Suppression of LethalPlasmodium yoeliiMalaria following Protective Immunization Requires Antibody-, IL-4-, and IFN-γ-Dependent Responses Induced by Vaccination and/or Challenge Infection

Abstract

Immunization with Plasmodium yoelii merozoite surface protein (PyMSP)-8 protects mice from lethal malaria but does not prevent infection. Using this merozoite surface protein-based vaccine model, we investigated vaccine- and infection-induced immune responses that contribute to protection. Analysis of prechallenge sera from rPyMSP-8-immunized C57BL/6 and BALB/c mice revealed high and comparable levels of Ag-specific IgG, but differences in isotype profile and specificity for conformational epitopes were noted. As both strains of mice were similarly protected against P. yoelii, we could not correlate vaccine-induced responses with protection. However, passive immunization studies suggested that protection resulted from differing immune responses. Studies with cytokine-deficient mice showed that protection was induced by immunization of C57BL/6 mice only when IL-4 and IFN-γ were both present. In BALB/c mice, the absence of either IL-4 or IFN-γ led to predictable shifts in the IgG isotype profile but did not reduce the magnitude of the Ab response induced by rPyMSP-8 immunization. Immunized IL-4−/− BALB/c mice were solidly protected against P. yoelii. To our surprise, immunized IFN-γ−/− BALB/c mice initially controlled parasite growth but eventually succumbed to infection. Analysis of cytokine production revealed that P. yoelii infection induced two distinct peaks of IFN-γ that correlated with periods of controlled parasite growth in intact, rPyMSP-8-immunized BALB/c mice. Maximal parasite growth occurred during a period of sustained TGF-β production. Combined, the data indicate that induction of protective responses by merozoite surface protein-based vaccines depends on IL-4 and IFN-γ-dependent pathways and that vaccine efficacy is significantly influenced by host responses elicited upon infection.

Elevated Levels of thePlasmodium yoeliiHomologue of Macrophage Migration Inhibitory Factor Attenuate Blood-Stage Malaria

“…Real-time PCR was used to quantitate the levels of PyMIF RNA using P. yoelii mif (pymif) forward primer 5Ј-TCAAAATGCGTTATCCGAAAT-3Ј and pymif reverse primer 5Ј-ACTTCCAGAAAATCGGAGGTT-3Ј as previously described (48). Assays were performed by using an Applied Biosystems 7900HT real-time PCR system (Applied Biosystems, Foster City, CA), and data were analyzed by using the Applied Biosystems sequence detection system (v2.2.1).…”

“…One week after this rechallenge, sera from the tertiary infection were collected for analysis of antibody responses. The level of anti-PyMIF antibodies present in serially diluted (1:100 to 1:3,200) sera from primary and tertiary P. yoelii 17X infection was measured by ELISA as previously described (48).…”

IL-27 Receptor Signaling Regulates Memory CD4 + T Cell Populations and Suppresses Rapid Inflammatory Responses during Secondary Malaria Infection

“…Acquired immunity to blood-stage malaria infection is believed to depend on CD4 ϩ T cells (with their ability to secrete IFN-␥ making a contribution to their protective role) and antibody (36)(37)(38). As we were unable to purify memory CD4 ϩ T cells from WT and WSX-1 Ϫ/Ϫ mice for transfer into naive mice, we are unable to separate the contribution of the memory CD4 ϩ T cells to protection during secondary infection from any effect of humoral immunity.…”

A Chimeric Plasmodium falciparum Merozoite Surface Protein Vaccine Induces High Titers of Parasite Growth Inhibitory Antibodies

“…Merozoite surface protein 8 (MSP8) is a target of protective, vaccine-induced antibody responses in the Plasmodium yoelii rodent model of malaria (11)(12)(13). Proof-of-concept studies showed that a high level of vaccine efficacy against challenge infection with lethal P. yoelii 17XL could be achieved by immunization of mice with a multicomponent vaccine including both P. yoelii MSP1 (PyMSP1) and PyMSP8 (14,15).…”