Scientists studying the dynamics of parasitic disease transmission are our first line of defence against Nature’s pathogenic forces.
LIKE the more well-known human malarias, Plasmodium knowlesi – an emerging zoonotic malaria present in monkeys – would be harmless without its mosquito vector.
This is how it works: a mosquito bites an infected human (or monkey) and feeds on its blood. As this happens, the Plasmodium parasites present in the infected host’s blood get sucked up too, ending up in the mosquito’s gut, where they undergo a sexually reproductive phase.
A new generation of microscopic single-celled creatures called sporozoites then emerges from eggs called oocysts, and migrate to the mosquito’s salivary glands, ready for injection into a new host during the mosquito’s next meal of blood.
Human malarias such as Plasmodium falciparum kill up to half a million people a year, mostly in sub-Saharan Africa.
The parasites “jump” from human to mosquito to human.
For the monkey malaria P. knowlesi, however, no evidence currently exists for human-to-human transmission.
Instead, scientists think humans are being infected when they get bitten by mosquitoes that have fed on infected monkeys, a sort of “spillover” effect.
Parasites are often host-specific. This means they have adapted to carry out their life cycles most efficiently in a particular (often animal) host, known as its “reservoir host”.
When such infections spill over into humans, it’s termed a zoonosis.
Scientists have now acknowledged P. knowlesi as the “fifth human malaria” but currently, it’s still just a disease that normally infects other animals, occasionally jumping into humans.
Considering the fact that its ability to infect humans is a relatively recent revelation, scientists have discovered that the parasite descends from a very old lineage. It has lived in South-East Asian jungles, within its macaque hosts, for possibly hundreds of thousands of years.
So the question on every scientist’s mind right now is: as urban and agricultural development encroach upon our forests, could humans become a reservoir host for P. knowlesi?
Straddling two worlds
It’s an intriguing question., and one that has a myriad of public health implications.
Let’s say a human-adapted strain of P. knowlesi were to develop, one that utilises humans as its reservoir host but has lost its ability to persist in monkey populations. Traditional control strategies, such as vector control and malarial treatments, could – in theory – easily keep it under control.
That’s pretty much what Malaysia has successfully been doing to keep killer malarial strains like P. falciparum and P. vivax in check.
However, if such a strain were to straddle both worlds – efficiently jumping from human to human, but also persisting in monkeys – that would make containment of outbreaks and eradication efforts very difficult.
So how do we keep an eye on things to make sure that doesn’t happen?
Well, scientists say we could look out for clusters of cases which demonstrate a self-sustaining chain of human-to-human transmissions without monkey hosts: for example, in a town with no forest or monkeys in sight.
So far, no one has observed anything like that. Most cases reported seem to occur sporadically.
Then again, it’s not like anyone has been systematically looking for it.
Doing so in a comprehensive manner would be time-consuming and involve a lot of trawling through medical records which, considering that people have only just begun diagnosing P. knowlesi in humans, there is probably going to be limited data to work with out there.
Nevertheless, cases have been spiking of late.
Dr Timothy William, an infectious disease physician from Sabah’s State Health Dept and another key figure in this area of research, recently published a study which showed that, despite P. malariae / P.knowlesi cases having been present at low levels for decades, the last 10 years have seen a significant increase.
Interestingly, the rise in P.knowlesi cases coincides with a dramatic reduction in the number of human malaria cases reported – a possible indication that success in our human malaria eradication efforts
have inadvertently opened up new niches for
Some think that increases in the prevalence of P. knowlesi in humans will serve to make human to human transmission – if it is not already happening – more likely.
Professor Dr Balbir Singh is head of the Universiti Malaysia Sarawak (Unimas) Malaria Research Centre. He is one of the main reasons why we know P. knowlesi commonly infects humans today, and he thinks the transition from monkeys to humans as a reservoir host could be happening.
“Then again, it could stay as a zoonosis for centuries,” he says in an interview at the 6th Asean Congress of Tropical Medicine and Parasitology in Kuala Lumpur recently.
In other words, there really is no real way of knowing. The best thing to do is prepare for the worst.
And the best way to do that is to arm yourself with knowledge.
Dr Balbir is part of a network of Malaysian scientists who have been studying the parasite.
A few years ago he and his team published a study that attempted to track the emergence of the parasite in humans and macaques in South-East Asia.
Dr Balbir pulls up a PowerPoint slide and points at a chart which resembles a super-detailed family tree – which it is.
But instead of tracing grandparents and cousins, it traces the genealogy of parasites based on the analysis of data derived from molecular DNA sequencing techniques.
