Leishmania parasites, tricking the human immune system

26 Aug 2009

Tatum Anderson

Source: PLoS Pathogens (see original article)

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Sand fly, Imperial College

Researchers have moved a step further to understanding how leishmaniasis, a parasitic infection that kills and disfigures, manages to bypass the human immune system so successfully.

Leishmaniasis parasites are carried by sand flies that live alongside at least 350 million people worldwide. The most virulent form of the disease, visceral leishmaniasis or kala-azar, affects people across the Indian subcontinent and in parts of East Africa and Brazil. Over 60,000 Indians, for instance, die every year of the disease. The ulcers and disfigurement caused by the disease can also be so severe and unsightly that many survivors are forced to live as social outcasts.

There is currently no vaccine available to treat kala-azar and comparatively little is known about the way that the parasites are transmitted by sand flies. Emerging research is showing, however, that both the number of parasites delivered to humans and the way in which these are delivered has an enormous effect on the outcome of infection.

Now, a consortium of UK researchers has worked out why the human immune system – in the form of scavenging cells called macrophages – does not kill invading leishmaniasis parasites. The researchers found that a protective packaging that is regurgitated by sand flies and that surrounds the parasites as they pass from sand fly to human encourages macrophages to nourish, rather than kill, the invaders. This means that the human immune system is "fooled" into establishing parasites within the victim – at least for the first few days after infection.

Some information is already available about this protective packaging. It is thought to be a gel-like substance produced by parasites when they are in the sand fly mid-gut. The gel, called promastigote secretory gel (PSG), then acts like a plug and prevents the fly from feeding on human blood without regurgitating the gel (containing the parasites) into the victim.

Researchers from Imperial College London, the Liverpool School of Tropical Medicine and the London School of Hygiene & Tropical Medicine say they have now discovered that PSG also plays a role inside the human body, after infection. Once the parasites are in the human bloodstream, the PSG gel entices macrophages to engulf them. It also encourages the macrophages to generate polyamines that help nourish the parasites in their first days in the new host.

The researchers, funded by Wellcome Trust, studied how PSG enticed macrophages to the site of entry. In experiments, the gel managed to recruit 108 times more macrophages to the bite site than saline and five times more than sand fly saliva. They also looked at the effect of PSG on parasite survival in vitro. More parasites survived in the first 48 hours following infection when PSG was present compared with survival in cells that were infected but had no added PSG.

Dr Matthew Rogers, lead author of the study from the Division of Investigative Science at Imperial College London believes that PSG is such an important component of the parasite’s infection apparatus it should fundamentally alter the way many scientists conduct research on leishmaniasis. To date many scientists study leishmaniasis by injecting parasites into tissues without including the gel (or indeed, sand fly saliva). Rogers believes that strategy this will have to change. “We must consider the way the parasites enter the body – along with the gel and saliva – if we are to recreate infection and get an accurate picture of what is going on,” he says.

The hope now is that scientists might be able to exploit this immunological trick to find ways to prevent infection. Imperial’s scientists want to investigate further the possibility of injecting a synthetic version of the gel to provide extra protection against this disease.