Protein-Specific Features Associated with Variability in Human Antibody Responses to Plasmodium falciparum Malaria Antigens.

Eugene W Liu,Aarti Jain,Aissata Ongoiba,Tuan M Tran,Peter D Crompton,David L Narum,Boubacar Traoré,Jeff Skinner,Krishan Kumar,Philip L Felgner

doi:10.4269/ajtmh.17-0437

Abstract

.The magnitude of antibody responses varies across the individual proteins that constitute any given microorganism, both in the context of natural infection and vaccination with attenuated or inactivated pathogens. The protein-specific factors underlying this variability are poorly understood. In 267 individuals exposed to intense seasonal malaria, we examined the relationship between immunoglobulin G (IgG) responses to 861 Plasmodium falciparum proteins and specific features of these proteins, including their subcellular location, relative abundance, degree of polymorphism, and whether they are predicted to have human orthologs. We found that IgG reactivity was significantly higher to extracellular and plasma membrane proteins and also correlated positively with both protein abundance and degree of protein polymorphism. Conversely, IgG reactivity was significantly lower to proteins predicted to have human orthologs. These findings provide insight into protein-specific factors that are associated with variability in the magnitude of antibody responses to natural P. falciparum infection—data that could inform vaccine strategies to optimize antibody-mediated immunity as well as the selection of antigens for sero-diagnostic purposes.

Highlights

In the context of natural infections as well as vaccination with attenuated or inactivated microorganisms, the magnitude of antibody responses varies across the individual antigens that constitute the microorganism
In 267 individuals exposed to intense seasonal malaria, we examined the relationship between immunoglobulin G (IgG) responses to 861 Plasmodium falciparum proteins and specific features of these proteins, including their subcellular location, relative abundance, degree of polymorphism, and whether they are predicted to have human orthologs
IgG reactivity was significantly lower to proteins predicted to have human orthologs

Summary

Introduction

In the context of natural infections as well as vaccination with attenuated or inactivated microorganisms, the magnitude of antibody responses varies across the individual antigens that constitute the microorganism. Most prior efforts to understand the mechanisms underlying immunodominance have focused on differences in immune responses between epitopes within a given antigen rather than differences between antigens of a given microorganism.[2] For example, prior studies have examined the link between immunodominance and antigenB cell receptor binding affinity,[3] epitope accessibility, hydrophilicity, and mobility,[4] as well as variation in antigen processing and presentation to CD4+ T cells via peptide-MHC II complexes.[5,6,7,8,9,10] While these features of B- and T-cell epitopes clearly influence immunodominance at the single antigen level, only recently has the genomics-based technology become available to examine protein-specific factors that underlie variability in antibody responses across the entire proteome of important pathogens. A study in which serum samples from subjects with tuberculosis were probed against a protein microarray containing the full Mycobacterium tuberculosis

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