Strain variation in tumor necrosis factor induction by parasites from children with acute falciparum malaria

Abstract

A small proportion of individuals infected with Plasmodium falciparum develop cerebral malaria. Why it affects some infected individuals but not others is poorly understood. Since tumor necrosis factor (TNF) has been implicated strongly in the pathogenesis of cerebral malaria, here we have compared different parasite isolates for their ability to induce TNF production by human mononuclear cells in vitro. Wild isolates were collected from 34 Gambian children with cerebral malaria and 66 children with uncomplicated malaria fever. Cerebral malaria isolates tended to stimulate more TNF production than mild malaria isolates, but there was considerable overlap between the two groups, and the present data provide only limited support for the hypothesis that cerebral malaria is caused by strains of P. falciparum inducing high levels of TNF. However, it is notable that the amounts of TNF induced by different wild isolates from a single locality differed by over 100-fold. The biological significance of this polymorphism deserves further scrutiny in view of the central role that TNF is believed to play in host defense and in the clinical symptomatology of human malaria.

Cytokine levels during mild and cerebral falciparum malaria in children living in a mesoendemic area

“…The time between onset of disease and recruitment should be considered to explain this discrepancy: IL-2 has a serum half-life of 6-9 min and rapidly disappears from circulating blood (Lotze et al 1985). Furthermore, cytokine production may precede the onset of clinical manifestations (Harpaz et al 1992), may vary with parasite stage (Allan et al 1995) or with parasite densities (Kwiatkowski et al 1990) and may be localized. In malaria-infected mice reactive lymphocytes disappear from the blood, but their number increases significantly in the spleen (Weiss 1990).…”

“…Although antibody-mediated responses are important (McGregor et al 1956), cell-mediated immunity is involved not only in protection but also in the pathogenesis of disease, and some reports suggest that host immunological responses, especially those mediated through cytokine cascade, may determine disease severity (Clark et al 1989). Plasmodium parasites are able to induce the production of several cytokines (Allan et al 1995;Jakobsen et al 1994) regulating the cellular immune response and possibly influencing the mechanisms of clinical disease (Grau et al 1989;Kwiatkowski et al 1990).…”

Malaria: toxins, cytokines and disease

“…The very low incidence of severe malaria (about 1% of infections) raises the question of genetic polymorphism in either the parasites or the host. As already mentioned, parasite strains may vary in their ability to induce TNF (Allan et al 1993) and attention is currently focusing on genetic differences in human populations. Resistance to severe malaria in West Africa, for example, appears to be…”

“…1991) and IL-6 (Jakobsen et al 1993), and IL-1 synergises strongly with TNF, both in nitric oxide induction and the induction of hypoglycaemia in mice infected with P. vinckei (Rockett et al 1994). Not all strains of parasite have the same TNF-inducing potential, which varies both within laboratory strains (Allan et a/. 1993) and between wild isolates (Allan et al 1995).…”

“…Not all strains of parasite have the same TNF-inducing potential, which varies both within laboratory strains (Allan et a/. 1993) and between wild isolates (Allan et al 1995). However, TNF-inducing molecules from cells infected with the rodent parasites or with P. fakiparum and P .…”