IDENTIFICATION OF XANTHURENIC ACID AS THE PUTATIVE INDUCER OF MALARIADEVELOPMENT IN THE MOSQUITO

Malaria is transmitted from vertebrate host to mosquito vector by matu re sexual blood-living stages called gametocytes(1,2). Within seconds of ingestion into the mosquito bloodmeal, gametocytes undergo gametoge nesis. Induction requires the simultaneous exposure to at least two st imuli in vitro: a drop in bloodmeal temperature to 5 degrees C below t hat of the vertebrate host(1-3), and a rise in pH from 7.4 to 8.0-8.2 (refs 1, 4). In vivo the mosquito bloodmeal has a pH of between 7.5 an d 7.6 (refs 5, 6). It is thought that in vivo the second inducer is an unknown mosquito-derived gametocyte-activating factor(5,7,8). Here we show that this factor is xanthurenic acid. We also show that low conc entrations of xanthurenic acid can act together with pH to induce game togenesis in vitro. Structurally related compounds are at least ninefo ld less effective at inducing gametogenesis in vitro. In Drosophila mu tants with lesions in the kynurenine pathway of tryptophan metabolism (of which xanthurenic acid is a side product), no alternative active c ompound was detected in crude insect homogenates. These data could for m the basis of the rational development of new methods of interrupting the transmission of malaria using-drugs or new refractory mosquito ge notypes to block parasite gametogenesis.