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

Date Published: January 23, 2018

Publisher: The American Society of Tropical Medicine and Hygiene

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

http://doi.org/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.

Partial Text

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. It is unclear whether the heterogeneity in antibody responses is associated with specific features of proteins, such as subcellular location, relative abundance, molecular weight (MW), degree of polymorphism, or whether a protein is predicted to have human orthologs. In the case of antibody responses to malaria, until recently, technical limitations, such as low-throughput serological assays and traditional cloning and protein expression methods that made < 0.5% of Plasmodium falciparum proteins available for analysis1 precluded systematic, unbiased analyses of the relationship between protein-specific features and host antibody responses. Indeed, 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 antigen-B 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.5–10 Here, we sought to gain insight into protein-specific factors that underlie heterogeneity in the magnitude of IgG responses to P. falciparum antigens in the context of natural infection—a study made possible by genomics-based technology that allows antibody responses to be interrogated across the entire or large portions of the proteome of important pathogens. When not accounting for interactions, we observed that IgG responses were higher to extracellular and plasma membrane proteins and correlated positively with both protein abundance and degree of protein polymorphism. By contrast, IgG reactivity was significantly lower to proteins predicted to have human orthologs and correlated inversely with protein MW.   Source: http://doi.org/10.4269/ajtmh.17-0437

 

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