Author: Moorhouse Anna
Institution: English and Cell and Molecular Biology
Date: May 2005
Which disease causes 43,000 deaths per year worldwide, threatens 100 million at-risk people in twenty-one countries, and is considered the fourth leading cause of mortality in Latin America?
Chagas disease, which is also called American trypanosomiasis, is an infection caused by the parasite Trypanosoma cruzi. Though its causes have been clinically known since its discovery by Dr. Carlos Chagas in 1909, very few people outside of Latin America have even heard of it.
In an article published in the July issue of Lancet, Dr. David H. Molyneux, a professor at the Liverpool School of Tropical Medicine, in the United Kingdom, writes that Chagas' disease is one of many "neglected diseases" found around the world.
"The Millennium Development Goals and a plethora of initiatives have focused on the control of HIV/AIDS, tuberculosis, and malaria," says Dr. Molyneux. "However, a large group of diseases has been confined to the other diseases' category by health policy makers and politicians. Despite the availability of cost-effective, stable, and successful control or elimination interventions, large numbers of the world's poorest people remain afflicted or are at risk from this group of diseases."
Kissing Bugs with Bite
Chagas disease is usually found in countries throughout Central and South America; however, cases have been found as far north as Texas, Oklahoma, and California. Since it is a vector-borne disease, the parasite must hitch a ride with an insect to get from one host to another. T. cruzi's preferred method of travel is the kissing bug, also known as triatomes.
Transmission is straightforward. When a kissing bug lands on an animal or person already infected with T. cruzi, it sucks up the parasite during its blood meal; characteristically "kissing" its host's eyelids, ears, or lips. The bug can then fly off and land on another animal or person and defecate on that host's skin. The parasite enters the new host's body through their eyes, mouth or any open cuts. The parasite can also be contracted through blood transfusions or eating uncooked food contaminated with kissing bug feces, though these routes are much more rare.
There are three stages of symptoms in the progress of the disease in humans. Just after infection, a small sore appears at the site of the bug bite where the parasite entered the body. If the parasite entered through the eye, then the patient's eyelid becomes swollen: an occurrence known as Romaña's Sign. After a few days, the lymph nodes may also begin to swell. During the acute phase, young children or immuno-compromised patients are especially susceptible to illness and death; however, most patients will go on to enter the next phase of the disease, known as the indeterminate stage, which is usually symptom-less and can last many months or years.
Adult Rhodnius prolixus taking a blood meal through human skin. The insect transmits the parasites which cause Chagas disease in feces that they deposit near the site of their bite. Scratching or rubbing by the person bitten can transfer the parasites into the body via the wound or other sites such as the eye. Credit: WHO/TDR/Stammers
The final, or chronic stage, can also last many years. Lesions appear on various organs of the body, including the heart, esophagus, colon or peripheral nervous system; the damage done to organs during this phase is irreversible and tends to weaken the body, sometimes fatally.
How the Genetically-Modified Insect Got its Genes
Research on Chagas' disease and other vector-borne diseases has taken many different tracks. Dr. Ravi Durvasula, assistant clinical professor at the Yale School of Public Health in Connecticut, has been developing one strategy using paratransgenetic kissing bugs.
Paratransgenetics is very much like the concept of genetically modified animals. Just as the genes of an animal are modified in a lab setting to produce new traits, bacteria can be modified to express new traits as well. In Durvasula's research, the kissing bugs themselves are not modified - instead, the bacteria that live within their guts are.
Since a kissing bug takes all its meals off vertebrate blood, which is admittedly a very limiting diet, the presence of bacteria in their digestive tracts ensures that the insects will get all the nutrients they need.
Trypanosoma cruzi in thin blood film (Leishmans stain) showing developing tryptomastigotes that have a free flagellum. Credit: WHO/TDR/Stammers
"[The bacteria] help process vitamins in the blood meal, completing the nutritional package for the insects," says Durvasula.
But, where do these bacteria come from and how do they find their way an insect gut? When the insects first hatch, they are essentially bacteria-free, Durvasula explains. They acquire their own supply of bacterial helpers through a process called coprophaging: the newborn insects probe the bacteria-infested feces of nearby adult insects and ingest what they need.
It was precisely this process, which inspired Durvasula to create "Cruziguard": a type of fake feces, in the form of a black paste which can be inoculated with modified bacteria. If placed on the walls of houses, where the insects like to land between bloodmeals, the bacteria will be taken up and a paratransgenetic kissing bug will be formed.
