ovalbumin and Malaria--Falciparum

Despite recent advances in treatment and vector control, malaria is still a leading cause of death, emphasizing the need for an effective vaccine. The malaria life cycle can be subdivided into three stages: the invasion and growth within liver hepatocytes (pre-erythrocytic stage), the blood stage (erythrocytic stage), and, finally, the sexual stage (occurring within the mosquito vector). Antigen (Ag)-specific CD8

Topics: Animals; Biomarkers; CD8-Positive T-Lymphocytes; Genetic Vectors; Hepatocytes; Humans; Immunization; Injections, Intravenous; Life Cycle Stages; Liver; Malaria, Falciparum; Mice, Inbred C57BL; Nanoparticles; Ovalbumin; Plasmodium berghei; Plasmodium falciparum; Polylactic Acid-Polyglycolic Acid Copolymer; Sporozoites

Although whole-parasite vaccine strategies for malaria infection have regained attention, their immunological mechanisms of action remain unclear. We find that immunization of mice with a crude blood stage extract of the malaria parasite Plasmodium falciparum elicits parasite antigen-specific immune responses via Toll-like receptor (TLR) 9 and that the malarial heme-detoxification byproduct, hemozoin (HZ), but not malarial DNA, produces a potent adjuvant effect. Malarial and synthetic (s)HZ bound TLR9 directly to induce conformational changes in the receptor. The adjuvant effect of sHZ depended on its method of synthesis and particle size. Although natural HZ acts as a TLR9 ligand, the adjuvant effects of synthetic HZ are independent of TLR9 or the NLRP3-inflammasome but are dependent on MyD88. The adjuvant function of sHZ was further validated in a canine antiallergen vaccine model. Thus, HZ can influence adaptive immune responses to malaria infection and may have therapeutic value in vaccine adjuvant development.

Topics: Adjuvants, Immunologic; Animals; Antibodies, Protozoan; Carrier Proteins; Hemeproteins; Hypersensitivity; Malaria Vaccines; Malaria, Falciparum; Mice; Mice, Inbred C57BL; Mice, Knockout; Myeloid Differentiation Factor 88; NLR Family, Pyrin Domain-Containing 3 Protein; Ovalbumin; Plasmodium falciparum; Protein Binding; Protein Conformation; Toll-Like Receptor 9

CD4(+) T cells respond to antigen immunization through a process of activation, clonal expansion to generate activated effector T cells followed by activation-induced clonal deletion of the responding T cells. While loss of responding T cells in post-activation death by apoptosis is a major factor regulating immune homeostasis, the precise pathways involved in downsizing of Plasmodium falciparum antigen-induced T cell expansions are not well characterized. We report in this study that splenic CD4(+) T cells from mice immunized with nonreplicating immunogens like OVA or recombinant blood stage P. falciparum antigens, PfMSP-3 and PfMSP-1(19) or crude parasite antigen (PfAg) undergo sequential T cell activation, proliferation followed by activation-induced cell death (AICD) in a dose- and time-dependent manner after Ag restimulation. While PfMSP-3 and OVA-induced AICD was mediated through a death receptor-dependent apoptotic program, PfMSP-1(19) and PfAg-induced AICD was via a mechanism dependent on the activation of mitochondria apoptosis signalling pathway through Bax activation. These results provide insights into the mechanism through which two blood stage merozoite antigens trigger different apoptotic programs of AICD in splenic CD4(+) T cells.

Topics: Animals; Antigens, Protozoan; Apoptosis; Caspases; CD4-Positive T-Lymphocytes; Cell Proliferation; fas Receptor; Female; Flow Cytometry; Immunization; Lymphocyte Activation; Malaria, Falciparum; Merozoite Surface Protein 1; Merozoites; Mice; Mice, Inbred BALB C; Mitochondria; Ovalbumin; Plasmodium falciparum; Proto-Oncogene Proteins c-bcl-2; Protozoan Proteins; Spleen