaccine, however, came with a problem: back mutation. This may result from recombination between wild type virus and the vaccine strain. Virulent virus is frequently isolated from recipients of the Sabin vaccine. The residual cases in countries that use the attenuated live virus vaccine (about 8 per year in the US until recently) resulted from mutation of the vaccine strain to virulence. About half of these cases were in vaccinees and half in contacts of vaccinees. Paralytic polio arises in 1 in 100 cases of infection by wild type virus and 1 in 4 million vaccinations as a result of back reversion of the vaccine to virulence. This was deemed acceptable as the use of the attenuated virus means that the vaccine strain of the virus still replicates in the body and gives gut immunity via IgA.

The vaccinee who has received killed Salk vaccine still allows wild type virus to replicate in his/her gastro-intestinal tract, since the major immune response to the injected killed vaccine is circulatory IgG. As noted above, this vaccine is protective against paralytic polio since, although the wild type virus can still replicate in the vaccinee's gut, it cannot move to the nervous system where the symptoms of polio are manifested.

By the way, today Polio vaccines have been further improved – and Polio hopefully eradicated soon.

Post-Polio Syndrome and Tinitus

Do you have [post-polio syndrome and] tinitus or roaring sounds in your ears?

26.5% - No.

21.3% - Yes, all the time.

27.7% - Yes, often.

10.4% - Yes, sometimes.

13.8% - Yes, rarely.

Translation and protein processing by picornavirus

Translation and protein processing by picornavirus

The picornavirus RNA binds to ribosomes and makes a single polypeptide, therefore the virus has just one gene. This polyprotein has regions that have proteolytic activity (they are cysteine proteases) that cleave the polyprotein to three precursor proteins (P1, P2, P3). P1 is cleaved to a VP0, VP1 and Vp3 plus a leader peptide of unknown function. VP0 gives rise to VP2 and VP4. P2 and P3 do not give rise to viral structural proteins. One of the proteins that comes from P3 is the VPG that is found at the 5' end of the viral RNA while other proteins from this precursor are the viral replicase and enzymes that modify the behavior of the host cell. P2 is also cleaved to give other cell-modifying proteins. Details of some of the cleavages are still vague.

Once the various viral proteins have been made in the infected cell, the replicase (also call a transcriptase or protein 3Dpol) copies the viral plus sense RNA to negative sense RNA. Other viral proteins are also involved in this process. As new positive strand RNAs are made, they can also be translated into more viral protein. There may be as many as half a million copies of viral RNA per cell. Some of the proteolytic events outlined above take place as the nucleocapsid is assembled. This is especially the case with the VP0 cleavage to VP2 and VP4. P1 protein is the precursor that gives rise to the four structural proteins of the nucleocapsid. Five copies of P1 first associate. Endoproteolysis then occurs to form VP0, VP1 and VP3. Twelve of these pentamers than associate to form an empty capsid (procapsid). The viral RNA now associates with the capsid and at the same time, VP0 is cleaved. Release is by lysis of the host cell.

At the same time as viral protein synthesis is occurring, host cell protein synthesis is shut off. The host cell mRNAs however remain fully functional when assayed in an experimental system, so selective degradation of cell mRNAs is not the reason for protein synthesis inhibition. One way host cell protein synthesis occurs is via the cleavage of initiation factor eIF-4, one of the cap binding proteins of the host cell's ribosomes so that cellular mRNAs cannot bind to the ribosomes. Association with cap-binding proteins is a prerequisite for the translation of most cellular RNAs. Thus, only uncapped messages such as that of the picornavirus are translated. Note that most viruses express capped RNAs similar to normal mRNA and so this mechanism of shutting down host protein synthesis is not available to them. The viral proteins also change the permeability of the host cell, altering the ionic composition of the cell and inhibiting cell mRNA association with ribosomes. Moreover, the large number of copies of viral RNA simply out-compete the cell's mRNAs.

Historic ME/CFS Outbreaks: Los Angeles 1934

Names used:
Atypical Poliomyelitis (Gilliam, 1938)
Epidemic Neuromyasthenia (Ramsay)

Location and Date:
Los Angeles County General Hospital, 1934

Described by:
Alexander Gordon Gilliam (1938) – Epidemiological study of an epidemic, diagnosed as poliomyelitis, occurring among the personnel of the Los Angeles county general hospital during the summer of 1934

Symptoms:
First considered as poliomyelitis (polio).

Initial symptoms similar to polio, but some features differed from polio:

• Localized muscle weakness in 80% of cases, yet no muscle wasting (unlike polio)
• No evidence of damage to the lower motor neuron
• Sensory symptoms (persisting far longer than in polio)
• Muscle pain, tenderness (persisting far longer than in polio)
• Fatigue on walking short distances
• Lapses of memory
• Loss of concentration
• Sleep disturbances
• Emotional lability (with "hysterical episodes")
• Reoccurrence of both systemic and neurological symptoms, some cases more disabled by recurrence than by original illness
• No mortality, but high morbidity (55% of staff off duty six month after peak of peidemic)
• Vaso-moto and trophic disturbances
• Excessive sweating or abnormal dryness of the skin of the extremities
• Coldness and cyanosis
• In more severe cases exfoliation of the skin
• Hypertrichosis and brittleness of the nails, with retardation or acceleration of growth

The outbreak in the Royal Free Hospital in London in 1955 was an almost exact replica of this outbreak according to A. Melvin Ramsay.

