title: Reduced immunogenicity of Plasmodium falciparum gamete surface antigen (Pfs48/45) in mice after disruption of disulphide bonds - evaluating effect of interferon-γ-inducible lysosomal thiol reductase.
abstract: Sexual stages of Plasmodium are critical for malaria transmission and stage-specific antigens are important targets for development of malaria transmission-blocking vaccines. Plasmodium falciparum gamete surface antigen (Pfs48/45) is important for male gamete fertility and is being pursued as a candidate vaccine antigen. Vaccine-induced transmission-blocking antibodies recognize reduction-sensitive conformational epitopes in Pfs48/45. Processing and presentation of such disulphide-bond-constrained epitopes is critical for eliciting the desired immune responses. Mice lacking interferon-γ-inducible lysosomal thiol reductase (GILT), an enzyme that mediates reduction of S-S bonds during antigen processing, were employed to investigate immunogenicity of Pfs48/45. It has been well established that the ability to reduce S-S bonds in antigens guides effective T-cell immune responses; however, involvement of GILT in the induction of subsequent B-cell responses has not been explored. We hypothesized that the ability to reduce S-S bonds in Pfs48/45 will impact the generation of T-cell epitopes, and so influence helper T-cell responses required for specific B-cell responses. Non-reduced and reduced and alkylated forms of Pfs48/45 were employed to evaluate immune responses in wild-type and GILT knockout mice and studies revealed important differences in several immune response parameters, including differences in putative T-cell epitope recognition, faster kinetics of waning of Pfs48/45-specific IgG1 antibodies in knockout mice, differential patterns of interferon-γ and interleukin-4 secretions by splenocytes, and possible effects of GILT on induction of long-lived plasma cells and memory B cells responsible for antigen-recall responses. These studies emphasize the importance of antigen structural features that significantly influence the development of effective immune responses.
authors.affiliation: Department of Tropical Medicine, School of Public Health and Tropical Medicine, Vector-borne Infectious Disease Research Center, Tulane University, New Orleans, LA, USA.
authors.forename: Kristen M
authors.initials: KM
authors.lastname: Merino
authors.affiliation: Department of Tropical Medicine, School of Public Health and Tropical Medicine, Vector-borne Infectious Disease Research Center, Tulane University, New Orleans, LA, USA.
authors.forename: Geetha P
authors.initials: GP
authors.lastname: Bansal
authors.affiliation: Department of Tropical Medicine, School of Public Health and Tropical Medicine, Vector-borne Infectious Disease Research Center, Tulane University, New Orleans, LA, USA.
authors.forename: Nirbhay
authors.identifier: 0000-0002-0358-4924
authors.initials: N
authors.lastname: Kumar
mesh_terms: D000818:Animals; D000913:Antibodies, Protozoan / Q000378:metabolism; D017951:Antigen Presentation; D001402:B-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D005260:Female; D016056:Immunodominant Epitopes / Q000737:chemistry / Q000276:immunology*; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D008288:Malaria / Q000276:immunology*; D017780:Malaria Vaccines; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D050862:Oxidoreductases Acting on Sulfur Group Donors; D010963:Plasmodium falciparum / Q000276:immunology*; D011487:Protein Conformation; D015800:Protozoan Proteins / Q000737:chemistry / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
chemical_list: D000913:Antibodies, Protozoan; D016056:Immunodominant Epitopes; D017780:Malaria Vaccines; D008562:Membrane Glycoproteins; D015800:Protozoan Proteins; C084847:pfs48-45 protein, Plasmodium falciparum; D015847:Interleukin-4; D007371:Interferon-gamma; D010088:Oxidoreductases; C483811:Ifi30 protein, mouse; D050862:Oxidoreductases Acting on Sulfur Group Donors
keywords: Pfs48/45; antigen processing; antigen structure; interferon-γ-inducible lysosomal thiol reductase; malaria; vaccine