Structural similarities between the metacyclic and bloodstream form variant surface glycoproteins of the African trypanosome

During infection of mammalian hosts, African trypanosomes thwart immunity using antigenic variation of the dense Variant Surface Glycoprotein (VSG) coat, accessing a large repertoire of several thousand genes and pseudogenes, and switching to antigenically distinct copies. The parasite is transferred to mammalian hosts by the tsetse fly. In the salivary glands of the fly, the pathogen adopts the metacyclic form and expresses a limited repertoire of VSG genes specific to that developmental stage. It has remained unknown whether the metacyclic VSGs possess distinct properties associated with this particular and discrete phase of the parasite life cycle. We present here three novel metacyclic form VSG N-terminal domain crystal structures (mVSG397, mVSG531, and mVSG1954) and show that they mirror closely in architecture, oligomerization, and surface diversity the known classes of bloodstream form VSGs. These data suggest that the mVSGs are unlikely to be a specialized subclass of VSG proteins, and thus could be poor candidates as the major components of prophylactic vaccines against trypanosomiasis. Author summaryThe African trypanosome is a single-celled parasite causing African Sleeping Sickness in humans and related diseases in animals. It has a unique protein coat made up mostly of a single protein, called the Variant Surface Glycoprotein, or VSG. The African trypanosome possesses several thousand different VSG genes. As the immune system of an infected host learns to recognize one coat protein and kill the trypanosomes, the parasite switches to a different VSG protein that is not recognized by the immune system. This allows the parasite to keep thriving in the host as this process repeats. This paper presents molecular images of a subset of VSG proteins that are on the surface of the organism when it is transferred to hosts by the bite of the tsetse fly-the first step in infection. We show that these so-called metacyclic VSGs are neither special nor unique compared to those VSGs that take over in the bloodstream during the course of infection. These results clarify the nature of these first VSG coats the host is exposed to and have important implications for trypanosome infection and vaccine development.