Neglected tropical diseases: Working with animals

Many of the parasites, bacteria and viruses that spread ‘neglected tropical diseases’ among the world’s poorest people can also infect livestock and other animals, while related species cause infectious diseases that are – for now, at least – confined to the animal kingdom. Animal diseases exacerbate the impact of neglected tropical diseases on people’s livelihood and health but they can also present opportunities for developing new approaches to tackling human disease. In the last article in our series on neglected tropical diseases, Michael Regnier finds out that looking at human and animal health together can lead to better results for all.

It started with a finger being pointed at Professor Keith Matthews. A colleague explained that a culture of cow cells in the lab down the hall had been contaminated with hordes of trypanosomes. Because the Matthews lab studied trypanosomes – tiny, single-celled parasites – they were prime suspects as the source of contamination.

It turned out that the ‘contaminant’ trypanosomes were not one of the species Matthews’s team studied, but a harmless relative called Trypanosoma theileri. As well as the trypanosome species that cause neglected tropical diseases (NTDs) such as human African trypanosomiasis (sleeping sickness) and Chagas’ disease, there are several species that live harmlessly inside their hosts – including cows.

Matthews realised that the harmless T theileri were more prevalent than he had ever imagined. In fact, this species has been found in cattle all over the world: from America, Belgium and Canada to Ireland and Iran. Assuming that the British cattle had also been infected at the time his colleagues took their samples, the researchers must have gathered some trypanosomes along with the bovine cells. In the lab, the trypanosomes thrived in the cell culture until they dominated it, giving the appearance of contamination.

Having cleared his lab’s name, Matthews could have left it there and returned to investigating changes in the trypanosome during its life cycle. Instead, in a flash of inspiration, he wondered if it would be possible to harness the ubiquity of the harmless trypanosomes, to modify them genetically and use them to introduce vaccines or drugs into cattle herds. He had already developed tools to alter the genetic make-up of trypanosomes – surely he could manipulate T theileri into being of practical use?

Professor Keith Matthews

“It’s essentially a simple delivery system,” explains Matthews, who is based at the University of Edinburgh. “Our research tools weren’t quite as transferable as I at first thought, but some logical modifications made it practical. Many different proteins can now be expressed at high levels, and we can use the trypanosome’s own trafficking signals to control whether they are expressed on the surface or secreted into the host’s bloodstream.” The project has been running for a number of years alongside the lab’s other interests, and a huge amount of work has been done, funded by the Wellcome Trust and the Biotechnology and Biological Sciences Research Council.

In October 2011, Matthews and his colleagues published the first paper demonstrating the viability of their approach using harmless trypanosomes to deliver vaccines and medicines to cattle. The next stage is to test trypanosomes that express several different antigens – characteristic proteins associated with infectious agents that can be recognised by the immune system – to see if the modified parasites protect against various infections in practice.

In theory, such genetically modified trypanosomes could be used to produce substances to stimulate the immune system to fight infection, or to deliver medicinal compounds directly into an animal’s bloodstream. The modified trypanosomes can be inoculated or ingested orally and will continue to release enough protein for the rest of the animal’s life – avoiding the need for booster vaccinations, for example.

Matthews stresses that the huge potential of this technique is the result of the depth of knowledge accrued from years of basic research – and that false accusation of ruining his colleagues’ cell culture, of course. “It’s amazing to me,” he says, “that this ‘blue-skies’ idea could potentially work. But it is completely dependent on the basic biology that has been done on pathogenic trypanosomes in many labs, over many years.”

One Health

Taking research into the causes of human disease and applying it to treating disease in animals is the reverse of what we usually expect from medical science, where studying diseases in animals is often a way of understanding human conditions. However, a new agenda – ‘One Health’ – is emerging in the global health research community. It suggests that infectious diseases no longer be pigeonholed as human or animal, but rather seen as existing in a wider ecosystem that contains humans, animals and the infectious agents themselves.

A prime example of the ‘One Health’ philosophy is the Southern Africa Centre for Infectious Disease Surveillance, or SACIDS, which is funded by the Wellcome Trust, the Rockefeller Foundation and the Google Foundation. Professor Mark Rweyemamu, Director of SACIDS, explains: “We study the interactions between humans, animals and the environment to improve health.

“Traditionally, we have considered human and animal disease separately, which makes perfect sense from a clinical perspective, of course. But the pathogens that cause infectious diseases do not distinguish humans from animals, and some people estimate that up to 75 per cent of human diseases come from animals.

“For example, rabies should not be a disease of people: we should be able to prevent rabies from reaching people. So every case of rabies in humans represents a failure down the chain. But we tend to treat what we see; we are not angry enough to say: ‘I shouldn’t be seeing this case.’ For rabies, our primary and all-out focus should be on controlling it in animals, thereby breaking the chain by stopping infected animals from transmitting rabies virus to humans.”

SACIDS is based in Tanzania and has national centres in the Democratic Republic of the Congo, Mozambique, South Africa and Zambia. Its aim is to undertake ‘transdisciplinary’ research into infectious diseases in the region. As well as crossing geographical boundaries, their approach breaks down barriers between human and animal health research and between natural and social sciences.

Surveillance is a key part of their work, but Rweyemamu says it is not enough just to monitor disease: “Epidemics and pandemics are a signal. Developed countries may think these diseases are not their problem but you cannot put a huge fence around Africa so that nothing gets out. We have to stimulate the North to realise it is their problem too. We need to tackle these problems at the source zoologically, and at the source environmentally.”

It is not just outbreaks of emerging – and re-emerging – infections that interest SACIDS. NTDs are equally relevant. “Epidemics cause headlines because we are all threatened, but chronic diseases hit farmers by reducing productivity and their economic viability,” says Rweyemamu. “That affects household income and household health. Tackling these diseases relies on technology, culture and governance.

