Priming in invertebrates is the acquired capacity to better combat a pathogen due to a previous exposure to sub-lethal doses of the same organism. It is proposed to be functionally analogous to immune memory in vertebrates. Previous studies with Anopheles gambiae mosquitoes provide evidence that the inhibitory response to a second challenge by the malaria parasite Plasmodium berghei resulted from a sustained activation of hemocytes by midgut bacteria. These bacteria probably accessed the hemolymph during a first aborted infection through lesions produced by parasites invading the midgut. Since the mosquito immune responses to midgut bacteria and Plasmodium overlap, it is difficult to determine the priming responses of each. We herein document priming induced in the aseptic An. albimanus midgut by P. berghei, probably independent of the immune response induced by midgut bacteria. This idea is further evidenced by experiments with Pbs 25-28 knock out parasites (having an impaired capacity for invading the mosquito midgut) and dead ookinetes. Priming protection against a homologous challenge with P. berghei lasted up to 12 days. There was greater incorporation of 5-bromo-2'-deoxyuridine into midgut cell nuclei (indicative of DNA synthesis without mitosis) and increased transcription of hnt (a gene required for the endocycle of midgut cells) in primed versus unprimed mosquitoes, suggesting that endoreplication was the underlying mechanism of priming. Moreover, the transcription of hnt and antimicrobial peptides related to an anti-Plasmodium response (attacin, cecropin and gambicin) was enhanced in a biphasic rather than sustained response after priming An. albimanus with P. berghei.

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The EtOAc extract of the stem bark of Hintonia latiflora showed the suppression of total parasitemia and the chemosuppression of schizont numbers, when tested in vivo against Plasmodium berghei infection in mice. Bioassay-directed fractionation of the EtOAc extract, using the in vitro 16 h and the in vivo 4-day suppression tests on P. berghei schizont numbers, led to the isolation of the new compound 5-O-beta-D-glucopyranosyl-7,4'-dimethoxy-3'-hydroxy-4-phenylcoumarin (1), along with the known 5-O-beta-D-glucopyranosyl-7-methoxy-3',4'-dihydroxy-4-phenylcoumarin (2). The structure of compound 1 was established on the basis of spectroscopic data interpretation. Compounds 1 and 2 suppressed the development of P. berghei schizonts in vitro with IC50 values of 24.7 and 25.9 microM, respectively. Compound 2 suppressed the development of schizonts at the dose of 40 mg/kg by 70.8% in the in vivo assay.

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