Cytokines kill malaria parasites during infection crisis: extracellular complementary factors are essential.

Abstract

SummaryMalaria infection crisis, at which the parasitemia drops precipitously and the parasite loses infectivity to the mosquito vector, occurs in many natural malaria systems, and has not been explained. We demonstrate that in a simian malaria parasite (Plasmodium cynomolgi in its natural host, the toque monkey), 'the loss of infectivity during crisis is due to the death of circulating intraerythrocytic gametocytes mediated by crisis serum . These parasite-killing effects in crisis serum are due to the presence in the serum of cytokines tumor necrosis factor and interferon y, which are produced by the host as a result of the malaria infection . The killing activity of each cytokine is absolutely dependent upon the presence of additional, as yet unidentified factor(s) in the crisis serum . nfectivity of malarial infections to mosquitoes is due to the presence of circulating gametocytes, the sexual stages that fertilize in the midgut o£ a blood-fed mosquito. In several malaria host-parasite systems, it has been noted that peaks of parasitemia are associated with "crisis" in the infection (1-3) and the simultaneous reduction or loss of infectivity of the parasite to mosquitoes (4, 5); neither of these phenomena has been explained . During a blood infection of Plasmodium cynomolgi in its natural host, the toque monkey, Macaca sinica, peak parasitemia is often accompanied by a crisis in the infection; this is most pronounced in splenectomized animals and is characterized by the appearance of morphologically abnormal intraerythrocytic parasites. At crisis, there is a sudden loss of infectivity of the parasites to mosquitoes, which persists for 5 to 7 days. We show here that the loss of infectivity at crisis is due to death of circulating intraerythrocytic gametocytes mediated by crisis serum . These killing effects in the crisis serum are due to the presence of the cytokines TNF and IFN-y ; the killing activity of each cytokine is absolutely dependent upon the presence of additional, as yet unidentified, factor(s) in the crisis serum . Materials and MethodsAnimals. The toque monkey, Macaca sinica, the natural host ofP. cynomolgi ceylonensis, was used in this study. Wild-caught adult animals of either sex, weighing between 1 and 4 kg, which were free of malaria infections as determined by the indirect immunofluorescence test, were used for experiments. Splenectomies were performed using standard sterile techniques as previously described (6) .

Human Host-Derived Cytokines Associated with Plasmodium vivax Transmission from Acute Malaria Patients to Anopheles darlingi Mosquitoes in the Peruvian Amazon

“…Unlike previous studies, we did not detect a relationship between elevated TNF-α and IFN-γ with decreased transmission. 30,31 Surprisingly, instead, elevation of IL-10, an anti-inflammatory cytokine, was associated with transmission blocking of vivax malaria to An. darlingi in acute infection in this study.…”

“…Nonetheless, unlike previous studies, we did not detect a relationship between elevated TNF-α and IFN-γ with decreased transmission. 30,31 We hypothesized that pro-inflammatory cytokines such as IFN-γ and TNF-α would be elevated among subjects in whom transmission is reduced or prevented because of damage to gametocytes in the setting of inflammation associated with IFN-γ and TNF-α. Unlike previous studies, we did not detect a relationship between elevated TNF-α and IFN-γ with decreased transmission.…”

Characterization of Plasmodium vivax Transmission-Blocking Activity in Low to Moderate Malaria Transmission Settings of the Colombian Pacific Coast

“…This blockage appears to be primarily mediated by antibodies and possibly other mediators, in what is called transmission-blocking (TB) immunity. 4,5 Immunological factors such as complement and cytokines appear to contribute to this TB immunity, [6][7][8] and together with antibodies are considered valuable in reducing the burden of malaria transmission, particularly in areas with low transmission intensity.…”

The early sporogonic cycle of Plasmodium falciparum in laboratory‐infected Anopheles gambiae: an estimation of parasite efficacy

“…During all these changes, parasites are exposed to blood factors (antibodies, white blood cells, complement and cytokines) ingested with the blood meal. These factors can inhibit or block fertilization or parasite development (Rener et al 1980;De Naotunne et al 1991). Subsequently, the ookinete has to cross epithelial cells of the midgut wall and sometimes the peritrophic membrane (according to the mosquito species) and forms a cyst under the basal membrane.…”