Cannon fodder for phagocytic cells
In the subsaharan Africa, blood-sucking tsetse flies transmit the trypanosomes that cause sleeping sickness, a neglected tropical disease.There is no vaccine, and the few effective drugs have nasty side-effects. By rapidly altering their surface antigens – the proteins recognized by the cells of the adaptive immune system – the pathogens stay one step ahead of the host’s defenses. This capacity for antigenic variation first drew the organisms to the attention of molecular biologists.
But how do trypanosomes get over the first hurdle, the host’s innate immune system? An international collaboration between teams led by LMU’s Professor Michael Boshart and his Belgian colleague Professor Etienne Payshas now shown that the parasites show amazingly altruistic behavior: The early invaders serve as cannon fodder. They are ingested and degraded by phagocytic cells, but in the process they manage to disable the innate immune response, clearing the way for the parasites that follow.
The project set out to define the role of receptor-like molecules called adenylatecyclases, which are exposed on the trypanosome cell surface and synthesize the intracellular messenger molecule cAMP. Strikingly, in these parasites, they are encoded by an unexpectedly large family of over 80 different genes. “We wanted to understand the function and surprising diversity of this gene family, and use it as a model for the evolution of molecular signaling systems in general,” says Boshart.
To the researchers astonishment, adenylatecyclases turned out to play a central role in the establishment and progression of infection in a mouse model system. They do so via a mechanism that was previously unknown in pathogenic protozoa. The invaders in the first wave are recognized, ingested and ultimately destroyed by phagocytic cells in the liver. During this process, however, the adenylatecyclases in the parasite membrane are activated.
Altruism in unicellular organisms
As a result, cAMPis released into the phagocyte cytoplasm, activating a signal protein that inhibits production of TNFα, an immune modulator which is essential for clearance of the parasitesfrom the circulation. “In the initial phase of infection some trypanosomes sacrifice themselves to repress the host’s innate immune response, which depends on phagocyte function,” says Boshart. “This altruistic behavior allows the rest to establish a productive infection.”
This is only one of the pathogen’s tricks. It also actively removes bound antibodies from its surface, as an earlier study involving the LMU group showed. The latest project was supported by the Belgian Ministry for Science (BELSPO) as part of the “Pôle d'Attraction Interuniversitaire” program. The productive cooperation will be continued within this research cluster. “Such a central mechanism in the parasite could eventually provide a point of attack for therapeutic agents,” Boshart suggests. (Science online, 14 June 2012) suwe / PH