Effector mechanisms against asexual erythrocytic stages of Plasmodium

Abstract

Evidence for a role for macrophages/monocytes is largely based on in vitro not in vivo observations. Products of activated macrophages particularly tumor necrosis factor-alpha (TNFα) are implicated in the killing of parasites. Access of cytokines and other factors might be through intracellular channels in the infected red blood cell. The cytotoxic elements in ‘crisis’ serum are uncertain but may include TNF, gamma-interferon (IFNγ), and lipid peroxidases. TNFα in excess, contributes to pathology. TNF, acting as a pyrogen and raising body temperature, may moderate parasite density by killing late asexual stages. Nitric oxide and other nitrogen intermediates, products of activated macrophages and a number of other cell types, have been demonstrated both in vitro and in vivo to have a protective role. Phagocytosis of infected erythrocytes and merozoites, enhanced by the presence of immune serum in some systems, has been reported. Killing of parasites by neutrophils is enhanced by immune serum and cytokines TNFα, IFNγ and lymphotoxin. A role for natural killer cells has been suggested. Evidence for antibody-dependent cellular cytotoxicity (ADCC) is controversial. Antibody-dependent cellular inhibitory activity (ADCI) (blood monocytes plus immune IgG) has been described for P. falciparum. Evidence for an important role for complement is conflicting; an involvement in the protective activity of phagocytic cells is reported. Antibody isotypes have been relatively little studied. In murine systems IgG 2a may have a role early in the protective immune response followed by IgG 1. In P. falciparum ADCI activity is mediated by IgG 1 and IgG 3, two cytophilic isotypes. Antigenic variation by the asexual erythrocytic stages has been described for a number of malaria species and appears to serve as an immune evasion mechanism. One variant antigen has been located on the surface of trophozoite/schizont-infected erythrocytes and may be involved in cytoadherence. In P. falciparum in vitro and P. chabaudi in vivo antigenic switching may be at the rate of 2% per generation.