Inflammatory cytokine and humoral responses to Plasmodium falciparum glycosylphosphatidylinositols correlates with malaria immunity and pathogenesis.

Pro-inflammatory cytokines induced by glycosylphosphatidylinositols (GPIs) of Plasmodium falciparum contribute to malaria pathogenesis and hence, the naturally acquired anti-GPI antibody thought to provide protection against severe malaria (SM) by neutralizing the stimulatory activity of GPIs. In previous studies, the anti-GPI antibody levels increased with age in parallel with the development of acquired immunity, and high levels of anti-GPI antibodies were associated with mild malaria (MM) cases. In the present study, the relationship between the levels of pro-inflammatory cytokines and anti-GPI IgG antibody responses, parasitemia, and the clinical outcomes were evaluated in SM and mild malaria (MM) patients. Sera from a total of 110 SM and 72 MM cases after excluding of ineligible patients were analyzed for the levels of anti-GPI antibodies, IgG subclasses, and cytokine responses by ELISA. While the total anti-GPI antibody levels were similar in overall SM and MM groups, they were significantly higher in surviving SM patients than in fatal SM cases. In the case of cytokines, the TNF-α and IL-6 levels were significantly higher in SM compared to MM, whereas the IL-10 levels were similar in both groups. The data presented here demonstrate that high levels of the circulatory pro-inflammatory, TNF-α, and IL-6, are indicators of malaria severity, whereas anti-inflammatory cytokine IL-10 level does not differentiate SM and MM cases. Further, among SM patients, relatively low levels of anti-GPI antibodies are indicators of fatal outcomes compared to survivors, suggesting that anti-GPI antibodies provide some level of protection against SM fatality.

Relationship between Antibody Levels, IgG Binding to Plasmodium falciparum-Infected Erythrocytes, and Disease Outcome in Hospitalized Urban Malaria Patients from Dakar, Sénégal.

Background. Management of clinical malaria requires the development of reliable diagnostic methods and efficient biomarkers for follow-up of patients. Protection is partly based on IgG responses to parasite antigens exposed at the surface of infected erythrocytes (iRBCs). These IgG responses appeared low during clinical infection, particularly in severe disease. Methods. We analyzed the IgG binding capacity to the surface of live erythrocytes infected by knob positive FCR3 strain. Sera from 69 cerebral malaria (CM) and 72 mild malaria (MM) cases were analyzed by ELISA for IgG responses to five antigens from iRBC and by flow cytometry for IgG binding as expressed in labeling index ratio (LIR). The relationship between IgG levels, LIR, parasitemia, age, and the clinical outcomes was evaluated. Results. We found a significant decrease of LIR in adult CM fatal cases compared to surviving patients (p = 0.019). In MM, LIRs were correlated to IgG anti-iRBC and anti-PfEMP3/5 levels. In CM, no correlation was found between LIR, IgG levels, and parasitemia. Conclusion. The IgG binding assay was able to discriminate outcome of cerebral malaria cases and it deserves further development as a potential functional-associated assay for symptomatic malaria analysis.

The use of crude Plasmodium falciparum antigens for comparison of antibody responses in patients with mild malaria vs. cerebral malaria.

BACKGROUND: Cerebral malaria (CM) is one of the major causes of death in African populations infected with Plasmodium falciparum. Only 1% of infected subjects develop CM. The reasons for these differences are not fully understood, but it is likely that the host humoral response against blood-stage antigens plays a role in protection from malaria, although the precise targets and mechanisms mediating immunity remain unclear. OBJECTIVE: The purpose of this study was to distinguish between defined P. falciparum-specific Ab response patterns in patients presenting with mild malaria (MM) vs. CM. METHODS: We used a panel of P. falciparum conserved antigens including crude blood-stage extracts schizont, merozoite and parasitised erythrocyte membranes and MSP-1p19, PfEB200, R23 and GST-5 recombinant antigens in a retrospective case-control study of symptomatic adults, one group presenting confirmed CM without fatal outcome and another group with MM. We further matched P. falciparum-specific Ab responses with those from individuals living in an endemic setting known to have protective immunity and considered them as "immune control" subjects (IC). Total IgG, IgM and IgG subclass Ab responses were determined using ELISA method. RESULTS: Substantial Ab responses were found in symptomatic patients, significantly lower than the "immune control" subjects, and with a limited quantitative difference between MM versus CM. Interestingly, asynchronous IgM response was evidenced in CM contrary to MM. CONCLUSION: Our results suggest that the contribution of an efficient IgG response against parasite multiplication is of importance in the evolution towards CM manifestation without fatal outcome and deserves further analysis for vaccine candidates.