NEB TV Ep. 24 – Neglected Tropical Diseases

Several of the most important neglected tropical diseases in humans are the result of infection with filarial nematode parasites. In this episode of NEB TV, learn more about these diseases and their impact, and how understanding their biology can help identify methods to detect, control and treat these parasites in the field.

Script

Deana Martin: Welcome to NEB TV. Today, I'm joined by Tilde Carlow who is the division head for our Genome Biology Group here at NEB. Hi Tilde. Tilde Carlow: Hi Deana. Deana Martin: And we're talking about neglected tropical diseases, and specifically NEB's research efforts in that area. Deana Martin: Tilde, how long has NEB been involved in parasitology research? Tilde Carlow: NEB has been involved in parasitology research for actually almost 40 years, so not long after the company was founded. It's largely the vision of our founder Don Comb, who was a great scientist and humanitarian, who was traveling in the tropics and actually witnessed first-hand the suffering that was actually inflicted by these neglected tropical diseases, and decided that he would like to do something to help towards the control and treatment of these devastating infections. Deana Martin: Mm-hmm (affirmative). And what are the goals of the program? Tilde Carlow: The goals of the program are to conduct basic research on these tropical diseases, the parasites that actually cause these diseases, with the hope that this knowledge can then be translated into methods to actually control and treat the parasites in the tropics. Deana Martin: And what areas of research do you focus on? Tilde Carlow: We focus on filarial worms, in particular. These worms are responsible for a number of really devastating diseases, from lymphatic filariasis to River Blindness Onchocerciasis, as well as a few other diseases, which are also caused by filarial worms. Tilde Carlow: All of these diseases are vector-born diseases, they are transmitted by a range of insects, which are found throughout the tropics. Deana Martin: Today, we will also be joined by Jeremy Foster, who is a research scientist here at NEB, and he will provide some more background on these filarial parasites. Then Tilde will come back and tell us about methods of detection. And lastly, we will hear from a researcher out in the field, and he's going to tell us a little bit about his work. Deana Martin: Are you ready? Tilde Carlow: Yep. Deana Martin: All right, let's get started. Jeremy Foster: These diseases are caused by filarial nematodes of which eight species infect humans. Both lymphatic filariasis and onchocerciasis are found throughout tropical regions where they threaten the well-being of about 20% of the world population. Jeremy Foster: Lymphatic filariasis is caused by three species of worm responsible for about 120 million infections in more than 80 countries. Onchocerciasis affects about 37 million people in 34 countries, mostly in Africa, but with smaller foci of disease also in South America. Jeremy Foster: These diseases are amongst a group of 17 so-called neglected tropical diseases. Neglected because they don't kill as many people as other diseases such as malaria. And neglected because they're not problems of the western world like HIV, or TB. And the consequence of this is that they're also relatively neglected in terms of research funding. Jeremy Foster: Although these parasites don't kill a great number of people, they cause an extreme amount of morbidity and disability. They're in fact ranked as the second leading cause of disability world-wide, after mental health issues. Jeremy Foster: These diseases are all transmitted by insects; various mosquito species for the lymphatic filariasis, and black flies that breed in rivers and streams in the case of onchocerciasis. Lymphatic parasites cause longterm chronic infections with about one third of infected people showing clear clinical disease. The pathology results mostly from inflammatory responses to dead and dying worms that leads to lymph vessel damage and dysfunction, and eventually gross swelling of the limbs and genitals, accounting for the more common name for this disease, which is elephantiasis. Jeremy Foster: In the case of onchocerciasis, adult worms live in subcutaneous layers under the skin and also in deeper tissues, where they form nodules that can be seen and felt. Larval worms migrate away from these nodules into the skin, causing inflammatory-mediated skin disease and intense itching. Quite frequently, the larvae also migrate into the eye where they cause visual impairment and blindness, accounting for the more common name of this disease, which is River Blindness. Jeremy Foster: We believe that by fully uncovering the biology of these worms, especially their metabolic capabilities, we'll be able to find areas of their biology that are not shared with humans, and that might then be developed as candidate drug targets for new treatments. Additionally, the genomes allow us to identify species-specific sequences for development of sensitive diagnostic assays. Jeremy Foster: The diseases are treatable, but we really only have three drugs available. The drugs kill larval worms, but don't usually fully reverse the extreme symptoms. An exciting recent development has been the finding that antibiotics that target a bacterium which lives within the worm tissues and is essential for the worm's survival, can also be used for to successfully treat the diseases. Jeremy Foster: Firstly, the available drugs have little activity against the long-lived adult worms, being mostly active against just the larval forms. This means that control is by repeated rounds of drug administration that need to be continued throughout the life span of the