The genetically modified (GM) bacteria can be tailored so that any kissing bug who picks up a T. cruzi parasite will not become infective. With this is place, the parasite will lose its vehicle and eventually die out as it loses access to its hosts.
Different stages of triatomine insects, the vectors of Chagas disease. Credit: WHO/TDR
Recent debate has centered around the fact that releasing GM bacteria or other GM animals into the wild could have a number of unpleasant ecological consequences. The Biotech Bugs Conference in September in Washington, DC, was held for exactly this reason: to examine the science and public policy surrounding GM insects.
"It's picking up. There's definitely more interest in [GM insects] now," says Durvasula. "The discussion is not whether we can do it or not, but... how are you going to regulate this?"
When asked whether any GM insects or paratransgenetic insects have been released yet, his answer was very direct: "Emphatically, no. Field release may be associated with significant consequences which have to be studied and modeled under experimental conditions... No one has talked about releasing yet."
Releasing GM insects could result in horizontal gene transfer, which is the possibility that the modified bacteria could enter other insect species and create havoc with the ecosystems present.
Acute Chagas Disease in a young child. The eye sign of Romana is present. This is frequently seen in acute cases and is presumed to mark the point of entry of the parasite. Credit: WHO/TDR
Drugs from Bugs and Other Research
Other research into Chagas' disease has delved into the realm of immune proteins and antibiotics. Dr. Carl Lowenberger, an associate professor at Simon Fraser University in British Columbia, Canada, has been looking into the possibility of harnessing immune proteins from the vectors themselves to create antibiotics that can be used by humans. His lab studies the immune responses of both mosquitoes and kissing bugs toward a variety of different parasites.
"Every stage where [the parasites] contact host tissues, the insect has a chance to respond," says Lowenberger.
The intensity of the insect immune response depends on a lot of factors, including the ability of the insect to recognize the parasite as a foreign object. In the case of T. cruzi and its vector, the mode of infection works so that the parasite never leaves the insect gut. This is different than the parasite responsible for malaria, which will travel through mosquito tissues and to its final destination in the mosquito's salivary glands. Lowenberger suggests that T. cruzi's method of transmission developed because the parasite is susceptible to the immune proteins produced by its vector, and by staying in the gut region, it effectively stays out of reach.
If this hypothesis is true, then identifying and reproducing the right immune proteins could be the way to develop a drug that could combat the disease in humans. This idea has already met with success using other insects.
A health worker searches for traces of triatomine insects in a rural dwelling. Triatomine bugs are the vectors of Chagas disease. Credit: WHO/TDR/Filho
"There is one insect immune protein that is being developed right now against herpes and hepatitis," comments Lowenberger. "There is an insect anti-fungal also being exploited."
Neglected No More
We can see now how a disease that is relatively unknown to the general public has in fact been creating vast waves of controversy and attention within scientific spheres. The study of both GM insects and insect immune proteins has opened up a whole range of new avenues for scientific exploration and medical progress.
Chagas may still be a "neglected disease", but hopefully not for much longer, because, as Durvasula says, "The bar has been raised."
References/ Suggested Reading
Beard CB, Cordon-Rosales C, and RV Durvasula. (2002). Bacterial Symbionts of the Triatominae and Their Potential Use in Control of Chagas Disease Transmission. Annual Review of Entomology. 47:124-42.
Biotech Bugs: September 20-21, 2004, The George Washington University, Cafritz Conference Center, Washington, DC. "Archived Webcast." "Bugs in the System: Issues in the Science and Regulation of Genetically Modified Insects." A Report Prepared by the Pew Initiative on Food and Biotechnology. Released Jan 22, 2004. "Fact Sheet: Chagas Disease." CDC, Division of Parasitic Diseases.
Jonietz, E. (2004). Biotech Bugs Take Wing. Technology Review. 107(4):20.
Lopez L, Ursic R, Wolff M, and C Lowenberger. (2003). Identification of a member of the defensin family of insect immune peptides from Rhodnius prolixus, the vector of Chagas disease. Insect Biochemistry and Molecular Biology. 33:439-47.
Molyneux, DH. (2004). Neglected"diseases but unrecognised successes-- challenges and opportunities for infectious disease control. Lancet. 363(9431):380.
Powell, K. (2004). Biologists try to work out bugs in GM insect technology. Nature Medicine. 10(3):216.