Low-Complexity Repetitive Epitopes of Plasmodium falciparum Are Decoys for Humoural Immune Responses

Abstract

Induction of humoural immunity is critical for clinical protection against malaria. More than 100 malaria vaccine candidates have been investigated at different developmental stages, but with limited protection. One of the roadblocks constrains the development of malaria vaccines is the poor immunogenicity of the antigens. The objective of this study was to map the linear B-cell epitopes of the Plasmodium falciparum erythrocyte invasion-associated antigens with a purpose of understanding humoural responses and protection. We conducted a large-scale screen using overlapping peptide microarrays of 37 proteins from the P. falciparum parasite, most of which are invasion-associated antigens which have been tested in clinical settings as vaccine candidates, with sera from individuals with various infection episodes. Analysis of the epitome of the antigens revealed that the most immunogenic epitopes were predominantly located in the low-complexity regions of the proteins containing repetitive and/or glutamate-rich motifs in different sequence contexts. However, in vitro assay showed the antibodies specific for these epitopes did not show invasion inhibitory effect. These discoveries indicated that the low-complexity regions of the parasite proteins might drive immune responses away from functional domains, which may be an instructive finding for the rational design of vaccine candidates.

The Conservation of Low Complexity Regions in Bacterial Proteins Depends on the Pathogenicity of the Strain and Subcellular Location of the Protein

“…This result is related to the subcellular location of the LCRs in the pathogenic strains: we see a higher abundance of LCRs in extracellular and outer membrane proteins. This is not surprising: pathogens use protein disorder to escape the host’s recognition system [ 34 , 35 ], and LCRs often produce disordered regions. However, polyX displays exceptional variability in the extracellular proteins of pathogens.…”

Analysis of genome characteristics and transmission of SARS-CoV-2 strains in North-East of Romania during the first COVID-19 outbreak

“…Such regions are considered to be highly immunogenic and, importantly, they share high simmilarity with human epitopes, thus making them a risk for antiviral drug or testing development [44]. The enrichment of glutamic acid was found as a feature of the highly immunogenic polypeptides, in other organisms as well [45].…”

Common low complexity regions for SARS-CoV-2 and human proteomes as potential multidirectional risk factor in vaccine development

“…The global analysis of antigens led to the conclusion that LCRs present in proteins containing glutamate-rich and/or repetitive motifs carried the most immunogenic epitopes. On the other hand the antibodies recognizing these epitopes appeared to be ineffective in an in vitro study [35] . In this context it seems to be very important to avoid the presence of LCRs in vaccine epitopes due to 1) low effectiveness of antibodies recognizing this region, even if LCRs are highly immunogenic and 2) the presence of LCRs in some human proteins.…”