The P. Vivax Comeback — Is Malaria Beating Natural Defense?

Africans who were thought to be protected against malaria infection by the Plasmodium vivax (P. vivax) parasite now seem to be at risk for the disease. Previously, these so-called “Duffy-negatives,” or people without the Duffy blood group protein, had a natural defense against vivax malaria by lacking the protein that allows the parasite to invade cells. Research conducted by Peter Zimmerman and his colleagues reveals that a recent development in P. vivax may have enabled the organism to infect otherwise unaffected individuals in the last five years.   

Malaria is a febrile illness (one marked by a fever) and can be fatal. The disease is typically transmitted by female Anopheles mosquitos, which are infected with one of the following four species of the protozoan parasite, Plasmodium: Plasmodium falciparum, Plasmodium malariae, Plasmodium ovale, and Plasmodium vivax. Unlike the other parasites, Plasmodium knowlesi is responsible for spreading a form of zoonotic malaria (malaria that is transmitted from animals to humans). Symptoms of P. vivax malaria are similar to those of the other types, including headaches, vomiting and diarrhea. Although malaria caused by the falciparum parasite can be very severe and life-threatening, P. vivax malaria rarely results in death. 

According to the World Health Organization, 219 million clinical cases of malaria occurred in 2010. Of those infected that year, 660,000 people died. Malaria is prevalent in over 100 countries and territories, especially in Sub-Saharan Africa and South Asia. P. vivax is common in temperate zones and is more widespread than Plasmodium falciparum. In fact, up to 65 percent of malaria in India is attributed to the vivax parasite. Surprisingly, vivax malaria was generally absent in Sub-Saharan Africa. This was because approximately 95 percent of all Africans are Duffy-negative, making falciparum the dominant plasmodium species in that region. Prophylactic antimalarial drug regimens, which help prevent infection, are recommended for people who are traveling to areas of increased risk. Other means of fighting off malaria include the use of insecticides and insecticide-treated bed nets. Today, rapid diagnostic tests are available to check a person’s blood for the presence of malarial parasites, and once diagnosed, P. vivax malaria can be cured with prescription drugs. Chloroquine and primaquine are the ones used most often. However, due to the rise of P. vivax malaria resistance to such drugs, alternate ones are also used.     

To discuss the biology and epidemiological (relating to the occurrence of disease in populations) implications of Duffy-independent vivax malaria, Zimmerman organized a symposium that was part of the 62nd Annual Meeting of the American Society of Tropical Medicine & Hygiene (ASTMH). On November 15, 2013, the session provided an overview of Duffy-independent vivax malaria in African as well as South American populations. David Serre described the new perspectives on P. vivax invasion pathways based on an analysis of all of the parasite’s genes. According to an article co-authored by Zimmerman, Serre, and others that was published in the Neglected Tropical Diseases journal on November 21, 2013, P. vivax strains found in African countries from Madagascar to Mauritania have the ability to cause clinical malaria in Duffy-negatives. This is likely due to a change in the DNA sequence of the P. vivax Duffy binding protein (PvDBP) gene, specifically its duplication or repeat within the chromosome, found in over 50 percent of the infected Malagasy patients (native or inhabitant patients of Madagascar) evaluated. The investigators discovered that the sequence containing the PvDBP is highly conserved (kept unchanged over the years), thus suggesting that the duplication took place in a recent evolutionary time frame and that it may be in response to constraints imposed by Duffy negative red blood cells. It could be that PvDBP polymorphisms (the existence of various forms) provide the protein with the capacity to interact with other invasion receptors, the receptors that facilitate the entry of a substance or organism, on the human red blood cell surface. Often it is found that a second copy of a gene empowers an organism to overcome a defense mechanism. If this is not the reason for the infection of Duffy negatives by P. vivax, however, the authors noted in their article that, “it may be necessary to identify a new parasite invasion ligand [a molecule that binds to a receptor].”          

If vivax malaria spreads in Africa, it can be a major setback for the field. Even though the parasite infects fewer individuals and does not result in as many hospitalizations and deaths when compared with falciparum malaria, vivax malaria relapses do occur. This is because the organism can remain dormant in the liver for years after a person is bitten by an infected mosquito. Moreover, since the parasites evade the immune system by constantly changing their surface and have a complicated life cycle, efforts to develop vaccine(s) have been difficult. There is currently no malaria vaccine that has been approved for human use. Consequently, research elucidating how P. vivax attaches to and enters cells could provide potential targets for vaccines and bring researchers one step closer to completing what the Centers for Disease Control and Prevention (CDC) describes as “one of the most important research projects in public health.”   



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