“An unfocused area in research on neglected tropical diseases has been the environment and ecosystems: finding the critical point in the pathogen’s lifecycle where we can stop it.”

Lateral thinking

Professor Marshall Lightowlers

Nothing exemplifies this better than the research of Professor Marshall Lightowlers of the University of Melbourne, Australia. He has studied parasitic tapeworms called cestodes for more than 30 years, with a view to developing vaccines to prevent the NTDs they cause: neurocysticercosis and echinococcosis, also called hydatid disease.

The tapeworm that causes neurocysticercosis – Taenia solium – lives only in humans and pigs. Where pigs are raised in close proximity to people without good sanitation, the tapeworm spreads in a cycle of infection between the two. Tapeworm eggs from raw or undercooked pork can cross the human gut wall into other tissues. Although the human immune system can kill the eggs, this produces calcified cysts which, in the brain, cause neurocysticercosis, leading to seizures or death.

In 1999, Lightowlers suggested that a vaccine against T solium infection for use in pigs was practical and should be pursued because, with no intermediate vectors harbouring a reservoir of infection, it should help to eradicate neurocysticercosis in humans. As he admits, his challenge – designed to stimulate discussion, funding and collaborators for his research programme – was somewhat presumptuous: “Of course, when we began our vaccine work, this was pie-in-the-sky ambition because nobody had ever made a defined antigen vaccine against any parasite of man or animals!”

Nevertheless, the Wellcome Trust awarded him an Animal Health in the Developing World grant to develop a vaccine against T solium and the results have been extraordinary: “This project saw the first field testing of a defined antigen livestock parasite vaccine to prevent the transmission of a cestode parasite that is the cause of neurological disease in humans,” he explains. “The trial achieved the complete elimination of the parasite’s transmission.”

Some of the field-testing of the vaccine was done in Peru in collaboration with Professor Hector Garcia, now a Wellcome Trust Senior Fellow in Public Health and Tropical Medicine. Separately, in 2003, Garcia and colleagues received a grant from the Bill and Melinda Gates Foundation to undertake a programme to eliminate T solium from the Tumbes region of Peru and the decision was taken to incorporate Lightowlers’s vaccine. A second grant in 2010 has expanded the programme and funded monitoring of the programme’s long-term effects.

The vaccine has since been adopted by the Global Alliance for Livestock Vaccines and Medicines, which is coordinating its industrial scale-up and registration. Indian Immunologicals, a major Indian livestock vaccine manufacturing company, is undertaking the commercial scale-up. If the commercial vaccine performs well in safety and efficacy trials and field testing, the vaccine could be ready for use in two years.

Pigs in northern Cameroon, one of the field testing sites for Prof Lightowlers's vaccine

However, while the scientific work seems nearly complete, Lightowlers says there will be huge practical hurdles to implementing the vaccine in some of the poorest communities in the world: “Often these people use no vaccines for their animals and have little understanding about disease and no knowledge of this particular infection. The countries in which T solium is transmitted typically have greater problems with other diseases such as HIV, malaria, diarrhoeal diseases and so on, so we will need support from outside, philanthropic agencies.

“The big attraction to spending money on T solium is that the disease is susceptible to eradication. Spend the money once and you achieve a sustainable reduction in the disease burden in the community.”

Lightowlers says he feels unbelievably privileged to have come this far: “I am full of excitement and some trepidation about making it to genuine field application and seeing evidence of a decrease in human disease as a consequence. I am fortunate to be in a very similar position with our vaccine against hydatid disease, so I am hoping to make a direct contribution to reducing two human diseases.”

Common interests

It is clear that research on infectious diseases benefits from studying and understanding all stages of the infectious agent’s life cycle. The ‘One Health’ agenda aims to extend and embed this approach in order to bring forth more innovative solutions for emerging infectious diseases and NTDs alike.

“If you want a sustainable attack on these infectious diseases, you must pool common interests and get rid of the silos in research,” concludes Rweyemamu. “‘One Health’ is about a common approach, common medicine. We are all using the same technology to study human and animal disease; the drivers are the same – globalisation, climate and so on. They are shared problems, and they can have shared solutions.”

This is the last in our series of blog posts accompanying a Wellcome News feature on neglected tropical diseases. Continuing some of the themes in this piece, however, next week we will take a look at ‘neglected zoonotic diseases’: a number of infections, such as anthrax, rabies and bovine tuberculosis, that are transmitted between animals and people and have also been identified by the World Health Organization as needing more attention.

Related resources:

Mott GA, Wilson R, Fernando A, Robinson A, MacGregor P, Kennedy D, Schaap D, Matthews JB, & Matthews KR (2011). Targeting cattle-borne zoonoses and cattle pathogens using a novel trypanosomatid-based delivery system. PLoS pathogens, 7 (10) PMID: 22046137

Lightowlers, M. (1999). Eradication of Taenia solium cysticercosis: a role for vaccination of pigs International Journal for Parasitology, 29 (6), 811-817 DOI: 10.1016/S0020-7519(99)00051-X

Lightowlers, M. (2010). Eradication of Taenia solium cysticercosis: A role for vaccination of pigs International Journal for Parasitology, 40 (10), 1183-1192 DOI: 10.1016/j.ijpara.2010.05.001

The Wellcome Trust website has a number of scientific animations showing the life cycles of many parasites, bacteria and viruses that cause diseases, including some NTDs. Eg:
Human African trypanosomiasis – fly / human
Chagas’ disease – insect / human

Image credits: Wellcome Images / maureendidde on Flickr / Marshall Lightowlers (main artwork); Keith Matthews (photo); Marshall Lightowlers (photo, pigs)