Systems biology of malaria explored with nonhuman primates

Abstract

"The Primate Malarias" book has been a uniquely important resource for multiple generations of scientists, since its debut in 1971, and remains pertinent to the present day. Indeed, nonhuman primates (NHPs) have been instrumental for major breakthroughs in basic and pre-clinical research on malaria for over 50 years. Research involving NHPs have provided critical insights and data that have been essential for malaria research on many parasite species, drugs, vaccines, pathogenesis, and transmission, leading to improved clinical care and advancing research goals for malaria control, elimination, and eradication. Whilst most malaria scientists over the decades have been studying Plasmodium falciparum, with NHP infections, in clinical studies with humans, or using in vitro culture or rodent model systems, others have been dedicated to advancing research on Plasmodium vivax, as well as on phylogenetically related simian species, including Plasmodium cynomolgi, Plasmodium coatneyi, and Plasmodium knowlesi. In-depth study of these four phylogenetically related species over the years has spawned the design of NHP longitudinal infection strategies for gathering information about ongoing infections, which can be related to human infections. These Plasmodium-NHP infection model systems are reviewed here, with emphasis on modern systems biological approaches to studying longitudinal infections, pathogenesis, immunity, and vaccines. Recent discoveries capitalizing on NHP longitudinal infections include an advanced understanding of chronic infections, relapses, anaemia, and immune memory. With quickly emerging new technological advances, more in-depth research and mechanistic discoveries can be anticipated on these and additional critical topics, including hypnozoite biology, antigenic variation, gametocyte transmission, bone marrow dysfunction, and loss of uninfected RBCs. New strategies and insights published by the Malaria Host-Pathogen Interaction Center (MaHPIC) are recapped here along with a vision that stresses the importance of educating future experts well trained in utilizing NHP infection model systems for the pursuit of innovative, effective interventions against malaria.

Keywords: Gametocytes; Host–pathogen interactions; Immunity; Macaca fascicularis; Macaca mulatta; New World monkeys; Pathogenesis; Plasmodium; Rhesus macaques; Systems immunology.

Fig. 1

Schematic of the life cycle of Plasmodium vivax and comparable sibling simian species, depicted to represent the unique biological features of these species in the life cycle of primate malaria species and the importance of clinical and experimental interventions. The figure represents neotropical NHP models of P. vivax or macaque NHP models of Plasmodium cynomolgi and other simian parasite species that serve as surrogates for P. vivax (reviewed in [–20]). The purple and green icons indicate where natural events and experimental manipulations can take place. The green mosquito icons refer to the natural inoculation of sporozoites through biting and the purple mosquito icons refer to the natural biting and infection of Anopheles ssp. mosquitoes by drawing in gametocyte-infected blood. The green medical symbol and syringe denoting the inoculation of sporozoites into the human and NHP hosts, respectively, refer to the possibility of challenging these hosts after immunization with a vaccine candidate to determine if protection can be induced. The purple medical symbol and syringe denote the collection of blood for testing involving human and NHPs, respectively. The purple syringe also signifies the specific collection of blood containing gametocytes from NHPs to artificially feed and infect Anopheles mosquitoes for supporting experiments on host–parasite biology within the vector host, transmission blocking vaccines, and access of sporozoites for in vivo or in vitro infection experiments. The unique biological features of P. vivax and comparable species depicted are the hypnozoite, the preferential invasion of merozoites into reticulocytes, the production of caveolae vesicle complexes (CVCs), represented as a mottled appearance of the infected RBCs, and the early and rapid development and circulation of gametocytes. Red arrows refer to processes relating to features that are currently in need of special research emphasis, answering questions like: (1) What is the make-up of hypnozoites and how are they activated? (2) What are the similarities and differences in primary and relapsing liver-stage schizonts and is their biology with merosome release in the blood stream comparable to rodent Plasmodium species where these were discovered? [21] (3) Which critical factors are required for reticulocyte host cell selection, invasion, and growth in these cells? And (4) what factors determine the development and circulation of gametocytes, potentially permitting transmission from the early stages of a blood-stage infection? “Reprinted from [19], with permission from Elsevier”. The artwork was created by Nagib Haque