Systems biology of malaria explored with nonhuman primates

Abstract

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.

MaHPIC malaria systems biology data from Plasmodium cynomolgi sporozoite longitudinal infections in macaques

“…Experiment 23 is an iteration of E04, with the same parasite-host combination, but with some sampling and treatment adjustments. E23 is the first in a series of three experiments that includes subsequent homologous (E24, P. cynomolgi M/B strain sporozoites) and heterologous (E25, P. cynomolgi Ceylon strain sporozoites) challenges of the same individuals as in the E23 cohort, in each case with an inoculum of 2,000 sporozoites 1 . One of the six subjects from E23 was not included in subsequent experiments (E24 and E25) due to persistent behavioral issues that prevented effective quality sample collections.…”

“…Macaca mulatta (n = 5) (IDs: RBg14, ROc14, RIb13, RAd14, ROh14), approximately five years of age and cleared of their previous E23 infection with P. cynomolgi M/B strain via treatment with the anti-malarial drugs artemether, chloroquine, and primaquine, were inoculated on July 21 st , 2015, (2 months after curative treatments following E23 1 ) again intravenously with 2,000 P. cynomolgi M/B strain salivary gland sporozoites produced and isolated at the CDC from multiple Anopheles species ( An. dirus , An.…”

“…gambiae , and An. stephensi ) and then profiled for clinical, haematological, parasitological, immunological, transcriptomic, lipidomic, and proteomic measurements 1 . The experiment included 8 pre-inoculation days, 49 experiment days, and 4 post-experiment days.…”

“…The Malaria Host-Pathogen Interaction Center (MaHPIC) posed the overarching hypothesis that “Nonhuman Primate host interactions with Plasmodium pathogens as model systems would provide insights into mechanisms, as well as indicators for, human malarial disease conditions 1 . From September 2012 through September 2017, highly collaborative MaHPIC teams of transdisciplinary scientists used systems biology approaches to design and implement 32 experiments named E01 – E32, including 12 longitudinal in vivo parasite infection experiments involving nonhuman primates (NHPs) to study molecular details that underpin pathogenesis and immunity: how malaria parasites cause disease and how infected hosts recover.…”

“…This species, like P. vivax and P. ovale , develops dormant forms in the liver, called hypnozoites, which can become activated to cause relapsing infections in the blood 6 , 7 . The MaHPIC experiments were designed to study the primary blood-stage infections and subsequent relapses, while detailing clinical, haematological, parasitological, immunological, transcriptomic and metabolomic features to investigate the overall progression and resolution of disease 1 . In addition, blood samples were allocated for complementary lipidomic and proteomic analyses.…”