A study by scientists at Oxford and Edinburgh universities, published in Proceedings of the Royal Society B and covered by BBC News online and The Scientist, has shown that the parasite suffers significant penalties if it doesn’t match its own bodyclock to the day-night pattern of its host. That is, it effectively suffers jetlag.
OxSciBlog asked co-author Dr Harriet McWatters of Oxford’s Department of Plant Sciences about the research and its implications for fighting disease.
OxSciBlog: What made you think that the malaria parasite might be able to tell the time?
Harriet McWatters: The symptoms of malaria (fever, chills) occur at regular intervals and usually at the same time of day. This is caused by the parasites emerging at the same time from red blood cells. This interval is always a multiple of 24 hours (48 or 72 hours in species that infect humans, and 24 hours in the rodent malaria we used in our study).
In order for the individual parasites to co-ordinate themselves so precisely, both with each other and the time of day, a clock must be involved.
OSB: How did you test your theory and what did you discover?
HM: We reasoned that parasites would do better when they were in synchrony with their hosts and did a very simple experiment with two separated groups of mice.
The first group was kept in a room lit between at 7am and 7 pm, the second in a room lit from 7pm to 7am. We created a mismatch between the internal clocks of the mouse and the parasite by initiating new infections in both groups in the morning, ie at lights on in room 1 and lights off in room 2.
We then watched the infections develop, counting the number of parasites in each group at regular intervals. Only half as many parasites were produced when there was a mismatch with the host’s bodyclock, or circadian rhythms.
This is very bad indeed for the parasites, as it substantially reduces their chance both of survival and of the possibility of transmission to a mosquito.
OSB: Why do the parasites emerge in the evening rather than at other times of day or night?
HM: We wanted to show that timing matters to the parasite. Clearly it does. We don’t yet know for certain why parasites choose to emerge in the evening but we have a few theories. In particular, we want to know why timing matters to the parasites: is it to evade the host’s immune system or to exploit a particular resource?
The parasites develop inside red blood cells, whose numbers peak in the evening. It could be that they time their emergence so as to make the most efficient use of a limited resource.
Alternatively, they could be trying to avoid components of the host’s immune response which are linked to the body’s circadian rhythm.
Or, it could be due to safety in numbers: if all the parasites emerge simultaneously then together they overwhelm the immune system and so increase their chance of infecting new red blood cells or a mosquito feeding on that blood.
OSB: How crucial is this timing to the survival and spread of the parasite?
HM: Our results suggest that it is very important indeed. We saw a 50% reduction in in-host replication rate. In addition, mismatched parasites produced only half the number of gametocytes. These are the reproductive stages which, when taken up by a mosquito, combine to form the next generation.
This means that the circadian mismatch is a double whammy for the parasites: it reduces by a half both the chance of survival in the host and the likelihood of transmission. This could well translate into a reduction in the ability to cause disease and for the disease to spread.
OSB: What are the implications for malaria treatments?
HM: We need to know why the parasite is so well co-ordinated with the host. It could be to shield the parasite from vulnerability to the immune system at a certain stage of its development. If so, this might make therapies more effective if they are given at a particular time of day.
OSB: Could your research improve the treatment of other infections?
HM: Although almost all organisms have bodyclocks that generate daily rhythms in behaviour and physiology, this is the first study showing the importance of circadian rhythms in host-parasite interactions.
We don’t yet know if this is a phenomenon specific to malaria or widespread among other protozoan parasites. If other parasites also need to synchronise their life cycle with their host’s daily rhythms, then developing means to weaken the parasite by disrupting this relationship could provide a new way of approaching treatments for these infections.
OSB: Are you planning further research in this area?
HM: Yes – we need to identify the mechanism by which the parasite knows what time it is. It could, for instance, be using host signals such as the rhythmic release of hormones like melatonin to tell the time or it could be responding directly to the daily pattern of light and dark. We would also like to know more about variability in timing, and whether the cell cycle can be speeded up or slowed down.