Roles of TNF in malaria and other parasitic infections.

Comprehension of the involvement of cytokines in the host response against invading parasites, to the detriment of the parasite and (in larger doses) to the host, is expanding rapidly. Most of these studies, largely for historic reasons and availability, have been done with TNF rather than the other mediators. As is emerging in other fields, study of interleukin-1 alone, and synergistically with TNF and IFN-gamma, warrants further exploration in parasitic diseases. There may well be a similar story for TNF-beta, waiting to unfold. It is appropriate here to show deference to earlier malariologists, back to the nineteenth century, whose observations and reasoning were evidently accurate when they attributed malarial illness and pathology (including cerebral malaria) to a malarial toxin (reviewed by Clark and Tomlinson, 1949). The only additional insight required of present-day workers has been to see the malaria parasite not as a source of a direct toxin, but of molecules, harmless in themselves, that can act as a trigger for toxic products of host origin. As a final twist, low concentrations of these host-derived "toxins" are not only harmless, but necessary for normal biological functions. They are deleterious only when overproduced.