MicrobiologyBytes

Stanley Prusiner was awarded the first ever SGM Prize Medal (to a microbiologist of international standing whose work has had a far-reaching impact beyond microbiology) at the SGM Spring meeting at Harrogate on 1st April 2009. MicrobiologyBytes was there and this is a summary of his Prize lecture.

Prions are infectious proteins which multiply by binding to a host cell protein and converting it into insolubile fibrils (“amyloid“). Prions are associated with infectious, inherited and sporadic diseases – a feature unique to these entities. Tikvah Alper was the first person to identify prions in the 1960s, but when Prusiner started working on them in 1974, at first he didn’t believe the protein-only hypothesis. After eight years of failing to be able to identify any nucleic acid associated with them, in 1982 he changed his mind and invented the name prion (“pree-on”).

In prion diseases, the cellular form of the protein, PrP^c, is converted into a disease-associated form, PrP^Sc. If prions really are infectious proteins, PrP^Sc produced in bacteria should be able to cause disease – and it does. It is also possible to produce synthetic amyloids with different biological properties – essentially strains of the protein.

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Quinacrine cures cultured cells of prions. In mice, the drug increases survival time of infected animals by up to 20%, but recently concluded clinical trials in humans have shown little effect. Prusiner’s group have found that quinacrine does work in stationary phase cells – such as those in the brain. Future trials of anti-prion (or amyloid) drugs need to be carried out in stationary cells. The latest assay uses genetically-modified mice which express luciferase when glial cells are disturbed. The resulting luminescence can be detected in the brains of live mice, and signs of disease can be recorded even before any neurological symptoms appear. This is up to eight times faster than waiting for the mice to die and examining their brains, and only requires one tenth of the animals. Prusiner hopes to use this approach to study Alzheimer’s and Parkinson’s disease, which also involve brain injury and amyloid deposits.

Stanley Prusiner’s take home message to all the students present was: it’s important to be lucky! But as Robin Weiss, SGM President, pointed out, Pasteur said: Fortune favours the prepared mind!

Related:

• Alzheimer’s Disease and Prions
• The Origin of BSE
• What the heck are prions for?
• Drugs for treatment of prion infections
• What drove the cow mad? Lessons from a fish

The organochlorine compound DDT (Dichloro-Diphenyl-Trichloroethane) was first synthesized in 1874, but its insecticidal properties were not discovered until 1939 by the Swiss scientist Paul Muller, who was awarded the 1948 Nobel Prize in Physiology and Medicine for his efforts. DDT kills by opening sodium ion channels in insect neurons, causing the neuron to fire spontaneously. This leads to spasms and eventual death. Insects with mutations in their sodium channel gene or with up-regulation of genes expressing cytochrome P450 may become resistant to DDT and similar insecticides.

In the early years of World War II DDT was used with great effect to combat mosquitoes spreading malaria, typhus, and other insect-borne human diseases among both military and civilian populations. After the war, DDT was made available as an agricultural insecticide, and its production and use skyrocketed.

In 1955 the World Health Organization began a program to eradicate malaria worldwide, relying largely on DDT. Though this effort was initially highly successful (reducing mortality rates from 192 per 100,000 to a low of 7 per 100,000), resistance soon emerged in many insect populations as a consequence of the widespread agricultural use of DDT. In the 1960s, the environmental impacts of indiscriminate spraying of DDT became known. As a persistent organic pollutant, DDT accumulated in the food chain and had severe effects on fish, amphibians, birds, and rather less well known impacts on mammals, including humans. DDT can still be found in the fat reserves of polar bears, penguins, and possibly you, thousands of miles away from where it was ever sprayed. In 1987 the US EPA classified DDT as a probable human carcinogen. DDT is also known to be an endocrine disruptor and to cause developmental problems in infants.

In the 1970s and 1980s, agricultural use of DDT was banned in most developed countries, in 1970 in Scandinavia, 1972 in the USA, but not until 1984 in the UK. The Stockholm Convention which came into effect in 2004 outlawed several persistent organic pollutants, and restricted the use of DDT to the control of insect vectors of human diseases. After these bans, the populations of many severely threatened species, such as the American bald eagle, rebounded.

In September 2006, the World Health Organization announced that DDT will be used as one of the three main tools against malaria, and recommended indoor spraying in epidemic areas and places with high malaria transmission. USAID now funds the use of DDT overseas. DDT sprayed inside a home provides protection from mosquitoes for up to six months. New studies show that despite mosquito resistance to DDT, it also acts as a powerful insect repellent.

