24- and 48-hour cycles of malaria parasites in the blood; their purpose, production and control

Abstract

1. 1. The 24-, 48- and 72-hour cycles of asexual malaria parasites in the blood are remarkable because (a) these periods are simple multiples of 24 hours, (b) all parasites behave synchronously and come to schizogony at the same time and, (c) schizogony occurs at an hour constant for each species (mid-day for plasmodia of man and monkeys, early morning or late evening for some plasmodia of birds). 2. 2. We speculated that these cycles might be connected with transmission by mosquitoes which bite only at night; but this explanation encountered the difficulty that the asexual parasites (which show the cycle) do not develop in mosquitoes, while orthodox views considered the gametocytes (which do develop in mosquitoes) to show no cycle but to remain unchanged in the blood for many days. We therefore re-investigated the gametocytes. 3. 3. Our studies on Plasmodium knowlesi, P. cynomolgi and P. cathemerium have demonstrated that there is in fact a cycle in the infectivity of gametocytes for mosquitoes and in the readiness of the male gametocyte to exflagellate. Both these come to a peak about midnight and fall to low levels during the day. A corresponding cycle can be demonstrated in the morphology of the gametocytes. 4. 4. Accordingly, we consider that the conception of long-lived gametocytes is incorrect. Actually gametocytes take a few hours longer than their asexual cycle to develop to the stage of infectivity for mosquitoes, they remain mature for only a short period (5–12 hours) and then they quickly degenerate and disappear. The illusion of unchanged gametocytes persisting in the blood for long periods is due to the constant replacement of short-lived individuals by a succession of new gametocytes derived from each schizogony. This statement probably applies to all plasmodia which show a synchronous asexual cycle, with the possible exception of P. falciparum which is unique in that the gametocytes take 9–12 days to develop and which requires special investigation. 5. 5. We conclude that the biological function of the synchronous cycle of asexual malaria parasites is to ensure that the short-lived appearance of mature gametocytes in the blood should coincide with the limited time at which vector mosquitoes suck blood (i.e. at night) and in this way to facilitate transmission; in short, it serves to make the gametocytes match the mosquitoes. 6. 6. The synchronization and orientation of the asexual plasmodial cycle are entrained by the temperature cycle of the host. If the temperature cycle of the host is inverted (e.g. by artificially lowering it to 35° during the daytime), the plasmodial cycle also becomes inverted after a lag of 2–4 cycles, and schizogony occurs at midnight instead of mid-day. This has been demonstrated with P. knowlesi and P. cynomolgi in monkeys and has been confirmed with P. cathemerium in duck embryos. 7. 7. When the temperature cycle of the host is allowed to return to normal, the malaria cycle gradually reverts to normal also, with a lag of 8 or more cycles. During this reversion the cycle of P. cynomolgi may be lengthened to 49 hours or shortened to 47 hours (instead of the normal 48 hours). Apparently malaria cycles which are slightly longer or shorter than a multiple of 24 hours represent a transitional phase of readjustment to the abnormal cycle of the host which has itself been altered by the infection.