Plasmodium vivax Liver Stage Development and Hypnozoite Persistence in Human Liver-Chimeric Mice

Abstract

Plasmodium vivax malaria is characterized by periodic relapses of symptomatic blood stage parasite infections likely initiated by activation of dormant liver stage parasites -hypnozoites. The lack of tractable animal models for P. vivax constitutes a severe obstacle to investigate this unique aspect of its biology and to test drug efficacy against liver stages. We show that the FRG KO huHep liver-humanized mice support P. vivax sporozoite infection, development of liver stages, and the formation of small non-replicating hypnozoites. Cellular characterization of P. vivax liver stage development in vivo demonstrates complete maturation into infectious exo-erythrocytic merozoites and continuing persistence of hypnozoites. Primaquine prophylaxis or treatment prevents and eliminates liver stage infection. Thus, the P. vivax/FRG KO huHep mouse infection model constitutes an important new tool to investigate the biology of liver stage development and dormancy and might aid in the discovery of new drugs for the prevention of relapsing malaria.

Do hypnozoites cause relapse in malaria?

“…x TREPAR-1359; No. of Pages 7 'nonrelapsing' primate parasite P. knowlesi [7], together with new information concerning P. vivax in liver-chimeric mice [81], represent support for the hypnozoite theory of relapse, as applied to recurrent primate malaria caused by species such as P. cynomolgi and P. vivax. Nonetheless, I consider the mere fact that P. vivax recurrences can be homologous to indicate that it is imperative on genetic grounds that studies be carried out to assess the possibility (if not probability) that there is a nonhypnozoite source(s) of at least a proportion of the relapse-like, homologous P. vivax recurrences now being identified regularly by researchers.…”

Development of vaccines for Plasmodium vivax malaria

“…In order to study hepatocyte invasion stages of P. falciparum as well as P. vivax, attempts have been made to establish in vitro liver models [77,78]. In addition, a reliable humanised mouse model for P. vivax liver stages is now available [79]. Both approaches will help to identify and test novel drugs and vaccines targeting hepatocyte stages.…”

Phenotypic Screens in Antimalarial Drug Discovery

“…Improvements in these areas are necessary to perform a high throughput-compatible screen for compounds with hypnozoiticidal activity. A bright spot has been the development of human liver-chimeric (huHep) FRG knockout mice that can be used as a model for P. vivax infection [59]. The use of these chimeric mice may allow researchers to develop activity profiles for possible radical cure drugs.…”