Mammalian African trypanosome VSG coat enhances tsetse’s vector competence

Abstract

Tsetse flies are biological vectors of African trypanosomes, the protozoan parasites responsible for causing human and animal trypanosomiases across sub-Saharan Africa. Currently, no vaccines are available for disease prevention due to antigenic variation of the Variant Surface Glycoproteins (VSG) that coat parasites while they reside within mammalian hosts. As a result, interference with parasite development in the tsetse vector is being explored to reduce disease transmission. A major bottleneck to infection occurs as parasites attempt to colonize tsetse's midgut. One critical factor influencing this bottleneck is the fly's peritrophic matrix (PM), a semipermeable, chitinous barrier that lines the midgut. The mechanisms that enable trypanosomes to cross this barrier are currently unknown. Here, we determined that as parasites enter the tsetse's gut, VSG molecules released from trypanosomes are internalized by cells of the cardiathe tissue responsible for producing the PM. VSG internalization results in decreased expression of a tsetse microRNA (mir-275) and interferes with the Wnt-signaling pathway and the Iroquois/IRX transcription factor family. This interference reduces the function of the PM barrier and promotes parasite colonization of the gut early in the infection process. Manipulation of the insect midgut homeostasis by the mammalian parasite coat proteins is a novel function and indicates that VSG serves a dual role in trypanosome biology-that of facilitating transmission through its mammalian host and insect vector. We detail critical steps in the course of trypanosome infection establishment that can serve as novel targets to reduce the tsetse's vector competence and disease transmission.tsetse | trypanosome | VSG | peritrophic matrix | vector competence

VSG overcomes an early barrier to survival of African trypanosomes in tsetse flies

“…Importantly, the mechanism by which trypanosomes traverse the PM to enable gut colonization in susceptible tsetse had been unknown until now. In PNAS, Aksoy et al (14) share their discovery of how trypanosomes disrupt the PM of the tsetse fly and implicate the variant surface glycoprotein (VSG) of the blood stream form (BSF)-famed for its critical part in escaping the immune system of the mammalian host (15)-in its disruption, revealing a dual role for VSG in the life cycle of trypanosomes.…”

“…To continue their development in the vector, procyclic trypanosomes need to escape into the ectoperitrophic space and colonize the gut. In PNAS, Aksoy et al (14) demonstrate that VSG molecules, abundantly present in the gut lumen as a by-product of lysed slender forms or after shedding by stumpy forms, are not squandered but are used to disrupt the structural and functional integrity of the PM, ensuring continuation of the parasite's life cycle (Fig. 1).…”

“…Aksoy et al found that trypanosomes reduced the expression of peritrophins, structural proteins that bind chitin, and digestive enzymes, both associated with PM formation in insects (16)(17)(18). Then Aksoy et al (14) used the entomopathogenic Serratia marcescens in an elegant microbial assay to assess the PM integrity in tsetse flies. If Serratia is protected by a functional PM, it multiplies and eventually kills the flies.…”

“…Moreover, miR-275 has been associated with gut function and digestion in mosquitoes (19). Upon neutralization of the function of miR-275 using an antisense oligonucleotide (ant-275), the expression of the Wnt signaling pathway and the Iroquois/IRX-family of transcription factors-established by Aksoy et al (14) as cardia-specific regulatory molecules in tsetse flies that govern the synthesis of the PM-as well as the expression of peritrophins, was inhibited in cardia tissue. Additionally, blood digestion and diuresis were delayed.…”

“…To address this important question, Aksoy et al (14) used the microbial assay with Serratia to test the most abundant surface molecule of BSF, VSG. The authors show that provision of soluble VSG (sVSG) in the bloodmeal promoted survival of tsetse flies, similar to BSF extracts.…”