How do African trypanosomes evade the complement system?

African trypanosomes are extracellular parasites that cause sleeping sickness in humans and nagana in livestock, leading to major health and economic burdens across sub-Saharan Africa. These parasites persist in the bloodstream by evading antibody responses through antigenic variation of a dense variable surface glycoprotein (VSG) coat. However, their extracellular lifestyle also exposes them to the complement system – a potent immune cascade that marks pathogens for destruction. Despite this, bloodstream-form trypanosomes resist complement-mediated killing in culture, suggesting their surface has evolved mechanisms to actively repel complement attack. I will define the molecular basis of complement evasion in African trypanosomes by identifying parasite surface proteins that interact with complement components, elucidating how these proteins inhibit complement activation, and determining their roles in immune evasion and parasite virulence. To achieve this, I will integrate structural biology, molecular parasitology, and murine models. Comparative studies across African trypanosome species will uncover species-specific immune resistance mechanisms. Furthermore, I will investigate whether disrupting complement evasion pathways enhances immune clearance and informs the development of novel vaccine strategies. By revealing how parasites neutralise a fundamental component of the immune system, this work will uncover new principles of host–pathogen interactions and inform novel complement-based therapeutic strategies across infectious diseases.