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Single-cell RNA sequencing of Trypanosoma brucei from tsetse salivary glands unveils metacyclogenesis and identifies potential transmission blocking antigens

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Significance African trypanosomes, Trypanosoma brucei spp., are transmitted by the bite of infected tsetse flies. Mammalian vaccines are not available, and diagnosis and treatment remain difficult in the affected remote… Click to show full abstract

Significance African trypanosomes, Trypanosoma brucei spp., are transmitted by the bite of infected tsetse flies. Mammalian vaccines are not available, and diagnosis and treatment remain difficult in the affected remote areas. The transcriptomic analysis of individual parasites from infected tsetse salivary glands provides insight into the developmental processes that give rise to infective metacyclic parasites transmitted to the host bite site. We describe proteins associated with the different parasite developmental stages in salivary glands and specifically highlight a family of nonvariant surface proteins associated with metacyclic parasites. Immunization with one member of this family reduced parasitemia early in the infection in mice, promising to be a potential candidate antigen for a transmission blocking vaccine approach. Tsetse-transmitted African trypanosomes must develop into mammalian-infectious metacyclic cells in the fly’s salivary glands (SGs) before transmission to a new host. The molecular mechanisms that underlie this developmental process, known as metacyclogenesis, are poorly understood. Blocking the few metacyclic parasites deposited in saliva from further development in the mammal could prevent disease. To obtain an in-depth perspective of metacyclogenesis, we performed single-cell RNA sequencing (scRNA-seq) from a pool of 2,045 parasites collected from infected tsetse SGs. Our data revealed three major cell clusters that represent the epimastigote, and pre- and mature metacyclic trypanosome developmental stages. Individual cell level data also confirm that the metacyclic pool is diverse, and that each parasite expresses only one of the unique metacyclic variant surface glycoprotein (mVSG) coat protein transcripts identified. Further clustering of cells revealed a dynamic transcriptomic and metabolic landscape reflective of a developmental program leading to infectious metacyclic forms preadapted to survive in the mammalian host environment. We describe the expression profile of proteins that regulate gene expression and that potentially play a role in metacyclogenesis. We also report on a family of nonvariant surface proteins (Fam10) and demonstrate surface localization of one member (named SGM1.7) on mature metacyclic parasites. Vaccination of mice with recombinant SGM1.7 reduced parasitemia early in the infection. Future studies are warranted to investigate Fam10 family proteins as potential trypanosome transmission blocking vaccine antigens. Our experimental approach is translationally relevant for developing strategies to prevent other insect saliva-transmitted parasites from infecting and causing disease in mammalian hosts.

Keywords: metacyclogenesis; tsetse; transmission blocking; cell; salivary glands

Journal Title: Proceedings of the National Academy of Sciences of the United States of America
Year Published: 2020

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