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Plague in Kazakhstan

13 Mar, 2012
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A gerbil basking in the sun outside its burrow. Credit: Dr Anne Laudisoit.

In the West, we tend to associate the ‘black death’ with images from medieval Europe: an eerie quiet in once-busy streets broken only by the jingling of a plague cart’s bell…red crosses daubed on the doors of stricken houses…and fires burning night and day to ‘purify’ the air.

Since the discovery of the Yersinia pestis bacterium in 1894, its transmission via fleas (the vector) in 1898 – and, crucially, the arrival of antibiotics in the 1940s – plague is no longer the dreaded spectre it once was. Provided it’s caught in time, the disease is quite easy to treat.

If treatment is delayed, however, things can get serious. The infection can spread from the lymph nodes (where it proliferates after the original bite) through the bloodstream to the lungs and other organs. “Once patients get respiratory symptoms, indicating the infection has reached their lungs, they have a 95 to 100 per cent chance of dying if they aren’t treated within 28 to 24 hours,” says Dr Anne Laudisoit from the University of Liverpool. With Wellcome Trust funding, she is studying the behaviour of Y. pestis in the wild in Kazakhstan.

The severity of disease it causes in people if left untreated (and the high likelihood it might be because cases are so rare today in the West) was demonstrated in 2002 when a couple from New Mexico holidaying in New York went to a doctor with flu-like symptoms. In fact, they had caught bubonic plague from infected rodents on their farm, something that simply hadn’t occurred to them as a possibility. By the time plague was diagnosed, the man was in a coma and had to have both legs amputated below the knee.

England saw several cases of human plague as recently as the start of the last century. Seven people from a village near Ipswich became ill with it between December 1906 and January 1907, only one of whom recovered.

The disease then seemed to die out, only to resurface three years later, infecting another seven people in late 1909 and early 1910. This time, three people recovered. Then, once again, as swiftly and mysteriously as it had arrived, plague disappeared, and to date there have been no further reported human cases in England.

‘Bring Out Your Dead’. A street in London during the Great Plague, 1665, with a death cart and mourners. Credit: Wellcome Library, London.

The Ipswich cases highlight some of the perplexing questions plague poses for biologists. In the pre-antibiotics era, what differences in immunity that enabled some people to recover and not others? Why did both outbreaks occur at the same time of year (winter)?

Where did the disease come from in the first place? Researchers assume it was brought by infected rats from a ship docking at the nearby port, but no one knows for sure. And, crucially, where did it go in the three years between the two outbreaks? Did it die out completely and get re-imported? Or did it persist in a host reservoir somewhere nearby?

With Wellcome Trust funding, Anne, along with Professor Mike Begon at the University of Liverpool and colleagues, hopes to clarify some of these conundrums by studying plague in one of its natural habitats: the vast steppes of Central Asia.

Giant gerbils

Plague is still endemic in the desert plains of Kazakhstan, extending to parts of Uzbekistan and western China and Mongolia. Many researchers believe that it was carried to the West by fleas hitching rides on the Mongols centuries ago.

Y. pestis obviously has a better chance of surviving in a host reservoir it doesn’t kill. Humans and cats are highly sensitive to infection and frequently die without antibiotics to eliminate it from their bodies, making them a poor choice of home for the bacteria. Camels, goats, dogs and many rodents by contrast have relatively few symptoms and are therefore ideal plague hosts.

In Kazakhstan, people have caught plague from eating infected camel meat. Generally, though, humans get plague when they are bitten by fleas that have fed on infected wild rodents. Of these, the main rodent hosts in much of Central Asia are the great gerbils. These giant rodents grow up to 20 cm in length and live in large, easily visible networks of burrows.

The risk of people catching plague from them is real, and workers in gas and oil stations (which have proliferated in Kazakhstan since the 1960s) are vaccinated against it as a matter of course. When outbreaks occur in villages sited near giant gerbil burrows, the entire village population has to be vaccinated.

Anne and her main method of transport. Credit: Dr Anne Laudisoit.

Plague used to be a far more serious problem before the 1940s (and antibiotics), killing scores of people every year in Kazakhstan and wiping out whole villages. The former Soviet Union, which controlled the region at the time, cracked down on the disease. Beginning in 1949, it sent teams into the steppes to collect gerbils and fleas to study the causes of plague, determine the extent of the outbreaks – and treat them when necessary.

That information was compiled in a vast archive of handwritten ledgers, forming a goldmine of data on plague for scientists. After the Iron Curtain was lifted in 1992, Professor Herwig Leirs, an ecologist at the University of Antwerp in Belgium, discovered the archive.

Professor Leirs teamed up with Mike Begon, Dr Stephen Davis and others to take advantage of this rich resource. Analysing the data, they determined that when the gerbil population exceeded a certain threshold (measured by the proportion of burrows occupied), plague outbreaks occur two years later. In a paper published in ‘Science’ in 2004, they suggested that detecting this ‘threshold abundance’ can act as an early warning system for the appearance of plague.

Subsequent trialling of the model revealed some flaws, however. “The model is pretty good at saying you really can’t expect plague here and getting that right,” says Mike. “But it would often tell you you’re going to get plague and then you don’t. Then the public health people end up wasting time and money controlling it when they don’t have to. So as far as they’re concerned, they get the wrong answer too often with it.”

Jumping rats

With Wellcome Trust funding, Mike, Anne, Stephen and colleagues aim to improve and develop that system. By collecting new data, they hope to be able to identify the reasons for these ‘false positives’ and eliminate them.

