UCLA

Endemic to sub-Saharan African, African trypanosomes are devastating protozoan pathogens that present a significant medical and economic burden. Transmitted by the bite of an infected tsetse fly, Trypanosoma brucei causes Human African Trypanosomiasis (HAT) and a related diseased called Nagana in animals. In both its tsetse fly and mammalian hosts, T. brucei closely interacts with host tissue environments. Parasites must traverse a number of tissue barriers and enact specific developmental changes to complete their transmission cycle. How T. brucei senses and responds to signals from its extracellular environment, however, is not well-understood. When tsetse fly midgut stage T. brucei is cultivated on a surface in vitro, they coordinate their movements to engage in a group behavior termed social motility (SoMo), an ability that requires sensing both surfaces and other cells then engaging signal transduction cascades to respond. Thus, investigating the mechanisms that control social motility may elucidate T. brucei signaling systems that are important for their transmission through their hosts in vivo. In vitro studies have demonstrated the importance of cAMP signaling in the regulation of social motility.

This dissertation describes the use of molecular and systems-level analyses to investigate the regulation of social motility and signaling systems in T. brucei. Through labeling of tsetse fly tissues in conjunction with infection of fluorescently labeled T. brucei, we show that phosphodiesterase B1 (PDEB1) knockout parasites, which are unable to engage in SoMo, are blocked in a specific step in their fly transmission cycle, demonstrating the requirement for T. brucei cAMP signaling in vivo. To identify novel regulators of social motility that may or may not act in the cAMP pathway, two different RNA sequencing experiments were performed, leading to the identification of three novel candidate genes as potential social motility regulators. Additionally, we show that when engaged in SoMo, T. brucei exhibits positive chemotaxis toward a neighboring E. coli colony. Further characterization of T. brucei signaling systems will provide greater insight into how these deadly pathogens navigate through their hosts, potentially leading to new treatments and transmission-blocking agents.