Malaria afflicts between 300 million and 500 million people each year. The World Health Organization estimates that around 1 million people die of malaria and malaria-related illness every year, with 90% of these deaths in Africa, mostly in children under the age of five. To put that in perspective, that is equivalent to the death toll of around ten of the nuclear bombs dropped on Hiroshima during World War II. Malaria also weakens the economies of poor countries. People who become infected cannot work or die. Infected children can suffer brain damage. The World Bank estimates that malaria costs Africa more than US$100 billion annually and this cost is growing by 1.3 per cent each year. In 2004, when Uganda publicly contemplated reintroducing DDT to fight malaria, the European Union made threats that the country’s US$32 billion agriculture exports could be at risk if tough new measures were not taken to ensure DDT residues did not find their way into food crops.

As a result of the WHO program, the number of African countries spraying DDT inside houses has exploded. Eritrea, Madagascar, Ethiopia, Swaziland, Senegal, Ghana, Angola, South Africa, Mauritius, Mozambique, Zimbabwe, Namibia, Zambia and Burkina Faso are all using the chemical. Uganda, where more than 100,000 people died from malaria in 2006, began spraying it this year in a pilot project, and Tanzania and Malawi may follow. But Rwanda, Burundi and Kenya (a major producer of pyrethrum, the main alternative to DDT) are so far refusing to adopt the use of the chemical. In 1995, South Africa stopped spraying DDT to control malaria, citing international pressures, but as soon as the ban started, the incidence of malaria rose.

DDT is cheap. Safer pyrethrum-based insecticides are 20 times more costly, often too expensive for developing countries. The price of controlling malaria in Africa has been estimated at US$1 billion per year, but foreign aid targeting the disease has never topped US$200 million.

So my question to you is this: imagine you are the president of the world, but with a limited budget. What would you do?

Related:

• Lean and Mean Invasion Machines
• Malaria is a continuing danger to UK travellers
• Africa Malaria Day 2007
• Malaria: now you see me, now you don’t

Bluetongue is a highly infectious virus disease of ruminants. Cattle and goats are major hosts of the virus, but in these species infection is usually asymptomatic despite high virus levels, allowing the disease to circulate in the absence of any symptoms. Sheep and deer are usually the only species to exhibit symptoms of infection. Bluetongue infections are marked by a high fever, excessive salivation, swelling of the face and tongue and cyanosis of the lips and tongue (turning blue). Infected animals become lame and listless. Ulcers appear around the mouth, nose and eyes. Then the neck may start to swell, followed by the head. The animal becomes lame, starts bleeding internally and breathing becomes difficult. The incubation period for bluetongue is 5-20 days. The mortality rate is normally low, but infected animals lose condition and there is a high mortality rate of 70% or more in susceptible breeds of sheep (due to secondary bacterial infections). While infected animals can recover, productivity is reduced with milk yields in dairy herds dropping by about 40%.

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Bluetongue virus (BTV) is a Reovirus of the genus Orbivirus. The virus is transmitted by midges, in particular Culicoides imicola and a few other species. Of more than 1,400 species of midges known world-wide, only around 20 culicoid species are known to be involved in transmission of bluetongue virus. Bluetongue can also be transmitted directly from one animal to another through semen and transplacentally. Bluetongue occurs in Australia, the USA, Africa, the Middle East, Asia and Europe, generally between latitudes 35°S and 50°N. It occurs around the Mediterranean in summer, subsiding when temperatures drop in winter. In Europe the disease has been spreading north since October 1998, possibly as a result of climate change. In August 2006 bluetongue spread to the Netherlands, then Belgium, Germany, Holland, and Luxembourg. The first ever case of bluetongue in the UK was reported in Suffolk on 23rd September 2007. On 28th September 2007 Defra confirmed that bluetongue is now endemic in the UK.

Unlike foot and mouth disease, bluetongue cannot be controlled by culling of infected livestock alone. Since midges form a reservoir of infection in endemic areas, you would also need to kill all the midges to eradicate the disease. Another complication is there are at least 24 distinct serotypes of the virus (based on the lack of cross neutralisation). Vaccination against one serotype does not usually confer protection against any of the other serotypes. The antigenic diversity of Bluetongue virus is due to both antigenic drift (accumulation of point mutations) and antigenic shift (reassortment of individual gene segments). The virus which has affected northern Europe and the UK is known as BTV8.

Live attenuated BTV vaccines containing a weakened form of the live virus are cheap, easy to produce and can be administered in a single dose. They are effective in controlling clinical outbreaks of bluetongue. However, the disadvantages of attenuated BTV vaccines are:

• Risk of reassortment with virulent wild viruses which potentially could give rise to new virulent strains.
• Potential for reversion to virulence both in the vertebrate host and in vector insects.
• Attenuated BTV can cross the placenta and pregnant ruminants vaccinated with attenuated vaccines may suffer foetal loss.
• Existing vaccines are designed for sheep; there is little data on their safety and effectiveness in other species.