Source:

A. Melvin Ramsay – "Myalgic Encephalomyelitis – The saga of the Royal Free disease", page 12

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Other historic synonyms.

Relation: Infection with Polio to Post-Polio Syndrome

Outcomes of poliovirus infection

Outcome	Proportion of cases
Asymptomatic	90–95%
Minor illness	4–8%
Non-paralytic aseptic meningitis	1–2%
Paralytic poliomyelitis	0.1–0.5%
— Spinal polio	79% of paralytic cases
— Bulbospinal polio	19% of paralytic cases
— Bulbar polio	2% of paralytic cases

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Progress to post-polio syndrome

Initial polio symptoms	Progress to post-polio later in life
Asymptomatic	?
Minor illness	?
Non-paralytic aseptic meningitis	14% to 42%
Paralytic poliomyelitis	25% to 50%

12 year polio incubation in immune-compromised patient

Analysis of poliovirus recovered from the stool of a patient with fatal poliomyelitis revealed that she had been infected with the virus 12 years earlier, probably when one of her children received the oral poliovirus vaccine. This case has the longest known incubation period for vaccine-derived poliomyelitis, and highlights our still rudimentary understanding of how poliovirus causes disease.
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This case emphasizes the need to continue research on poliovirus. Our knowledge of how the virus causes disease is still rudimentary – as is evident by our failure to understand the 12 year incubation period of the case described here. Although the polio eradication campaign has had excellent results, it can be compromised by vaccine-associated disease. Individuals with B lymphocyte deficiencies will be a reservoir for the virus and can lead to infections if immunization levels drop. It would be highly beneficial to identify all individuals with chronic poliovirus infections, and treat them with antivirals. Unfortunately, such compounds do not exist – underscoring the need to continue research to identify drugs that can be used to treat poliovirus infection.

Post-Polio Syndrome

Post-polio syndrome (PPS, or post-poliomyelitis syndrome or post-polio sequelae) is a condition that affects approximately 25–50% of people who have previously contracted poliomyelitis—a viral infection of the nervous system—after the initial infection. Typically the symptoms appear 15–30 years after recovery from the original paralytic attack, at an age of 35 to 60. Symptoms include acute or increased muscular weakness, pain in the muscles, and fatigue. The same symptoms may also occur years after a nonparalytic polio (NPP) infection. The precise mechanism that causes PPS is unknown. It shares many features with the post-viral chronic fatigue syndrome, but unlike that disorder it tends to be progressive, and as such can cause a tangible loss of muscle strength. Treatment is primarily limited to adequate rest, conservation of available energy, and supportive measures, such as leg braces and energy-saving devices such as powered wheelchairs, analgesia (pain relief) and sleep aids.

Increased activity during intervening healthy years between the original infection and onset of PPS can amplify the symptoms. Thus, contracting poliomyelitis at a young age can result in particularly disabling PPS symptoms.

Numerous theories have been proposed to explain post-polio syndrome. Despite this, there are currently no absolutely defined causes of PPS.

Diagnosis of post-polio syndrome can be difficult, since the symptoms are hard to separate from complications due to the original poliomyelitis infection, and from the normal infirmities of aging. There is no laboratory test for post-polio syndrome, nor are there any other specific diagnostic criteria. … In general, PPS is a diagnosis of exclusion whereby other possible causes of the symptoms are eliminated.

Sounds like CFS to me! I wonder what happens if you have post-polio and fall into the hands of the psychobabblers: CBT/GET for you! After all, without a definite cause, it must be psychosomatic (sorry for my sarcasm).

But there is some training that should and can be done:

Muscle training at aerobic levels without maximum exercise is useful to maintain muscular function and ameliorate fatigue13 and muscular training in warm water seems to be particularly useful. … Inactivity increases the risk of obesity, diabetes, cardiovascular, and muskuloskeletal problems and so polio patients who take part in physical activity have significantly less symptoms than physically inactive patients. All polio patients with or without post-polio syndrome should therefore be advised to take part in physical activity, but they should not be performing static muscular training at maximum effort (anaerobic level) and they should allow intermittent breaks.

Elisabeth Farbu: Post-Polio Syndrome – Diagnosis and Management

No anaerobic training – same as in ME/CFS.

By the way:

Factors that increase the risk of polio infection or affect the severity of the disease include immune deficiency, malnutrition, tonsillectomy, physical activity immediately following the onset of paralysis, skeletal muscle injury due to injection of vaccines or therapeutic agents, and pregnancy.

And:

The molecular mechanisms by which poliovirus causes paralytic disease are poorly understood. Early symptoms of paralytic polio include high fever, headache, stiffness in the back and neck, asymmetrical weakness of various muscles, sensitivity to touch, difficulty swallowing, muscle pain, loss of superficial and deep reflexes, paresthesia (pins and needles), irritability, constipation, or difficulty urinating.