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Trypanosomes are a large group of unicellular protozoan parasites infecting a wide range of mammalian hosts, including humans and domestic animals. Most of these parasites are transmitted by insects, and some species can cause severe diseases in both humans and animals. In Africa, trypanosomes inflict a heavy socioeconomic burden due to their detrimental effect on human welfare and agricultural development.
The species Trypanosoma brucei, which is transmitted by tsetse flies, is responsible for epidemics of the fatal human disease sleeping sickness (human African trypanosomiasis) in Sub-Saharan Africa. Sleeping sickness occurs in 36 African countries and causes the second highest mortality rate after HIV/AIDS in some parts of the continent. Most of the affected people depend on agriculture, fishing and hunting and live in rural area with limited access to health services. Wild and domestic animals can harbor the human parasite and form a secondary reservoir of infection for tsetse flies under certain conditions. However, the largest economical impact is probably made by trypanosome species affecting cattle by reducing milk and meat production. Animal African trypanosomiasis is also known by the common name Nagana.
Trypanosome life cycle
Infection occurs when an infected tsetse fly bites a human or animal and injects the parasite into the skin. The initially injected short and stumpy form of the parasite enters the lymphatic system and passes into the bloodstream of the mammalian host where it grows into a long and slender form and multiplies. In the bloodsteam, the parasites travel to other body fluids, including the lymph and spinal fluid, and are even able to pass the blood-brain barrier.
The parasite can only complete its life cycle in the tsetse fly. Tsetse flies become infected when they take up the parasites during a blood meal. The parasites then enter the midgut of the fly where they differentiate and eventually travel to the salivary glands of the fly from where they get injected into the next mammalian host with the saliva on biting.
Antigenic variation is the process of altering the surface of a pathogen to escape the host immune response. African trypanosomes have evolved an incomparable mastery of this process. By regularly changing the variant protein on their cell surface they disguise themselves from the adaptive host immunity that has evolved to destroy them.
This elegant interplay between host and pathogen is rooted fundamental molecular biology and genetic processes that are the research focus of the Hovel-Miner Lab. We seek to identify new factors and mechanisms associated with antigenic variation in order to uncover basic biology phenomena and identify potential drug targets toward the future treatment of neglected tropical diseases.
Genomic organization and DNA instability in antigenic variation
African trypanosomes exemplify the process of antigenic variation through their ability to change their gene expression from one member of a large family of hypervariable genes to the next. A key genetic event in this process (termed duplicative gene conversion) is an unbalanced chromosomal translocation akin to those that cause genetic disorders and cancers in human genomes. It is now clear that these genetic events in trypanosomes can be potentiated by DNA damage and their outcomes are affected by the genomic locations of the hypervariable genes. This has lead to a widely accepted model in which random DNA break formation results in similarly random antigen gene selection. A central goal of the Hovel-Miner lab is to test the hypothesis that antigenic variation arises through random events. By using a combination of molecular genetics, biochemistry, next-generation sequencing, and mathematical modeling we seek to determine the extent to which the process of antigenic variation is stochastic as opposed to directed by external factors. Refining our understanding of the mechanisms controlling antigenic variation will result in the identification of druggable targets against African trypanosomiasis as well as furthering our understanding of the fundamental genetic processes that result in chromosomal translocations.
Production and application of a T. brucei whole genome overexpression library
Production of a T. brucei whole genome overexpression library is currently underway in a collaboration between Drs. Hee-Sook Kim, Danae Schulz (both of the Papavasilou lab), and the members of the Hovel-Miner lab. We anticipate that this genetic tool will be available to the African trypanosome research community by 2017. The Hovel-Miner lab is contributing the completion and validation of the library and will apply the library to the identification of novel factors associated with both the basic biology and pathogenesis of T. brucei.