Cell-Mediated Effector Molecules and Complicated Malaria

Abstract

In this review I attempt to advance hypotheses that might help contribute toward understanding the molecular pathogenesis of cerebral malaria (CM) and other complications based on a now widely accepted argument that the illness and pathology occasioned by Plasmodiumfalciparum infection might not necessarily be due to the direct effects of the parasite’s ‘toxins’ and/or exoantigens or even its sequestration and consequent attendant effects in vital organs but rather to the parasite’s mediated production of microbicidal molecules by the host. Tumor necrosis factor (TNF)-α is implicated in the pathogenesis of complicated malaria. There is a positive correlation between high levels of TNF-α and severity of malaria. The role of nitric oxide in the pathophysiology of complicated malaria is not clearly understood. Mononuclear phagocytes by virtue of their capacity to secrete toxic intermediates like reactive oxygen intermediates can inhibit the growth of both murine and human plasmodia. The role of interleukin-10 (IL-10) in malaria is also not well characterized to date. IL-10 is a powerful immunosuppressor factor. It acts as a natural dampener of immunoproliferative and inflammatory responses. Although transforming growth factor-β has a crucial role in inflammation and repair, its role in complicated malaria is not too clearly understood. Furthermore, the anatomical source of these microbicidal molecules is not precisely known. The role of immune complexes (IC) in the pathophysiology of complicated malaria has hitherto not been tested. I argue here that IC play a critical role in influencing the outcome of malarial disease; IC-mediated stimulation of leukocytes to produce high levels of both TNF-α and NO and the fact that leukocytes are probably the principal anatomical source of these microbicidal and other pro-inflammatory mediators in complicated malaria provide a much more plausible explanation for the pathogenesis of CM and other complications. I also review the arguments that help contribute to rationalize hypoglycemia and hyperlactatemia in malarial disease and to some extent severe anemia. I am therefore tempted to conclude that CM and other complications are probably immune-mediated diseases or, at least, they present an inflammatory pathogenesis.

Augmented plasma microparticles during acute Plasmodium vivax infection

“…An interesting finding was the presence of leukocyte and erythrocyte derived-MPs during acute P. vivax malaria. The role of leukocytes in malaria pathogenesis is still not fully understood; nevertheless, it has been shown that these cells are the main source of pro-inflammatory cytokines, especially TNFα which is highly pyrogenic [ 32 ]. The presence of MPs derived from these cells provides evidence for their activation in acute vivax malaria.…”

Inhibition of Activin A suppressed tumor necrosis factor-α secretion and improved histopathological conditions in malarial mice

“…IL-10 is a key immunoregulator that counteracts excessive inflammatory responses caused by Th1 cells (Nyangoto, 2005) and pro-inflammatory cytokines such as TNF-α and IFN-γ, thus confers protective immunity to erythrocytic malaria parasites (Artavanis-tsakonas et al, 2003). In experimental cerebral malaria, the inhibitory effect of IL-10 on the release of TNF-α and IFN-γ has been found to benefit the host by counteracting the pathological role of macrophage (Kossodo et al, 1997).…”

Cytotoxic T Cell-Derived Granzyme B Is Increased in Severe Plasmodium Falciparum Malaria

“…This is in contrast to P. vivax, where a direct and protective interaction between infected erythrocytes and CD8 + T cells has been demonstrated. This effect is attributed to the MHC-I expression of reticulocytes as host cells of P. vivax, which makes them susceptible for a granulysinmediated permeabilization and subsequent GrzB-mediated killing (15).…”

“…In P. falciparum malaria, numerous attempts were undertaken to correlate the T cell phenotype and or cytokine production with the clinical outcome of the disease. Several studies indicate that the ratio of pro-inflammatory TNFα and anti-inflammatory IL-10 may influence disease outcome (15). Although this might represent a reasonable explanation for disease manifestation this dichotomy is not present in every cohort studied.…”