Cytokines in the Pathogenesis of and Protection against Malaria

Abstract

Malaria is caused by the protozoan Plasmodium, transmitted to humans by Anopheles mosquitoes. The most dangerous of the plasmodia infecting humans is Plasmodium falciparum. Most of the clinical signs of this disease are caused by the parasite at stages in which it multiplies asexually in red blood cells. P. falciparum infection is most severe in children. However, only a small proportion of infected children develop severe complications; in nonimmune individuals these can cause severe and life-threatening disease. The reasons for these differences are not fully understood, but it is likely that host genetic, immune, and social and geographic factors play a role. Malaria is the world's most prevalent parasitic disease and against which effective control measures are urgently needed. Many attempts have been made by using several Plasmodium antigens both in model systems and in humans to develop a malaria vaccine. However, the results, although encouraging, are far from satisfactory (36, 73). One of the difficulties hindering the design of a successful vaccine against Plasmodium is our current incomplete knowledge of protective immunity and how it can be induced. Moreover, the pathogenesis of two of the most severe complications of P. falciparum malaria, cerebral malaria (CM) and severe malarial anemia (SA), both appear to involve dysregulation of the immune system (56). Therefore, a greater appreciation of the mechanisms of protective immunity on the one hand and of immunopathology on the other would provide crucial clues as to how manipulation of the immune system may best be achieved in order to reach the goal of better vaccines.The purpose of this review is to summarize recent work on the role of cytokines in antiparasitic immune responses and immunopathology caused by blood-stage parasites. Although, other points in the biological cycle of Plasmodium offer attractive sites for prophylactic intervention, all clinical symptoms are provoked by this parasitic stage.

Common and Divergent Immune Response Signaling Pathways Discovered in Peripheral Blood Mononuclear Cell Gene Expression Patterns in Presymptomatic and Clinically Apparent Malaria

“…Several parasite virulence factors that interact with Toll-like receptors, including hemozoin with TLR9 (6) and GPIs with TLR2 and TLR4 (23,29), that induce signal transduction pathways through the transcription factor NF-B, which in turn propagates signals to the nucleus to regulate the expression of proinflammatory cytokines such as TNF-␣, IL-1␤, and IL-6 and chemokines such as macrophage inflammatory protein 1␣ and IL-8 (22,46), have recently been demonstrated. Significantly, expression levels of these proinflammatory cytokines correlate directly with the severity of disease (1,18).…”

“…It has been previously established that the level of proinflammatory cytokine secretion in malaria infection correlates directly with the severity of disease (1,2,18). In particular, TNF-␣ has numerous biological effects on host cells including the upregulation of adhesion molecules such as intracellular adhesion molecule 1 (CD54) on the surface of postcapillary endothelium (4,10,43) to which malaria-infected erythrocytes sequester (31).…”

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

“…The IL-10 has been shown to reduce the inflammatory immune reaction mediated by pro-inflammatory cytokines such as IFN-γ and TNF-α, but at the expense of host ability to control the infecting parasite. [33][34][35][36] Mouse studies have consistently shown IL-10 to be an important cytokine in decreasing inflammation and protecting the host in murine malaria models. [37][38][39] In human malaria, several studies have demonstrated association of low IL-10 levels with more severe disease such as cerebral malaria and severe anemia.…”

Correlation between parasitemia and spleen size in patients with P. falciparum infection

“…12 Liver is an alternative organ besides the spleen as a place for eliminating the parasitized red cells. 16 We found splenomegaly in 37 (35.6 %) patients. This result was smaller than that of other study which found splenomegaly in 45% to 75% of patients.…”