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A kiss to be avoided

Kissing bug. Although the name sounds friendly, the insect is anything but. Officially known as Rhodnius prolixus, this small South American insect and its blood-sucking ways are the focus of much attention from University of Florida chemistry professor Adrian Roitberg and his colleagues, Marcelo A. Martí, Mariano C. Gonzalez Lebrero, and Dario A. Estrin, at the University of Buenos Aires in Argentina. Why? When the kissing bug puckers up, it often leaves behind a calling card for future disease and possibly even death.

Spreading disease

The kissing bug is associated with the spread of Chagas (pronounced SHA-gus) disease.

The disease is caused by the parasite Trypanosoma cruzi; experts estimate 16 million people in Latin America are infected. The disease is beginning to spread to North America as people migrate, but so far only six cases have been reported in the United States.

The bugs acquire the parasite by biting an infected mammal or person; once infected, the bugs pass the parasite in their feces. During the day, kissing bugs tend to remain hidden in vegetation or in cracks in the floors and walls of houses. After dark, when the homes’ inhabitants are sleeping, the bugs emerge and crawl on them, often biting and sucking blood on their faces near their lips (thus the name kissing bug) and then defecating. The sleeping person may then unintentionally scratch or rub the insect feces into the bite site, or rub the feces into the eyes or mouth, thus putting the parasite into the body. Most people with Chagas disease do not know they are infected as symptoms may be non-existent or mimic other common illnesses. Without treatment the infection is lifelong and sometimes fatal.

How it happens

Most blood-sucking insects possess salivary proteins which, upon injection into the victim’s tissue, help the insects improve their feeding. One group of these salivary proteins, the nitrophorins (NPs), takes advantage of the vasodilator properties of nitric oxide (NO) to perform their task. (NO is a small reactive molecule that is thought to be produced by the heme protein NO synthase. NO participates in a variety of physiological functions like regulating blood pressure by dilating blood vessels, neurotransmission, and immune response.) Because the kissing bug spreads Chagas disease, the bug’s NPs are one of the most studied.

Pathways to Prevention

Pioneering work in the laboratories of William R. Montfort and F. Ann Walker at the University of Arizona cloned four NPs from the kissing bug and characterized them spectroscopically and kinetically, and, for three of them, structurally. Results showed that all function by binding NO in a pH sensitive manner. The NO is synthesized in the salivary glands where it binds tightly to NP at a low pH of around 5. Once NPs are injected in the victim’s tissue (which has a pH of approximately 7.4), a conformational change occurs which allows NO to be released.

Roitberg’s team specializes in the study of conformational changes in large proteins such as the one described above. The team used NCSA’s machines to study the NO release mechanism of one of their clones, NP4, at a molecular level. Molecular dynamics simulations and hybrid mechanical/molecular simulations revealed that in contrast to most heme proteins that control ligand affinity by modulating the bond strength to the iron, NP4 has evolved a cage mechanism that traps the NO at low pH (Figures 1 and 2) and releases it upon the cage opening when the pH rises (Figure 3). To their knowledge, this is the first case where the mechanism of a heme protein ligand affinity regulation directly linked to a conformational change has been explained at molecular detail using computer simulations. Their work was published in the Journal of the American Chemical Society. Understanding conformational regulation of ligand affinity is important since it may play a crucial role in regulating heme protein function and, ultimately, lead to better prevention of Chagas disease.

This work was supported by the National Science Foundation, the National Institutes of Health, Argentina’s National Agency of Scientific and Technological Promotion, the National Scientific and Technical Research Council of Argentina, and the University of Buenos Aires.

Team members
Adrian Roitberg
Marcelo A. Martí
Mariano C. Gonzalez Lebrero
Dario A. Estrin

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