Residents of Daraweesh village in Sudan were monitored for Plasmodium falciparum infection and malaria morbidity in 3 malaria seasons from 1993 to 1996. Malaria parasites were detected microscopically and by polymerase chain reaction (PCR) in a series of cross-sectional surveys. PCR revealed submicroscopical infections during the dry season, particularly among individuals who had recovered from a malaria episode following successful drug treatment. Clinical and subclinical infections were contrasted by assaying for allelic polymorphism at 2 gene loci, MSP-1 and GLURP and 2 hypotheses examined with reference to these data: that clinical malaria is associated with infection with novel parasite genotypes not previously detected in that host, or alternatively, that clinical malaria episodes are associated with an increased number of clones in an infection. We detected more mixed infections among clinical isolates, but people carrying parasites during the dry season were not found to have an increased risk of disease in the following malaria season. There was a clear association of disease with the appearance of novel parasite genotypes.

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Bovine macrophage-derived tumour necrosis factor-alpha/cachectin (TNF-alpha) was synthesized when peripheral blood mononuclear cells (PBMC) and purified adherent PBMC from naive and Theileria annulata-infected cattle were incubated in vitro with concanavalin A (Con-A) or bovine recombinant interferon gamma (Bo rIFN-gamma). TNF-alpha production was also induced when adherent PBMC were cultured with T. annulata macroschizont-infected cells. In contrast, non-adherent PBMC from sublethally infected cattle produced interferon (IFN) when incubated with Hu rIL-2, Con-A, phytohaemagglutinin (PHA) or T. annulata macroschizont-infected cells growing as cell lines in vitro. Whilst PBMC from lethally infected cattle spontaneously produced IFN-gamma during advanced stages of infection, the sera of such animals contained type 1 IFN (alpha/beta). IFN was also produced by T. annulata macroschizont-infected cell lines maintained in vitro. This work suggests that cytokines serve as crucial links between proliferating Theileira-infected cells and the characteristic clinical symptoms of tropical theileriosis.

The following bovine (Bo) and human (Hu) cytokines--Bo rTNF-a, Bo rIFN-g, Hu IFN-a, Hu rIL-1, Hu rIL-2--significantly inhibited the in vitro development of trophozoite-infected cells of three stocks of Theileria annulata and of Theileria parva (Muguga). However, none of these cytokines inhibited the proliferation of established T. annulata or T. parva macroschizont-infected cell lines. Indeed, Bo rTNF-a and Hu rIL-2 consistently enhanced the proliferation of macroschizont-infected cell lines of both species and the blastogenesis of uninfected lymphocytes in trophozoite-infected cultures. These results suggest that cytokines could help in resistance to challenge infections by preventing the further development of trophozoite-infected cells but provide no evidence that any of the above cytokines directly help to resolve primary infections by inhibiting the growth of macroschizont-infected cells. These findings also suggest that both TNF-a and IL-2 could play a role in the pathogenesis of Theileria infections by promoting the proliferation of macroschizont-infected cells and the associated lymphoid hyperplasia.

A series of projects on Theileria annulata funded by the European Union (STD1/STD2/STD3) have provided convincing evidence that macrophage and natural killer (NK) cell-dependent immune mechanisms may directly control the proliferation of different stages of T. annulata in cattle. The evidence for this conclusion and the implications for vaccine development are discussed in the following paper.