Researchers have identified a ‘new’ and distinct form of the malaria parasite which naturally infects humans. This finding adds another human malaria parasite to the previously identified 5 species of Plasmodium already known to infect humans. After analysing the DNA sequences of Plasmodium parasites from the ovale species, the investigators determined that the Plasmodium ovale parasite, which has until now been considered to be a single species, is actually 2 different species. The independent teams of investigators institutions in France, New Zealand, Papua New Guinea, Portugal, Singapore, Thailand, UK and USA have now identified the 2 differing types of P. ovale species in DNA samples from Ghana, Nigeria, Sa˜o Tome´, Sierra Leone, Uganda and Burma (Myanmar). They “propose to name these species Plasmodium ovale curtisi (classic type) and Plasmodium ovale wallikeri (variant type), in honor of [malaria researchers] Christopher F. Curtis (1939–2008) and David Walliker (1940–2007), respectively” .
I spoke with lead author Colin Sutherland of the London School of Hygiene and Tropical Medicine and the Hospital for Tropical Diseases to discuss the recent findings.
Onome: How common are Plasmodium ovale infections and where are they found?
Colin: P. ovale is usually considered a rare & unimportant parasite. There’s a recent review about ovale malaria which called it ‘the bashful parasite’ in the sense that it’s hiding away, it doesn’t want us to see it. However, [there are] consistent reports of it throughout Sub-Saharan Africa, East and West Africa, and it’s been cropping up in South East Asia for certainly the last 10 years. There’s no reason to think that it hasn’t always been there but been poorly recognized. I think there are reports of ovale malaria in Papua New Guinea certainly going back into the early to mid 20th century…. no reports of ovale malaria in the Americas have been confirmed.
Onome: How did you come to start working on ovale?
Colin: In the work that we do here in the hospital and also in the malaria reference lab, we need to have very reliable malaria reference techniques for distinguishing each species. Ovale is quite difficult to distinguish from vivax sometimes by microscopy, so we do rely a lot on the PCR method developed by George Snounou some 20 years ago. However, [we] have noticed that a proportion of ovale parasites that you can see down the microscope are missed by that assay.
Onome: And how did you come to identify this novel species?
Colin: We had difficulty in diagnosing ovale [particularly in Asia]. [Our initial response] was that perhaps the parasite had diverged and Asian parasites would be different from African ones. Then a report from another group indicated that both ‘variant’ and ‘classic’ ovale were both found in Myanmar. We began to wonder whether we would find both in Africa, so we started looking carefully at Nigerian isolates. We get a lot of imported cases of malaria in the UK from Nigeria and that provided evidence that both [ovale parasites] were there together. As we sequenced and evaluated more genes, we realized that [differences were] right across the genome between the 2 [species]. When you add to that the fact that the parasites can be found in both [Africa and Asia], this was really the icing on the cake. If the [2 species] can exist in the same place, even in the same village at the same time, and not recombine, then in our view they must be genetically separate species.
Onome: Now that you’ve identified a new ovale malaria plasmodium species, do you anticipate more new plasmodium species?
Colin: Yes. I think this is an important question. Our ability to discern [species] is much better than it used to be. I think that P vivax and possibly P malariae are worth looking at more closely. They are more widely globally distributed and there’s the possibility of some speciation effects in those isolates as well. However, I think ovale might be different in that it’s probably fairly recently moved into humans from non-human primates. The reason we see 2 species now may simply be that they’ve made that jump from one host to another on 2 different occasions. Even today, chimpanzees [with] the misfortune of living near humans can become infected with human ovale parasites. So it’s the case that we’re more of a risk to them rather than the other way round.
Onome: In the manuscript you commented that falciparum and ovale are often found together. What does this mean for the human host in terms of treatment options?
Colin: One aspect we’re very interested in is the impact of artemisinin combination therapy (ACT). P. ovale, unlike P. falciparum, can sustain infection in liver stages, as does P. vivax. There’s some evidence from Asia that post ACT treatment for P. falciparum malaria, ovale parasites can emerge; we’ve seen this in one or 2 people in East Africa where there’s a bit of vivax around. We fear that P. ovale may also share this advantage. So, widespread use of ACT which will have a particularly good effect on P. falciparum might allow ovale to persist. While ovale won’t increase in numbers, it will [become] a more substantial proportion of existing malaria cases because of liver stage hypnozoites.
Onome: And what are the treatment options for ovale infections?
Colin: Acute ovale infections respond very well to chloroquine, and there’s no reason to change from chloroquine when there’s no resistance. The problem with using chloroquine in the field, of course, is that it will then exacerbate the benefit of chloroquine resistance to P. falciparum co-infections. [We] would hope that ovale will be controlled with the new ACTs. But we’ll need to identify places and people with persistent ovale liver stage infections, and look at radical treatment [for certain individuals].
Onome: Do you think there’s any possibility that this species may become more virulent, for example if ovale becomes a more prevalent parasite with ACT treatment?
Colin: I don’t really think that is a danger. I think [ovale] it needs to be seen as a more pervasive and common cause of malaria morbidity than we’ve previously realized, but not of severe disease. Talk to anyone who’s had ovale malaria. They’ll tell you it’s well worth getting rid of. We recently had a chap in the hospital just a few weeks ago, who also had sickle cell anaemia; he’s had relapsing ovale malaria for the last year and been bedridden, basically has been unable to work.
Onome: Initially you hypothesized that the limitations in these parasites might be geographical. Now you think it may be based on host blood cell type. Can you comment further on that?
Colin: Yes. We quite like this hypothesis. There’s no direct evidence for it, but it’s a hypothesis you can test very directly. So, we’ve asked for funding from the Wellcome trust to do some longitudinal studies and look at people with different blood groups in different endemic areas, and see if that can explain the distribution of the 2 species. We can get the answer quite quickly when we start the study. If proved wrong we’ll have to come up with another explanation.
Onome: Finally, would you like to comment on the importance of this finding and put it in the wider context of where malaria treatment and elimination options are at the moment?
Colin: There are 3 aspects. The first is that in recognizing that ovale malaria is a complex of 2 species, we’ve now improved our ability to diagnose it. We now have tools to pick up both of them reliably. So [better diagnosis and surveillance] is an advantage for elimination and control. Secondly we’ve shown that the prevalence of [ovale] in Africa is higher than we’d thought, we’re now finding prevalence of 2-3% in central and Eastern Africa (Uganda and Equatorial Guinea). And we’re going to do some studies in West Africa. That means [ovale] is a significant parasite that needs to be considered in terms of [malaria] elimination programs. Thirdly, if we have correctly guessed the mechanism keeping them apart…
Onome: You call it a guess, yes?
Colin: Yes... Ok, there is some evidence that there is divergence in the reticulocyte binding proteins of the 2 parasites; that’s really the clue. But [as for] the blood group idea, there’s no evidence for that yet. But if it is true, then we’ve actually got a handle on something that prevents the parasite from invading the erythrocyte. Understanding [cell] invasion is probably one of the best ways to develop new tools against malaria, both vaccine and drug based. So, this [may be a] model of 2 closely related parasites that may differ profoundly in their ability to invade red blood cells. We think there’s an important general understanding in malaria parasite invasion to be gained from that.