Hemolysis as a Signal to Initiate Plasmodium vivax Relapse

Background: P vivax has evolved to colonize the sub-tropics and survive long periods without suitable conditions for mosquito transmission through appropriate timing of its relapses. Relapse is one of the defining characteristics of Plasmodium vivax yet it is unknown how the parasite manages to time its relapses to maximize transmission. Some distinct signal(s) must reach the hypnozoite in the liver in order to initiate relapse in a manner than does not activate all latent parasites at once.Hemolysis of erythrocytes is a strong indicator of a new malaria infection which is an excellent surrogate for transmission potential. Hemolysis is a likely relapse initiator. Methods: A literature review was done working back from classical papers seeking epidemiological indications of relapse. Results: Vivax relapses occur after infectious diseases characterized by hemolysis (such as P falciparum) but do not occur after diseases without hemolysis (such asinfluenza). Both alpha and beta thalassemia have been associated with increased vivax prevalence in Vanuatu and Sri Lanka respectively. The most severe G6PD mutations are found outside the tropics suggesting that these particular hemolytic polymorphisms were selected for their ability to interfere with vivax lapses. Blood transfusions increased the relative risk of vivax relapse nearly three fold in US Army soldiers during the Korean War. Malaria cases follow transfusion from the eradication era in Yugoslavia were predominately P malariae within the first month and predominately P vivax after one month. Greater than one month is beyond what one would expect with even the smallest inoculum, suggesting that the hemoglobin load associated with transfusion may have triggered vivax relapses.One case report described injection of primate malaria blood in a human yielding not the primate parasite injected but P vivax presumably from relapse. It is possible that the hemolytic action of the 8-aminoquinolines explains their unique ability to kill hypnozoites. Conclusions: It is plausible that hemolysis sends a reliable redox signal from the blood to the hepatocyte indicating favourable conditions for transmission and thus triggering relapse. Hemolysis maybe a key signal sensed by the hypnozoite that initiates P. vivax relapse.