There have been attempts to develop inactivated (killed) whole virus vaccines for BTV for the past 25 years, but none have yet been produced commercially. Inactivated vaccines are they more expensive to produce than attenuated vaccines and also require at least two doses with an adjuvant to generate a protective immune response. Bluetongue virus is not usually contagious for humans, and meat and dairy products pose no hazard. However, there is some concern over the potential spread via blood from infected people.

Bluetongue: Latest News

Related:

• Will bluetongue come to the UK on the wind in 2007?
• Sheep virus ‘low risk to the UK’

• 23rd September: A suspected new case of foot-and-mouth is being investigated on the Hampshire-West Sussex border. Bluetongue is confirmed on a farm in Suffolk.

• 21st September: Another case of foot-and-mouth disease was confirmed on a farm in the Egham area of Surrey. Around 40 cattle were culled on the premises, which are within the existing 3km protection zone.

• 18th September: Defra confirms fifth infected premises since the start of the outbreak.

• 14th September: Defra announces that a second farm in Surrey is affected, imposes new protection and surveillance zone and confirms that sequencing tests of the virus have shown it to be type 01 BFS67, the same strain of virus responsible for the August outbreak.

• 12th September: Defra confirms a new case of FMD in Surrey.

• 8th September: The last restrictions imposed on livestock movement in the UK following the foot-and-mouth disease outbreak were lifted, but the earliest the UK can achieve international foot-and-mouth disease-free status is 7th November.

• August 2007: On 3rd August Defra confirmed an outbreak of foot and mouth disease on a farm near Guildford in Surrey. Defra confirmed that the FMDV strain found in Surrey is most similar to strains used in international diagnostic laboratories and in vaccine production, including at the Pirbright site shared by the Institute of Animal Health (IAH) and Merial Animal Health Ltd, a pharmaceutical company. The present indications are that this strain is an O1 BFS67-like virus, isolated in the 1967 Foot and Mouth Disease outbreak in Great Britain. This strain is present at the IAH and was used in a batch manufactured in July 2007 by the Merial facility. On a precautionary basis Merial has agreed to voluntarily halt vaccine production. Defra confirms a second case of foot and mouth on a farm within the 3km protection zone. Between 50 and 100 cows on the affected farm have been culled. As expected, the Health and Safety Executive’s initial report concludes that “there is a strong probability that the FMDV strain involved in the farm outbreak originated from the IAH or the Merial sites”. The letter to the Minister says “There is no reason to prevent the Institute for Animal Health from operating providing that all the usual biosecurity protocols are followed rigorously” but that “The situation regarding Merial is less clear cut, and I would advise that further work be done before any operations involving live pathogens are restarted. As the report indicates there are doubts about the integrity of the drainage system, including pipe work which leads to the final effluent treatment plant”. The report also says “Release by human movement must also be considered a real possibility. Further investigation of the above issues is required and is being urgently pursued”. Chief veterinary officer Debby Reynolds told a news conference she had ordered livestock on a third farm in Surrey to be culled on suspicion the disease may have spread.

Defra: Interactive map

10 Facts About Foot and Mouth Disease:

1. Foot-and-mouth disease (FMD) is a highly infectious disease of hoofed animals (ungulates) such as cattle, sheep, goats and pigs. It can also infect elephants, rats, and hedgehogs.
2. The symptoms of FMD are fever followed by the development of vesicles (blisters) chiefly in the mouth and on the feet.
3. Affected animals suffer weight loss from which they do not recover for several months, and in cows milk production can decline significantly. Although most animals eventually recover from FMD the disease can be fatal, especially in newborn animals.
4. Foot and mouth disease is caused by a Picornavirus.
5. FMD has an incubation period of 2-14 days before symptoms appear. The virus can survive in dry faecal material for 14 days in summer, in slurry for six months in winter, in urine for 39 days and on the soil for up to 28 days.
6. Some infected animals remain asymptomatic carriers of FMD which can transmit the disease to other animals.
7. The last major outbreak of foot and mouth disease in the UK in 2001 led to the slaughter of between 6.5 to 10 million animals and is estimated to have cost the country up to £8.5 billion.
8. The United States, Canada, Australia, Japan, Indonesia and Korea are currently free of FMD, but the disease is present in Eastern Europe, Asia, Africa and South America.
9. Vaccination against FMD is difficult because there are seven serotypes of the virus and a vaccine for one serotype does not protect against any others. Vaccination only provides temporary immunity. Defra Decision Tree for Disease Control Strategies against FMD
10. Humans can be infected with foot-and-mouth disease through close contact with infected animals, but this is extremely rare and human infections are not fatal. Because the virus that causes FMD is sensitive to stomach acid, it cannot spread to humans via consumption of infected meat or milk.