Immunodominant surface epitopes power immune evasion in the African trypanosome

Abstract

The African trypanosome survives the immune response of its mammalian host by antigenic variation of its major surface antigen (the Variable Surface Glycoprotein, or VSG). Here we describe the antibody repertoires elicited by different VSGs. We show that the repertoires are highly restricted, directed predominantly to epitopes on the surface of the VSGs. They are also highly discriminatory: minor alterations within these exposed epitopes confer antigenically-distinct properties to these VSGs and elicit different repertoires. We propose that the patterned and repetitive nature of the VSG coat focuses host immunity to a restricted set of immunodominant epitopes per VSG, eliciting a highly stereotyped response, minimizing cross reactivity between different VSGs and facilitating prolonged immune evasion through epitope variation.

An Epitope-Focused Trypanosome-Derived Vaccine Platform Elicits High-Affinity Antibodies and Immunity Against Fentanyl Effects

“…Figure 4D). Notably, these pairs are also not represented in naïve mouse BCR repertoires or repertoires from mice infected with live T. brucei (see companion paper (Gkeka et al, 2021)). In addition, these BCRs had very similar or even identical heavy and light chain CDR3 regions and shared several SHMs, suggesting that these cells are clonally related (Table 1).…”

“…During infection, the pathogen produces successive populations of “switched” cells that express different VSGs on the surface. VSG proteins with unique and immunodominant epitopes generate antibody repertoires that are highly focused on a given VSG (see companion paper (Gkeka et al ., 2021)), but are unlikely to recognize switched cells. The host immune system thus invests considerable resources into a given VSG, efficiently clears parasites expressing it, only to find itself naïve to switched cells with different VSGs.…”

“…Furthermore, antibody responses to VSG arrays are remarkably restricted in variable gene usage through an "epitope-focusing" effect that is potentially unique to this organism (see companion paper (Gkeka et al, 2021)).…”

“…This repetitive array facilitates epitope presentation to the immune system, driving both T-dependent and T-independent protective antibody responses (Reinitz and Mansfield, 1990; Verdi et al ., 2020). Furthermore, antibody responses to VSG arrays are remarkably restricted in variable gene usage through an “epitope-focusing” effect that is potentially unique to this organism (see companion paper (Gkeka et al ., 2021)).…”

Structural and Immunological Similarities Between the Metacyclic and Bloodstream Form Variant Surface Glycoproteins of the African Trypanosome

“…Using intact protein mass spectrometry, the absence of such a sugar in the crystals was confirmed (Supplementary Fig 5). However, because VSG3 sugars have been shown to be heterogeneous (16) and labile (49), it cannot be ruled out that carbohydrate modifications were lost during the process of purification, crystallization, and/or preparation for mass spectrometry.…”