Modelling the contribution of the hypnozoite reservoir to Plasmodium vivax transmission

  • White M
  • Karl S
  • Battle K
  • et al.
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Plasmodium vivax relapse infections occur following activation of latent liver-stages parasites (hypnozoites) causing new blood-stage infections weeks to months after the initial infection. We develop a within-host mathematical model of liver-stage hypnozoites, and validate it against data from tropical strains of P. vivax. The within-host model is embedded in a P. vivax transmission model to demonstrate the build-up of the hypnozoite reservoir following new infections and its depletion through hypnozoite activation and death. The hypnozoite reservoir is predicted to be over-dispersed with many individuals having few or no hypnozoites, and some having intensely infected livers. Individuals with more hypnozoites are predicted to experience more relapses and contribute more to onwards P. vivax transmission. Incorporating hypnozoite killing drugs such as primaquine into first-line treatment regimens is predicted to cause substantial reductions in P. vivax transmission as individuals with the most hypnozoites are more likely to relapse and be targeted for treatment.Malaria is one of the world's most deadly infections, causing 100s of 1000s of deaths each year despite being both preventable and curable. Malaria is caused by Plasmodium parasites, which are transmitted between humans by mosquitoes. When a mosquito bites a human, Plasmodium is injected into the bloodstream with the mosquito's saliva. The parasite then travels through the bloodstream to the liver, infects liver cells and multiplies within those cells without causing any noticeable symptoms. After remaining silent in the liver for weeks or months, the now abundant parasite ruptures the host liver cell, re-enters the bloodstream, and begins infecting red blood cells. If another mosquito bites the infected individual and takes a blood meal, the parasite moves into the mosquito and the cycle of transmission continues.There are several species of Plasmodium that are known to cause malaria. The most widely studied species is P. falciparum, which also causes one of the deadliest types of malaria. However, another Plasmodium species called P. vivax is the most widely distributed species and, despite being less virulent than P. falciparum, is particularly dangerous because it causes recurring malaria.In contrast to P. falciparum, P. vivax has the ability to form hypnozoites: a dormant form of the parasite that can remain inside liver cells for long periods of time, sometimes for years. The reservoir of P. vivax hypnozoites can regularly populate the bloodstream with the infectious form of the parasite, triggering relapses of malaria. Even if an individual suffering a relapse receives prompt treatment to clear parasites in the blood, more parasites may emerge from the liver and cause new blood-stage infections.White et al. developed a mathematical model to help understand how P. vivax is transmitted. Unlike many of the established models of malaria transmission, the new model accounts for the reservoir of P. vivax hypnozoites in the liver, and assumes that hypnozoites in the reservoir either die, or are activated and enter the bloodstream, at a constant rate. This produces patterns that closely match how often relapses occur in patients. White et al. go on to predict that although many infected people have few or no hypnozoites in their liver, some have many hypnozoites, and these people are more likely to suffer from malaria relapses. This suggests that if the initial treatments given to malaria sufferers incorporate additional drugs that kill the hypnozoites in the liver, then it may be possible to substantially reduce the extent of P. vivax transmission.




White, M. T., Karl, S., Battle, K. E., Hay, S. I., Mueller, I., & Ghani, A. C. (2014). Modelling the contribution of the hypnozoite reservoir to Plasmodium vivax transmission. ELife, 3.

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