adult worms to prevent the presence of larval forms in the circulation or in the skin, thereby stopping transmission to other people. Additionally, there are recent reports that in some situations, these drugs are not working as well as they used to, suggesting that the problem with resistance may be just around the corner. Also, using some of these drugs in patients who are co-infected with other parasites can cause serious adverse events, even death, so this is limited for use in areas where the different species co-exist. Jeremy Foster: Fortunately, the new antibiotic treatments hold promise as they target both larval and adult worms, can be used in people co-infected with different parasite species, and it can be given as a single short course of antibiotic. Tilde Carlow: For diagnosis of filariasis in humans, the way it's normally done is by collecting blood or skin from people and looking for the presence of baby worms. These are microfilaria which circulate in the blood or skin. In the case of the bloodborne microfilaria, you will find that these microfilaria reach peak numbers in the circulation between 10 p.m. and 2 a.m. in the morning, so ideally this is the time when one would go out and actually collect blood from people, so you can imagine this in not a very popular technique. Tilde Carlow: Once you have blood or skin from people, you look using a microscope for the presence of these small baby worms. It's actually very challenging to find these worms. It's very difficult to distinguish one type of worm from another, so there's great need for improved simpler methods that can be performed in the field with actually very few resources. Tilde Carlow: There are various immunoassays which are available as an alternative to microscopy, however most of these actually suffer from problems; problems from cross-reactivity, problems with lack of sensitivity. PCR, or the polymerase chain reaction, is much more sensitive than the immunoassays and does not suffer from cross-reactivity issues. However, these assays tend to be quite difficult to perform, require a good amount of expertise, as well as sophisticated equipment. Tilde Carlow: LAMP is an alternative to PCR for the amplification of parasite DNA in blood or skin. It's a simple method that can be performed isothermally in one step, and all you need is a water bath or a water heater, and does not require the different cycles of temperature which is required for PCR. Tilde Carlow: Colorimetric LAMP is a really nice option, whereby you can actually determine if the parasite is present, or not, just by simple color change in the tube. Tilde Carlow: Colorimetric LAMP can be used to detect infection in both humans and the insect vectors. It can be used to distinguish people who may respond well to treatment, versus those who may react badly to treatment. We can use the test to monitor infection in vectors to determine which areas that populations would be at risk of disease. Tilde Carlow: The next steps for colorimetric LAMP assays are to transfer them to our colleagues who are working in areas where these diseases are endemic, to use them to determine which individuals would benefit most from treatment, and also to use them to monitor the insect populations to determine which areas are now at risk of disease. Also, they can be used to determine when is the best time to actually start the mass drug administration campaigns, which areas, and when is an appropriate time to actually stop these types of treatments. Tilde Carlow: After mosquitoes, ticks are actually the second most important vector of infectious diseases, and they're responsible for a number of diseases actually world-wide. Locally, we have the deer tick, which is responsible for several really important diseases, including Lyme, Babesia, anaplasmosis. We have used the knowledge we have gained from our research on neglected tropical diseases and transferred that to the development of similar colorimetric LAMP-based assays for these various tick-borne diseases. Tilde Carlow: We hope that these assays will help to monitor the spread of these diseases, as well as eventually, hopefully, help in the control of these various tick-borne diseases which are actually spreading throughout the United States, as well as the rest of the world. Samuel Wandjii: I'm Professor Samuel Wandjii, Head of Department of Microbiology and Parasitology at the University of Buea in Cameroon. Samuel Wandjii: We have a large portfolio in filarial assay research that involve working both the human and the vectors, so we look at epidemiology in the human population. We look at the transmission at the level of the vector. We look at the diagnosis in human, and we look at experimental model in small animal to see if we can develop a model that can be used for drug screening. Samuel Wandjii: For the detection of filarial infections, we use both microscopy and molecular biology techniques. Within the molecular biology techniques, we use qPCR and LAMP assays. LAMP assay is definitely more advantageous because not only is more sensitive, it's more specific, it's less time-consuming. LAMP assay enable us to detect infection both in human and in the vectors. Deana Martin: Tilde, thanks so much for joining me today. Tilde Carlow: You're welcome. Deana Martin: I find the whole topic really interesting, and the research that you're doing is really great. But where can people go to learn more? Tilde Carlow: You can find more on our website at NEB.com, looking at the research department where our publications are listed, as well as on PubMed. Deana Martin: Okay, great. Thanks so much for joining us today, and if you have any suggestions for future episodes, please let us know.
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