Date Published: November 30, 2017
Publisher: Public Library of Science
Abstract: Basic science holds enormous power for revealing the biological mechanisms of disease and, in turn, paving the way toward new, effective interventions. Recognizing this power, the 2011 Research Agenda for Malaria Eradication included key priorities in fundamental research that, if attained, could help accelerate progress toward disease elimination and eradication. The Malaria Eradication Research Agenda (malERA) Consultative Panel on Basic Science and Enabling Technologies reviewed the progress, continuing challenges, and major opportunities for future research. The recommendations come from a literature of published and unpublished materials and the deliberations of the malERA Refresh Consultative Panel. These areas span multiple aspects of the Plasmodium life cycle in both the human host and the Anopheles vector and include critical, unanswered questions about parasite transmission, human infection in the liver, asexual-stage biology, and malaria persistence. We believe an integrated approach encompassing human immunology, parasitology, and entomology, and harnessing new and emerging biomedical technologies offers the best path toward addressing these questions and, ultimately, lowering the worldwide burden of malaria.
Partial Text: Since the first agenda for malaria eradication was published in 2011 , there have been many significant developments in basic science, including an enhanced understanding of parasite biology (both gametocyte and liver stages) as well as mosquito biology (Table 1). Some of these advances could not have been predicted 5 years ago, such as the use of mouse models engrafted with human liver to advance the biology of liver-stage parasites (including the quiescent P. vivax hypnozoite stage) and the development of powerful genome-editing capabilities based on clustered regularly interspaced short palindromic repeats/associated protein-9 nuclease (CRISPR/Cas9) technology. In contrast, little progress has been achieved in several key research areas that were previously prioritized and, as such, they remain important stumbling blocks on the road to eradication.
The findings presented in this paper result from an extensive literature review of published and unpublished materials and the deliberations of the 2015 Malaria Eradication Research Agenda (malERA) Refresh Consultative Panel on Basic Science and Enabling Technologies. Electronic databases were systematically searched for published literature between January 1, 2010, and July 2, 2016, without language limitations. Panelists were invited to recommend additional literature and additional ongoing research projects. A 2-day workshop was held with the majority of the panel members, including field researchers, specialists from basic science, malaria genomics and epigenomics, regenerative medicine, and National Institutes of Health representatives. The panel broke into 6 breakout sessions to identify the problems that need to be solved in asexual blood stages, liver stage and mosquito, mosquito, P. vivax, population genetics and resistance, and transmission. The panel discussed what research is needed to address these problems and considered 6 crosscutting themes in CRISPR technologies, immunology and malaria vaccines, genomics tools for malaria, metabolism and malaria, structural biology, and diagnostics for malaria. Each group fed back to plenary session, where further robust discussions and input occurred. This helped refine the opportunities and gap areas in which research is needed. The final findings were arrived at with inputs from all panelists and several iterations of the manuscript.
The past 5 years have seen rapid progress in understanding the biology of Plasmodium infection in the human liver. Increased availability of primary human hepatocytes has allowed the development of multiple in vitro platforms, all tailored toward the concept of a miniaturized experimental liver model [28, 29, 124]. Importantly, these innovations have allowed the liver stages of infection to be fully recapitulated outside the human host for the first time [26, 125]. They have also spurred the development of reagents to explore the biology of sporozoite infectivity and liver stage development and provided the first glimpse of the P. vivax hypnozoite [26, 28].
In the drive towards elimination and eradication, a key question is how and where malaria infection persists in both humans and mosquitoes, both in individuals as well as populations. Recent genomic studies indicate that parasites may also persist in an additional zoonotic reservoir in nonhuman primates [167–169], although how this contributes to disease transmission in humans is currently unclear.
As illustrated above, recent advances in basic science are providing deeper insights into the biology of the parasite, the mosquito vector, and the human host as well as their interactions at molecular, cellular, and organismic levels. Coupling these insights with recent technologies that help pinpoint potential methods to intervene or disrupt essential interactions can spur the use of novel tools to help eliminate and, ultimately, eradicate malaria.