Martin Rono talks about the findings of his recently published paper on ‘Adaptation of Plasmodium falciparum to its transmission environment’ which has since been published on Nature How does Plasmodium falciparum adapt to its transmission environment
What was the study about?
We were investigating how the malaria parasites adapts when faced with different opportunities for transmission in its natural environment in the hope of better predicting what would happen when malaria control which is done by reducing mosquito numbers, or by making people immune using vaccines.
We found that parasites from areas with limited opportunities for transmission (low transmission areas) put more effort into transmission between hosts and less into multiplication inside the host. Parasites from high transmission areas prefer, instead, to put their energy into multiplying inside the host.
At the molecular level, we confirmed what has only been shown relatively recently which is that the switch to reproduction is controlled at the epigenetic level. Modifications of the gene’s chromosome environment leads to some genes being switched on and others switched off, leading to more genes being switched on and so on. We identified some of the players in this molecular cascade such as the AP2-G gene which controls sexual reproduction in plasmodium.
Were these findings unexpected?
Previously we published a paper in Nature (Gandon et al., 2001) that predicted that if a vaccine was to be used as a Malaria control measure parasites from high transmission areas would adapt by evolving and have higher multiplication rates inside the host and thus be more likely to kill the hosts. However, this had only been proven by work in mouse malaria in the lab and from theoretical modelling of how malaria works, and we needed to check out our hypothesis in the field.
We studied populations that had different levels of ‘natural vaccination’ as a consequence of being exposed more or less to the parasite in different transmission intensity settings. Since we couldn’t measure the parasite’s virulence levels directly (that would involve injecting lots of people with dangerous parasites) we looked at the parasite’s gene expression levels and read these for signs of adaptation.
We can’t say for sure whether the adaptation we found was due to different levels of immunity in the host population (i.e., vaccination) as opposed to other transmission intensity-related factors such as mosquito abundance, the number of concurrent infections per host or something else. But the fact that the parasite populations were consistently different between three different experiments from high vs. low transmission intensity settings tells us that the parasite does evolve to suit its local setting and therefore might change again when malaria control begins to bite. That this adaptation went in the same direction as our prediction (i.e., higher multiplication early in the infection in high transmission areas, this at the expense of producing transmission forms) adds weight to our earlier argument back in 2001 that controlling malaria by targeting multiplication rates rather than targeting transmission may not be a good idea in the long-run.
So how does the parasite adapt its life cycle when faced with anti-malaria control measures? What does this adaptation do to protect it?
Like most organisms, malaria parasites have to choose how much effort they put into ‘growth’ (multiplying inside the host) and how much into reproduction (transmitting to new hosts). Inherent in the parasite’s life cycle is a trade-off between the two. This is because transmissible forms of the parasite are created directly from multiplying forms: when one of the latter converts to the former, it sacrifices many multiplications for the sake of a single transmission form.
What is interesting about our findings is that this growth-reproduction juncture in the parasite’s life cycle is the target of transmission-intensity-related adaptation. We think that the parasite is controlling the switch between these two forms in a way that maximizes total transmission output from an infection (fitness) according to the opportunities and limiting factors dictated by its transmission environment. When mosquitos are few, or immunity is not limiting multiplication, the parasite can afford to and will benefit from putting more into transmission. When mosquitoes are plentiful, or immunity is holding it back, the parasite will benefit more from investing in multiplication. We therefore expect that malaria control programmes that cut into transmission intensity, e.g., by mosquito control or bed nets, will select for parasites that invest more in transmission and multiply less fast early in the infection. We expect this to lead to less virulent infections.
What are the implications to Malaria control measures?
Our conclusions coincide with those from our Nature 2001 paper which showed (theoretically) that using malaria control strategies that target in-host multiplication (anti-replication vaccines, drugs) may force the parasite to become nastier while strategies that target transmission (bed nets, infection- and transmission-blocking vaccines) are likely to do the opposite. However, we do not argue that drugs and vaccines should not be used: they save millions of young lives both now and in the future. But there are many ways to skin the malaria cat and we need to formulate control programs with parasite evolution in mind.