Drug-resistant Malaria is Able to Infect Diverse Mosquito Vectors

 

[box]Utsav Radia reports on worrying news regarding a resistant form of Plasmodium falciparum [/box]Anopheles-gambiae

A novel drug-resistant form of the malarial parasite, Plasmodium falciparum, that was originally isolated in South East Asia has now been observed to also infect African mosquito species. Researchers at the National Institute of Allergy and Infectious Disease (NIAID) in the US suggest how spread of this deadly new strain into the continent is possible.

Malaria is an infectious disease caused by five species of protozoan parasites of the genus Plasmodium spread by the female Anopheles mosquito. In 2015, approximately 3.2 billion people (nearly half of the world’s population) were at risk of malaria.

Each of the five Plasmodium species differs in terms of geographical distribution and clinical severity. Plasmodium (P.) falciparum is most common in sub-Saharan Africa, Papua New Guinea and the Solomon Islands and is associated with the greatest mortality. P. vivax is found mainly in North Africa, the Middle East, Central and South America and in the Indian subcontinent; it causes less severe disease but can relapse. P. ovale is found mostly in West Africa and is often asymptomatic. P. knowlesi has been documented in Borneo and Southeast Asia. P. malariae occurs worldwide, although mainly in Africa; it is rarely fatal but may cause glomerulonephritis.

Malaria has three broad cycles (two in the human: erythrocytic and exo-erythrocytic; and, one in the mosquito vector: sporogonic cycle). During a blood meal, a malaria-infected female Anopheles mosquito inoculates sporozoites into the human host. These sporozoites infect liver cells and mature into schizonts, which rupture and release merozoites. P. vivax and P. ovale have a dormant stage whereby they can persist in the liver as hypnozoites and cause relapses by invading the bloodstream weeks or years later. After initial replication on the liver, the parasites undergo asexual replication in the blood as merozoites infect erythrocytes.  Some parasites differentiate into sexual erythrocytic stages called gametocytes. It is the blood stage parasites that are responsible for the clinical manifestations of the disease: jaundice, anaemia, hepatosplenomegaly and thrombocytopenia.

An Anopheles mosquito ingests the male microgametocytes and female macrogametocytes during a blood meal and these penetrate the mosquito’s stomach, generating zygotes. The zygotes slowly develop to become motile and elongated, invading the midgut wall of the mosquito, where they develop into oocysts. The oocysts grow, rupture and release more sporozoites which travel up to the mosquito’s salivary glands, ready to infect the next human host.

The mainstay of antimalarial pharmacological treatment includes: chloroquine – which acts to disrupt membrane function and promotes cell autodigestion; sulphadoxine/pyrimethamine – which target folate synthesis; quinine – which allows free radical accumulation in cells, causing cell death; and, antibiotics such as doxycycline (a slow-acting blood schizontocidal agent) and clindamycin (a lincosamide that works by inhibiting the 50S ribosomal component, not given independently in treating malaria). Artemisinin based compounds are used in more severe cases, however its mechanism of action hasn’t been fully elucidated yet.

Despite great international endeavours to eradicate it, malaria still poses a serious threat to humans around the globe. Antimalarial medicines have been one of the most powerful tools used throughout history in the fight against malaria. However, nearly all species of P. falciparum is resistant to chloroquine and sulphadoxine/pyrimethamine (Fansidar®). The advent of using insecticide treated bednets and artemisinin-combined therapies (ACT) had recently appeared to show promise. ACT includes a class of antimalarial compounds discovered from the sweet wormwood plant Artemisia annua.

Scientists from the National Institute of Allergy and Infectious Disease in the US, led by Dr Rick Fairhurst, conducted a study at the Thai-Cambodia border, which is considered to be a large epicentre of ACT resistant malaria parasites. The study, published in the journal Nature Communications, showed that an artemisinin-resistant form of malaria, which was commonly found to infect Anopheles dirus  and Anopheles minimus (native vectors in South East Asia), also readily infected the major African vector Anopheles coluzzi (formerly Anopheles gambiae M). The ability of artemisinin-resistant parasites to infect highly diverse Anopheles species, combined with a higher gametocyte prevalence in human patients may suggest a possible rapid expansion of these resistant parasites in neighbouring countries. This will further detriment previously ongoing efforts to prevent global spreading of the parasites.

Dr Fairhurst, lead of the US study, mentioned “This is just one more piece to the puzzle that looks like a worldwide catastrophe…while such transmission has not been seen yet in the wild, this study shows that it is possible…we have parasites that are not only resistant to Artemisinin…they have no barrier to infecting multiple different mosquitoes and then transmitting the infections…to another human.”

According to the WHO, 6.2 million malaria deaths have been averted in the last 15 years. Artemisinin plays a key role in treating malaria in humans and it would seem we couldn’t afford to lose this drug.

Despite this, further research is currently being done into preventing transmission of microgametocytes and macrogametocytes from infected humans to Anopheles vectors. Perhaps a fresher perspective into treatment may yield a promising new future for malaria treatment?

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