AMHERST, Mass. - The Bill and Melinda Gates Foundation recently announced a three-year, $478,000 grant to Samuel Black, professor of veterinary and animal sciences at the University of Massachusetts Amherst, to work with an international team developing a vaccine to control and cure trypanosomiasis, a fatal disease of cattle in sub-Saharan Africa and a major obstacle to raising livestock there.
As an expert in identifying molecular interactions between mammalian hosts and African trypanosomes that suppress immune system responses and cause pathology, Black will study the mechanism and specificity of vaccine-induced protection against trypanosomiasis in mice and cattle. He says, "By understanding how the vaccine works with the immune system in cattle, we can increase its effectiveness and direct it in a more targeted way. This work should allow us to improve the vaccine by enhancing aspects of the animals' immune response."
Black explains that Animal African Trypanosomiasis (AAT), also known as nagana, is endemic in 36 countries in sub-Saharan Africa and caused by three species of trypanosomes, Trypanosoma brucei, T. congolense and T. vivax. These protozoan parasites are transmitted to mammals in the saliva of biting tsetse flies and multiply in the blood plasma and tissues of mammal hosts.
In the mammal host each trypanosome is sheathed in a protein coat known as variable surface glycoprotein (VSG), which stimulates potent antibody and inflammatory responses. However, these responses do not completely eliminate parasites from the blood and tissues, because trypanosomes infrequently change their expressed VSG coat to a new and distinct form, he adds.
This identity-changing trick allows some parasites in each parasitemic wave, and in tissues, to escape being killed by the host's immune response. Surviving parasites then seed the next wave, resulting in infections characterized by repeating waves of parasites in the blood, months-long bouts of fever and weakness punctuated by brief remissions. Trypanosomiasis results in anemia, weight loss and a drop in productivity and fertility in infected cattle and can be fatal.
Black points out that mammals such as the Cape buffalo, eland and rhinoceros that evolved over eons alongside African trypanosome organisms do get infected with the parasites, but unlike susceptible mammals such as cattle and people, their immune systems remain fully functional throughout infection, allowing them to control parasitemia and prevent debilitating disease.
To scientists trying to use this chink in the parasite's armor, it was not at all clear how to reprogram the immune systems of trypanosomiasis-susceptible hosts to similarly control trypanosomes and resist its pathology. However, John Mansfield, professor of bacteriology at University of Wisconsin-Madison and the lead investigator for the Gates Foundation grant, has recently discovered how to do this, Black explains.
Despite the incredible diversity among trypanosome surface protein coats, VSGs share a conserved stretch of amino acids located near the parasite's plasma membrane. Mansfield discovered that naïve infected mice do not mount an immune response to this peptide, but mice that had been immunized with recombinant conserved VSG peptide mounted a strong peptide specific immune response, which was boosted upon trypanosome infection.
Black adds, "Importantly, this immunization increased the infected host's ability to control T. brucei in the tissues and bloodstream and greatly decreased the severity of trypanosomiasis-induced pathology." A similar response in cattle would protect against animal African trypanosomiasis and thus greatly increase the productivity of integrated agricultural systems in sub-Saharan Africa by removing a major constrain to food security in that region, he adds.
The Gates Foundation funding will support translating Mansfield's finding into a vaccine against AAT. Other researchers on the team are at the University of Wisconsin-Madison, the Free University of Brussels, Makerere University in Uganda and the University of Edinburgh. Each will take a specific role. The Mansfield group will develop a cohort of T. brucei conserved VSG peptides that maximally protect mice and cattle against T. brucei-induced trypanosomiasis.
Another group will concentrate on identifying conserved peptide components of T. congolense VSG coats. Using lab and field isolates of these parasites, the Black laboratory together with a group in Edinburgh University will determine whether immunization with conserved trypanosome plasma membrane proteins other than VSG peptides, or co-immunization with conserved VSG peptides, will have an impact on disease control. Finally, the Black laboratory will investigate the mechanism of vaccine efficacy as a step towards optimizing this.
Black says the team will test the hypothesis that "immunization of cattle and other mammals with a combination of several conserved VSG and plasma membrane peptides will prime them to resist trypanosomiasis pathology, to mount more efficient protective immune responses and eventually to self cure and resist reinfection."