Sand fly guts could hold key to parasitic disease vaccine

Sand fly guts could hold key to parasitic disease vaccine

--- Deadly tropical disease could be thwarted by adapting parasite survival molecules to kill them within the guts of fly hosts ---

--- Versatile technique has potential for the development of a new wave of parasite treatments ---

The humble sand fly could offer hope against vector-borne parasitic diseases, like malaria and Lyme’s disease, after scientists discovered how the deadly leishmaniasis disease is spread.

Using atomic-force microscopy to map the adhesive forces on the surface of the parasitic protozoa that attach to the guts of the sand fly, the experiments, performed at the University of Sheffield, were able to show how it behaves at a molecular level.

In doing so, they discovered that targeting the molecules that help the parasite bind to the gut – making it less sticky – can prevent infection, suggesting the same technique could even work with a variety of other parasitic infections.

Leishmaniasis is responsible for an estimated 40,000 deaths a year and is transmitted by the bite of a female sand fly. Overreliance on the few available effective drugs – many of which are toxic – has led to a worldwide rise in drug resistance. Parasitic diseases, meanwhile, cause one third of all deaths worldwide every year.

The study, published in the Royal Society of Chemistry’s Chemical Science journal, was carried out by a collaboration between the University of Sheffield, Durham University, and the London School of Hygiene and Tropical Medicine.

May Copsey, Executive Editor for Chemical Science at the Royal Society of Chemistry said: “Tropical diseases such as leishmaniasis remain one of the biggest causes of death and morbidity in the poorest communities of developing countries around the world. The answers to tackling these persistent threats are often found in the most surprising places, and this work is an amazing example of just what we can learn from the most unsuspecting corners of nature through intensive research.”

“This is also a fantastic example of how a multidisciplinary approach can be extremely effective in tackling a complicated biological problem of global medical importance.”

Leishmaniasis, which is most commonly found in the tropics and sub-tropic regions of Africa, southern Europe, Asia, the Americas and southern Europe, causes painful ulcers and skin sores in its victims, which can erupt weeks or months after the initial insect bite. Visceral leishmaniasis, its most serious form, has a high fatality rate if left untreated.

To disrupt the parasites’ ability to successfully attach themselves to the gut and resist expulsion during defecation – the weakest point in their life cycle – the UK and Irish team looked at the variability of different forms of Leishmania – the parasites that cause the disease – and their ability to attach themselves to the midguts of sand flies.

This can be used to understand the molecular roles involved in hosting parasitic pathogens, and how interference with the process could be a potent target for blocking transmission. In doing so, they have discovered the potential to form the basis of a block to the transmission of leishmaniasis and other parasite-borne diseases.

According to the World Health Organization, vector-borne diseases account for more than 17 per cent of all infectious diseases. Malaria alone leads to around 500,000 deaths a year.

To test their theory, the team used atomic force microscopy (AFM) – an ultra-high-resolution scanning probe technique – to investigate the strength of the binding of different molecules to individual, live cells and ‘map’ their localisation and distribution. To achieve this, they applied sugar-coated polymers to the tips interacting with the parasite to mimic a mucus which coats the midgut of the majority of sand flies in the world.

In using this approach with parasites lacking key surface glycans, they built a map of the distribution of the adhesion events and discovered the underlying molecular interactions that allow Leishmania parasites to colonise their sand fly hosts.

In combination with mathematical modeling, this reveals that a transmission-blocking vaccine could be effective against leishmaniasis if the molecules with a strong ability to bind with the surface of the gut are targeted. Matthew Rogers, one of the paper’s lead authors suggested that “Our research reveals a universal mechanism of survival for all Leishmania in sand flies worldwide that may eventually lend itself to a control strategy against all Leishmania.” Mark Geoghegan, another author, said: “The tip of an AFM is tiny - more than a thousand times smaller than the width of a human hair - and we were able to perform complicated chemistry on it to mimic a biological process. The technology has the potential to go far beyond what we have performed.”

The paper, Glycan–glycan interactions determine Leishmania attachment to the midgut of permissive sand fly vectors, can be found at http://rsc.li/chemsci-leishmaniasis.