The fate of sporozoites.

In their tribute to Colonel Shortt on his 80th birthday, the renowned malariologists P.G. Shute and Sir Gordon Covell eloquently placed the discovery of the exoerythrocytic (EE) hepatic phase of mammalian malaria parasites in the following historical context (1). "Just as the name of Ross will forever be associated with the discovery that mosquitoes transmit malaria, so too, will the names of Shortt and Garnham will be remembered in connection with the primary tissue phase of the parasite." It has been 52 years since Shortt & Garnham published their milestone finding (2) of the cyst-like body, filled with thousands of merozoites, in the liver of a rhesus monkey that had been inoculated 102 days before with Plasmodium cynomolgi sporozoites from 500 mosquitoes. With their bold experiment they solved a centuries-old mystery -- the source of malaria's parasitaemic relapses. An outstanding parasitological gaffe had been the claim by Fritz Schaudinn (best remembered as the co-discoverer of the Treponema causation of syphilis) that the Plasmodium vivax sporozoite penetrated the erythrocyte (3). Schaudinn's accompanying drawings showed "the theatrical picture of the entry of a malaria sporozoite into a red blood cell", as Knowles commented (4). We may now wonder how such an erroneous observation could have been made by so distinguished and expert a protozoologist. We may also wonder at the pervasiveness of Schaudinn's authority, so powerful that it overrode all the failures to substantiate his findings. According to Shute & Covell (1) the first doubts of Schaudinn's theory came from the malariatherapy centres treating paretics. In practices that today would bring down the wrath of hospital patient oversight committees (and a phalanx of lawyers bearing malpractice briefs), malaria, mostly P. vivax, was induced either by direct inoculation of infected blood (continental European style) or by inoculating sporozoites by mosquito bites or in isolated salivary glands and ground-up thoraces (British style). The blood-inoculated patients were readily, radically, cured with quinine but the sporozoite-induced infections relapsed after the same therapy. The proof, albeit still circumstantial, that Schaudinn was totally wrong, that there was a missing link in the life cycle of human malaria, came from the remarkable experiment of Sir Neil Hamilton Fairley in Australia (5). Fairley showed that the blood of volunteers injected with large numbers of P. vivax sporozoites was infectious to other volunteers for only 30 minutes. The blood then became "sterile" until 7 days later when it once again became infectious to volunteers. Although P. knowlesi had been known as a primate malaria since 1932 (6), during the first half of the 20th century -- until the discovery of P. berghei (7) in a wild tree rat of the Congo -- the avian malarias served as the main experimental models. Distinguished researchers of that period were bird malaria experts, e.g., Huff in the United States, Brumpt in France, Raffaele in Italy, and James in Britain. Bird malarias also relapsed after quinine treatment. Tissue and organ smears from infected birds revealed exoerythrocytic schizonts in reticulo-endothelial and hemoblastic cells (8-10). Prediction held that the exoerythrocytic stage of human and primate malarias would also be located in these tissues and the malaria birdmen were chagrined when the site turned out to be the hepatocyte. Shortt was a traditonalist who held to the importance of lineage in science. He would peer over his half-glasses to issue a stern rebuke to a former student (who might by then be a full professor) for a serious "transgression", such as straying into helminthology: "Remember who your teachers are!" he would say. That line of teachers, in his view, went from the student to Shortt to Rickard Christophers to Ross. In a sense, all present malaria researchers are students in the lineage of Shortt (and, of course, Garnham) and it is fitting in this new millennium to be mindful of the far-reaching impact of the discovery of the EE bodies. …