Mechanisms of naturally acquired immunity toP. falciparumand approaches to identify merozoite antigen targets

Abstract

Malaria is one the most serious infectious diseases with over 200 million clinical cases annually. Most cases of the severe disease are caused by Plasmodium falciparum. The blood stage of Plasmodium parasite is entirely responsible for malaria-associated pathology. The population most susceptible to severe malaria are children under the age of 5, with low levels of immunity. It is only after many years of repeated exposure that individuals living in endemic areas develop clinical immunity. This form of protection prevents clinical episodes by substantially reducing parasite burden. Naturally acquired immunity predominantly targets blood-stage parasites with antibody responses being the main mediators of protection. The targets of clinical immunity are the extracellular merozoite and the infected erythrocyte surface, with the extremely diverse PfEMP1 proteins the main target here. This observation provides a strong rationale that an effective anti-malaria vaccine targeting blood-stage parasites is achievable. Thus the identification of antigenic targets of naturally acquired immunity remains an important step towards the formulation of novel vaccine combinations before testing their efficacy in clinical trials. This review summarizes the main findings to date defining antigenic targets present on the extracellular merozoite associated with naturally acquired immunity to P. falciparum malaria.

Differential IL-18 Dependence of Canonical and Adaptive NK Cells for Antibody Dependent Responses to P. falciparum

“…Acquisition of non-sterilizing immunity to malaria is characterized by a progressive reduction of inflammation with the gradual development of acquired cellular and humoral responses (8,9). Immune responses to erythrocytic stages of the parasite lifecycle are associated with naturally acquired immunity (10). Pathogen-associated molecular patterns from blood stage P. falciparum parasites, either alone or in association with haemozoin (the residue of hemoglobin digestion by the parasite), are potent inducers of NK cell activating cytokines, including IL-12, IL-18, and type 1 interferons (11)(12)(13).…”

Plasmodium falciparumimmunodominant IgG epitopes in subclinical malaria

“…Landmark studies in the 1960s showed that purified IgG from malaria-immune adults transferred to acute-malaria infected children leads to reduction of both fever and parasitemia (7), thus indicating that antibodies against P. falciparum proteins play a critical role in controlling the blood stage of the infection. However, it is still unknown which of the 5,300 proteins presently annotated in the P. falciparum genome (PlasmoDB, www.plasmodb.org) elicit the production of protective antibodies (8). In addition to allelic variations of MHC molecules, the degree of antigen exposure, antigen abundance and host immunodominance impede that all possible antigens could be recognized by natural immune responses (9).…”

Exploring mechanisms of host control and parasite growth during experimental blood-stage malaria in vivo

“…Mechanisms by which they control parasite numbers in vivo have also been reviewed [105,[107][108][109]. Protection against malaria is thought to depend on the functionality of antibody produced against either parasite proteins exported on the surface of pRBC or to those expressed on the surface of the merozoites [105]. The mechanism by which antibodies protect against malaria remains unclear, although this information is a key to development of effective anti-malarial vaccines.…”

“…In endemic populations, naturally-acquired immunity to malaria takes 10-15 years of exposure to develop, as individuals experience repeated exposures to malaria parasites [30]. Efforts have been made to identify potential antigenic targets of protective antibodies [105,106]. The mechanism by which they control parasite numbers in vivo has also been reviewed [105,[107][108][109].…”

“…Efforts have been made to identify potential antigenic targets of protective antibodies [105,106]. The mechanism by which they control parasite numbers in vivo has also been reviewed [105,[107][108][109]. Protection against malaria likely depends on the functionalities of antibodies produced against parasite proteins exported to the surface of pRBC and/or to those expressed on the surface of merozoites [105], However, the mechanism by which antibodies protect against malaria remains unclear.…”