Of the five Plasmodium species known to infect humans, P. falciparum and P. vivax cause the most malaria cases worldwide, and thus pose the greatest public health challenge. Conducting comprehensive field studies, we discovered that both of these human pathogens have their origins in African apes (1-7). We found that chimpanzees and gorillas harbor at least six Plasmodium species that are closely related to P. falciparum (comprising the Laverania subgenus) as well as parasites that are nearly identical to human P. vivax (1-7). Phylogenetic analysis of ape-derived sequences showed that P. falciparum evolved following a single host switch of a gorilla parasite (1, 6), while P. vivax emerged from within a Plasmodium species that infects both chimpanzees and gorillas (3). Although the origins of the human pathogens are now well established, nothing is known about the evolutionary and mechanistic processes that led to their emergence; yet, such information is critical to understand how ape parasites crossed the species barrier and whether such events are likely to occur again. In this resubmission application, we propose to address these questions by characterizing the ape precursors of the human parasites at the whole genome level and by determining the species and host preferences of the Anopheles vectors that transmit these ape parasites. Our hypothesis is that comparative and population genomic studies of ape Plasmodium parasites, coupled with analyses of their transmitting mosquito vectors, will yield new insight into the biology of P. falciparum and P. vivax and reveal the processes that allowed ape parasites to colonize humans. One major obstacle has been that ape Plasmodium samples are virtually impossible to obtain due to the endangered species status of their hosts. In the past grant period, we have solved this problem by developing a selective whole genome amplification (SWGA) technique that generates -- from unprocessed ape blood and fecal samples as well as infected mosquitoes -- sufficient numbers of parasite genomes for nextgen sequencing. Using this novel technology, we have already sequenced several near full-length ape Plasmodium genomes, which revealed a horizontal gene transfer in the precursor of P. falciparum (RH5 locus) and a new reticulocyte binding protein gene (RBP-3) in ape P. vivax. We will use fecal and blood samples and infected mosquitoes to sequence the genomes of additional members of each of the six ape Laverania species (Aim #1) as well as chimpanzee and gorilla P. vivax parasites (Aim #2). Comparative genomic analyses will identify loci that are unique to ape versus human Plasmodium species as well as genes that have been subject to positive selection. These genetic studies will be complemented by field and laboratory studies of the Anopheles vectors that transmit ape Plasmodium parasites (Aim #3), as well as hypothesis driven mechanistic studies of host-parasite interactions (Aim #4). Execution of these aims will substantially advance our understanding of the pathways that led to the emergence of P. falciparum and P. vivax, and inform eradication efforts of future zoonotic risk.

Public Health Relevance

Malaria is one of the most devastating infectious diseases in the world and one of the major public health problems. This application will use novel tools to characterize the ape precursors of the human malaria parasites P. falciparum and P. vivax, which have only recently been discovered in wild-living chimpanzees and gorillas, as well as their transmitting mosquito vectors. Knowledge gained from comparative genomics and Anopheles vector studies will provide new insight into the evolution, biology and pathogenesis of the human parasites, and will inform malaria eradication efforts by identifying potential zoonotic threats.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI091595-08
Application #
9624361
Study Section
Genetic Variation and Evolution Study Section (GVE)
Program Officer
Joy, Deirdre A
Project Start
2011-09-20
Project End
2020-01-31
Budget Start
2019-02-01
Budget End
2020-01-31
Support Year
8
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Barbian, Hannah J; Connell, Andrew Jesse; Avitto, Alexa N et al. (2018) CHIIMP: An automated high-throughput microsatellite genotyping platform reveals greater allelic diversity in wild chimpanzees. Ecol Evol 8:7946-7963
Loy, Dorothy E; Rubel, Meagan A; Avitto, Alexa N et al. (2018) Investigating zoonotic infection barriers to ape Plasmodium parasites using faecal DNA analysis. Int J Parasitol 48:531-542
Loy, Dorothy E; Plenderleith, Lindsey J; Sundararaman, Sesh A et al. (2018) Evolutionary history of human Plasmodium vivax revealed by genome-wide analyses of related ape parasites. Proc Natl Acad Sci U S A 115:E8450-E8459
Plenderleith, Lindsey J; Liu, Weimin; MacLean, Oscar A et al. (2018) Reply to Forni et al., ""Multiple Selected Changes May Modulate the Molecular Interaction between Laverania RH5 and Primate Basigin"". MBio 9:
Plenderleith, Lindsey J; Liu, Weimin; MacLean, Oscar A et al. (2018) Adaptive Evolution of RH5 in Ape Plasmodium species of the Laverania Subgenus. MBio 9:
Cowell, Annie N; Loy, Dorothy E; Sundararaman, Sesh A et al. (2017) Selective Whole-Genome Amplification Is a Robust Method That Enables Scalable Whole-Genome Sequencing of Plasmodium vivax from Unprocessed Clinical Samples. MBio 8:
Liu, Weimin; Sherrill-Mix, Scott; Learn, Gerald H et al. (2017) Wild bonobos host geographically restricted malaria parasites including a putative new Laverania species. Nat Commun 8:1635
Loy, Dorothy E; Liu, Weimin; Li, Yingying et al. (2017) Out of Africa: origins and evolution of the human malaria parasites Plasmodium falciparum and Plasmodium vivax. Int J Parasitol 47:87-97
Clarke, Erik L; Sundararaman, Sesh A; Seifert, Stephanie N et al. (2017) swga: a primer design toolkit for selective whole genome amplification. Bioinformatics 33:2071-2077
Wroblewski, Emily E; Guethlein, Lisbeth A; Norman, Paul J et al. (2017) Bonobos Maintain Immune System Diversity with Three Functional Types of MHC-B. J Immunol 198:3480-3493

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