Immunodominant surface epitopes power immune evasion in the African trypanosome

A structural classification of the variant surface glycoproteins of the African trypanosome

“…However, unlike VSG3, the structure of VSG1954 showed no evidence of O -linked glycans, despite possessing a conserved glycosylation sequence [ 16 , 17 ]. Whether this absence is due to unknown regulatory processes yet to be identified, to the sugar being labile and removed during purification/crystallization as has been observed for VSG3 [ 45 ], or to a difference between metacyclic and bloodstream VSGs, was unclear. Therefore, pursuing additional studies of related VSGs could aid in determining how many VSGs are so modified.…”

“…A mechanistic understanding of antigenic variation in the African trypanosome will require a complicated mixture of knowledge regarding the epitope space exposed to the host immune system and how the repertoires of antigen recognition in immune cells respond to this chemical space in the dynamic process of coat switching and the adaptive immune response [ 45 ]. At the most basic level, such an understanding necessitates a thorough knowledge of VSG antigenic diversity.…”

“…In contrast, in class B the bottom lobe residues are present at the N-terminal portion of the NTD sequence between the amino acids that form the first and second helices of the bundle (S6 Fig) . Further cementing this broad division into two main super-families are two observations. The first is that all class A VSGs studied to-date are found as dimers in solution and in protein crystals (the latter either as non-crystallographic dimers in the asymmetric unit or as monomers in the asymmetric unit where a crystallographic two-fold symmetry produces the dimer, [18,21,45]), whereas all studied class B VSGs are characterized by the same trimeric arrangement in the crystals (either through crystallographic or non-crystallographic symmetry, with monomers or trimers in the asymmetric unit, respectively), with biochemical evidence of monomer to trimer transitions based on protein concentration [24]. The second fact is that many of the class B VSGs are post-translationally modified by O-linked carbohydrates, whereas none of the class A VSGs have been found so modified.…”

Rare VariableM. tuberculosisAntigens induce predominant Th17 responses in human infection

“…Unlike other infectious pathogens in which the targets of protective immunity undergo antigenic variation to escape immune recognition through diversifying evolutionary selection (Crawford et al 2009; Wang et al 2010; Rimmelzwaan et al 2009; Croucher et al 2011; Seifert et al 1994; Gkeka et al 2023; Schneider et al 2023; Chew et al 2022), T cell epitopes in the commonly-studied immunodominant Mtb antigens are highly conserved(Comas et al 2010; Coscolla et al 2015). In this study, we characterized T cells from people protected from progressive/active TB that recognize the rare exceptions, that is, antigens with T cell epitopes that exhibit evidence of diversifying evolutionary selection (variable T cell epitopes) (Coscolla et al 2015), the RVMA.…”

“…A characteristic feature of host-pathogen relationships is the coevolutionary arms race in which antigens that induce host-protective (and therefore pathogen-detrimental) immune responses are driven to escape recognition through diversifying evolutionary selection and antigenic variation. Antigenic variation to escape immune recognition has been observed for diverse pathogens, including viruses like HIV (Crawford et al 2009), HCV (Wang et al 2010) and influenza (Rimmelzwaan et al 2009); bacteria including Streptococcus pneumoniae (Croucher et al 2011) and Neisseria gonorrhoeae (Seifert et al 1994); parasites such as Trypanosoma brucei (Gkeka et al 2023) and Plasmodium falciparum (Schneider et al 2023; Chew et al 2022); and even tumor cells (Matsushita et al 2012; Marty Pyke et al 2018; Marty et al 2017; Hoyos et al 2022). In an earlier study, we hypothesized that antigenic targets of protective immunity to Mtb could be discovered by studying evolutionary selection pressure through T cell epitope sequence variation in phylogeographically diverse clinical isolates.…”