Far from the Madding Crowd: the Molecular Basis for Immunological Escape ofPlasmodium falciparum

Abstract

Like Thomas Hardy's famous novel Far from the Madding Crowd, Plasmodium falciparum parasites display their most relevant survival structures (proteins) involved in host cell invasion far away from the immune system's susceptible regions, displaying tremendous genetic variability, to attract the immune response and escape immune pressure. The 3D structure localisation of the conserved amino acid sequences of this deadly parasite's most relevant proteins involved in host cell invasion, as well as the location of the highly polymorphic, h i g h l y i m m u n o g e n i c r e g i o n s , c l e a r l y demonstrates that such structures are far apart, sometimes 90° to 180° opposite, thereby rendering the immune response useless. It is also shown here that these conserved, f u n c t i o n a l l y -r e l e v a n t s t r u c t u r e s a r e immunologically silent, since no immune response has been induced.

Plasmodium falciparum Blood Stage Antimalarial Vaccines: An Analysis of Ongoing Clinical Trials and New Perspectives Related to Synthetic Vaccines

“…The blood-stage antimalarial vaccine candidates’ immunogenicity results described here (mainly based on P. falciparum protein conserved regions) have indicated that although moderate Ab titers are induced after a first immunization, they do not induce long-lasting protective immunity. This is consistent with our research demonstrating that, although conserved regions are functionally important for target cell binding, they are poorly recognized by host immune system due to being located far from the highly polymorphic regions used by the parasite as an evasion mechanism to distract the immune system (Patarroyo et al, 2017b); such polymorphic regions are immunodominant but confer just strain-specific immunity (Hisaeda et al, 2005; Curtidor et al, 2017).…”

“…mHABPs have proven highly immunogenic and protection inducing against experimental malaria in Aotus monkeys. This experimental model is susceptible to human malaria, having an immune system 90–100% identical to humans, as demonstrated by DNA sequencing (Suárez et al, 2006), thereby explaining the aforementioned proteins’ suitable profiles as vaccine candidates (Patarroyo et al, 2011, 2017b; Rodriguez et al, 2008).…”

Conserved Binding Regions Provide the Clue for Peptide-Based Vaccine Development: A Chemical Perspective

“…The parasite’s life-cycle complexity is just one challenge to be understood in depth, as it has developed different evasion mechanisms, such as protein variation, antigenic polymorphism, altered peptide ligands (APLs), alternative invasion pathways, cryptic epitopes, immunosuppression, immunological smoke-screens and antigen shedding, thereby inducing long- or short-lived non-protective immune responses [ 74 , 75 , 76 , 77 , 78 , 79 , 80 ]. Repetitive antigens (used erroneously as vaccines) have been targets for strong, but not protective, immune responses.…”

“…Although these sequences are available for the immune system, they are immunologically silent due to the particular and specific 3D structure they adopt [ 123 , 124 ]. Furthermore, protein 3D studies have shown that parasite cHABPs from the most functionally-relevant structures involved in host cell invasion are craftily located far away from highly polymorphic and immunogenic regions to distract the immune response [ 79 ].…”

“…On the other hand, our group’s structural data showed that cHABPs (identical to their recombinant counterparts) mediated receptor-ligand interactions by forming part of H-bond-stabilised channels or troughs and were located far from or opposite to highly polymorphic regions, suggesting an immune escape mechanism [ 79 , 228 ]. It was found that cHABPs became highly immunogenic and sterile immunity inducers in the Aotus experimental model when aa establishing H-bonds with own aa, with those from other cHABPs or binding to host cells were modified [ 77 , 229 , 230 , 231 ].…”