“The 2004 paper was based on analysis of old data. We’re now in the business of collecting new data to try to improve the model’s predictive power,” says Mike.

They’ll be collecting the new data in two ways: the intensive trapping of gerbils and fleas in the field and, with Dr Elisabeth Addink and her team at the University of Utrecht, by the burrows via remote sensing. The vast territory is divided into 36 sectors. Some of these are ‘quiet’ (identified as such in the 2004 paper) – with little or no plague even when there are enough rodents to warrant an outbreak – but others are active plague sites.

A remote sensing image of a square, near Bakanas, with the status and exact GPS coordinates of each burrow. A blue arrow indicates the gerbils in a burrow have tested positive for Y. pestis. Credit: Dr Anne Laudisoit.

The remote sensing work is partly a proof-of-concept study to ascertain how much data can be collected from satellite imagery. It aims to count both the number of burrows and their occupancy status – whether they are occupied, empty, or temporarily home to individual visiting gerbils. If it proves useful and accurate, it would be an extremely cost-effective method of monitoring burrows and identifying impending high-risk outbreaks.

In quest of new biological data Anne spent much of last year in Kazakhstan – armed with insect repellent and emergency antibiotics – trapping rodents and fleas from both active and ‘quiet’ sites, and she’ll be repeating the exercise over the next two years. Her ‘trapping’ sites are close to but not overlapping with the satellite sectors, to prevent their physical presence interfering with the remote sensing.

The team will be examining the new data gathered from the field work and remote sensing to identify differences between active and quiet plague sites that will help them establish the status of plague at any particular point in time, in a given place.

“Where is plague when we can’t see it? That’s our central question,” says Mike. “If we can find out, we can anticipate it emerging and control it before there’s an outbreak.”

They also hope to shed more light on some of the broader questions about plague’s cryptic behaviour in the wild. What  factors allow Y. pestis to survive there? Does it completely disappear to be later reintroduced from a distant location? Or does it remain present in host reservoirs, within the rat-flea-rat transmission cycle, but at levels too low to be detected?

Does it persist without any reliance on this cycle – perhaps in the soil? If the gerbils come into constant contact with Y. pestis in the soil of their burrows – and consequently develop immunity to it – this may explain their greater resistance to the organism. “We don’t know the answers to any of these questions,” says Anne.

To compound the riddle, Kazakhstan’s giant gerbils may not be plague’s only rodent hosts there. “The Russians focused on the great gerbils but we want to collect and study other native rodents more systematically, to see if they are also a repository for plague,” says Anne. Some – including another giant, a jumping rat aptly nicknamed the ‘jumpin’ great jerboa’ – are proving almost impossible to trap.

She’s also collecting every species of flea and tick she comes across in the field, to see which are plague vectors. And her team will be testing the rodents they trap for other infections.  “Co-infection can influence immune status. So we want to look at other pathogens and how they influence how plague behaves in individual animals.”

Infections they have found to date include the typhoid and Lyme disease bacteria – and they expect to find leishmania. “There is leishmania in the west of the country, but we haven’t yet got any  data on leishmania in the region we’re looking at.”

Once they’ve identified the precise factors that reactivate human outbreaks of plague – thereby improving the reliability of the early warning system – Anne, Mike and colleagues hope to use that information to develop a more cost-effective and focussed control system.

“In principle you could control plague by going to Kazakhstan and fumigating every burrow in the high-risk region,” says Mike. “But widespread control is very expensive and uses a huge amount of manpower. It makes more sense to target the burrows where occupancy is above the threshold – and other conditions are favourable for plague – and just fumigate those. It’s all about using inevitably scarce resources sensibly.”

References

  • Davis S, Begon M, De Bruyn L, Ageyev VS, Klassovskiy NL, Pole SB, Viljugrein H, Stenseth NC, & Leirs H (2004). Predictive thresholds for plague in Kazakhstan. Science (New York, N.Y.), 304 (5671), 736-8 PMID: 15118163
  • First Major Pandemic: The Plague of Justinian in the 6th and 7th centuries originated in China and spread to Central and South Asia, North Africa and Arabia, and Europe, wiping out half of Europe’s population before its last recurrence in 750.
  • Second Major Pandemic: The Black Death of the 14th century began in China or nearby in Central Asia and spread to Europe along the Silk Road and by ship. It may have reduced the world’s population by a quarter – from 450 million to 350-375 million in 1400.
  • Third Major Pandemic: A major bubonic plague pandemic began in the Yunnan province in China in 1855 and spread to all inhabited continents, killing more than 12 million people in India and China alone. According to the World Health Organization, the pandemic was considered active until 1959, when worldwide casualties dropped to 200 per year.
  • The plague bacillus was first cultured by Alexandre Yersin in Hong Kong in 1894.
  • In 1898, Paul-Louis Simond, who was studying bubonic plague in Bombay, proposed transmission by rat fleas.
  • After 1920, the spread of plague was largely halted by international regulations that mandated control of rats in harbours and the inspection and rat-proofing of ships.
  • By 1950, plague outbreaks around the world had become isolated, sporadic and manageable with the modern techniques of surveillance, flea and rat control, and antimicrobial treatment of patients.
  • From 1969 to 1993, around 1356 human plague cases in around 10 to 15 countries per year were reported to the WHO. Recently, however, both the global number of human cases and the number of countries reporting plague have been increasing.
  • Plague is still one of three quarantinable diseases subject to international health regulations (along with cholera and yellow fever).

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