“This is the common ancestor for P. knowlesi, before it diverged into two different lineages, one of which is P. knowlesi,” he explains.
The date this is estimated to have happened? Anything between 98,000 and 478,000 years ago.
(The other lineage, incidentally, eventually branched out to include the human malaria Plasmodium. vivax, about 45,000 to 213,000 years later. P. falciparum, in contrast, is thought to have originated in Africa about 50,000 to 330,000 years ago, eventually spreading out across the globe alongside its human hosts.)
“Macaques colonised Asia about 5 million years ago. So they were in South-East Asia before humans migrated there.”
Humans are generally thought to have arrived on the scene in Asia much later, somewhere around 70,000 years ago.
Dr Balbir thinks humans have been getting infected with P. knowlesi since the very beginning of human habitation in the forests of South-East Asia.
And he says that, with increasing human population sizes coupled with ecological changes through deforestation, the idea of a switch to humans as the preferred host for this species is not that far-fetched.
Vectors are everything
If P. knowlesi were to move into town and start infecting humans, its vector would have to move too. And only one genus of mosquito can act as the chauffeur – Anopheles.
Parasitologist Dr Reuben Sharma, who is looking at the presence of P. knowlesi in monkeys on the peninsula, says any transition to humans as a reservoir host would have to come as a “package”. That is, the mosquitoes would have to come out of their jungle habitat and breed in areas where there are humans.
Interestingly, prior to the 1960s, no one really knew what species of Anopheles carried the parasite.
But after the first case of P. knowlesi in an American surveyor was recorded, surveys were initiated and the data started trickling in.
Dr Indra Vythilingam, an entomologist and consultant for the Dept of Parasitology in Universiti Malaya’s Faculty of Medicine, says three main vectors have been identified in Malaysia: An. balabacensis in Sabah, An. latens in Sarawak, and An. cracens in the peninsula.
With over 30 years of experience in the field, including time on the World Health Organisation’s Expert Advisory Panel for Vector Biology and Control, Dr Indra has noticed a change.
“Back in the pre-malaria eradication days, species such as An. campestris and An. epiroticus, both vectors for human malaria, used to be common along coastal areas in Malaysia. But these have been brought down to very low numbers, thanks to malaria eradication programmes.
“Since then, other species have become more dominant.”
The changing environment of Malaysia is also an important factor. When a niche becomes vacant, some other organism usually comes in to fill its place.
In the 1960s, two-thirds of the country was covered in virgin forest, and a lot of the species of Anopheles Dr Indra has talked about were found only deep in the jungle.
Dynamics of infection
Environmental degradation and deforestation, however, have seen mosquitos and monkeys coming to the forest edge.
Some species such as An. cracens have been found in villages.
There is much we don’t understand about the basic transmission dynamics of P. knowlesi.
For example, why is it that some in some sites, the number of P. knowlesi-carrying mosquitoes discovered by Dr Indra’s study group seemed so small compared to the number of infected monkeys in the area? Could this mean there are more unidentified vectors?
At the same time, our rapidly changing environment is likely to raise even more issues, which make understanding the behavioural ecology of P. knowlesi’s mosquito vectors crucial. Does it only breed in jungles? If we cut the jungle down, is it capable of re-establishing itself
in a newly-developed human residential area?
Which vectors feed at what time of the day, and which should we target for vector control?
Studying vectors is painstaking, hard work. Researchers have to pack lots of kit, trek through the forest, and in this case, set up all kinds of traps – including 10m-high platforms, to reflect the normal elevation at which certain mosquitoes will feed on monkeys.
“We spend over 12 hours collecting mosquitoes, so if one comes back positive for oocysts and sporozoites, it makes our work exciting,” laughs Dr Indra.
A lack of manpower makes going too deep into the jungle impractical. This could affect the data, as there may be other species of Anopheles circulating infections within the monkey population.
For now, however, Dr Indra is concentrating on the basics.
Science is a hard slog, but it is important – being our first line of defence against Nature. The battle between man and pathogen has raged for millions of years, and our most important weapon today is to learn enough to stay one step ahead.
It’s the World Health Organisation’s 66th anniversary today. Each year on its anniversary, WHO highlights a new priority area for public health. This feature on simian malaria coincides with the theme for 2014, vector-borne diseases. This is the concluding part of our feature on simian malaria; the first part appeared in Fit4Life on April 6, 2014. For more on vector-borne diseases, go to http://bit.ly/1g4pnKl