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Plasmodium Knowlesi: a Superb in Vivo Nonhuman Primate Model of Antigenic Variation in Malaria

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Plasmodium Knowlesi: a Superb in Vivo Nonhuman Primate Model of Antigenic Variation in Malaria SPECIAL ISSUE REVIEW 85 Plasmodium knowlesi: a superb in vivo nonhuman primate model of antigenic variation in malaria M. R. GALINSKI1,2*,S.A.LAPP1, M. S. PETERSON1,F.AY3,C.J.JOYNER1, K. G. LE ROCH4,L.L.FONSECA5,E.O.VOIT5 and THE MAHPIC CONSORTIUM6 1 Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA 2 Division of Infectious Diseases, Department of Medicine, Emory University, Atlanta, GA, USA 3 La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA 4 Department of Cell Biology & Neuroscience, Center for Disease and Vector Research, Institute for Integrative Genome Biology, University of California Riverside, CA 92521, USA 5 The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia, 30332-2000, USA 6 Malaria Host–Pathogen Interaction Center, www.systemsbiology.emory.edu (Received 7 April 2017; revised 3 June 2017; accepted 6 June 2017; first published online 17 July 2017) SUMMARY Antigenic variation in malaria was discovered in Plasmodium knowlesi studies involving longitudinal infections of rhesus macaques (M. mulatta). The variant proteins, known as the P. knowlesi Schizont Infected Cell Agglutination (SICA) anti- gens and the P. falciparum Erythrocyte Membrane Protein 1 (PfEMP1) antigens, expressed by the SICAvar and var mul- tigene families, respectively, have been studied for over 30 years. Expression of the SICA antigens in P. knowlesi requires a splenic component, and specific antibodies are necessary for variant antigen switch events in vivo. Outstanding questions revolve around the role of the spleen and the mechanisms by which the expression of these variant antigen families are regulated. Importantly, the longitudinal dynamics and molecular mechanisms that govern variant antigen expression can be studied with P. knowlesi infection of its mammalian and vector hosts. Synchronous infections can be initiated with established clones and studied at multi-omic levels, with the benefit of computational tools from systems biology that permit the integration of datasets and the design of explanatory, predictive mathematical models. Here we provide an historical account of this topic, while highlighting the potential for maximizing the use of P. knowlesi – macaque model systems and summarizing exciting new progress in this area of research. Key words: SICAvar genes, var genes, Plasmodium falciparum, epigenetics, mathematical models, systems biology, multi- omics, host–pathogen interactions, longitudinal infections, macaques. INTRODUCTION transmission (Zhou et al. 2016). Taking all these aspects into account, understanding antigenic vari- Antigenic variation of parasite-encoded proteins ation mechanisms and chronicity may lead to new expressed at the surface of Plasmodium infected strategies to boost the host immune system for clear- RBCs (iRBCs) is critical to parasite survival. In ing parasitemias and in turn support malaria elimin- turn, host immune responses against these proteins ation strategies (Alonso et al. 2011). are important for host survival and the establishment Malaria antigenic variation has been most promin- and maintenance of chronic asymptomatic malaria ently associated with the Plasmodium falciparum infections (Howard, 1984; Galinski and Corredor, Erythrocyte Membrane Protein-1 (EMP-1) variant 2004; Arnot and Jensen, 2011). Upon repeated antigens, which are encoded by the large var multi- exposure to parasites with different variant antigen gene family with about 60 members dispersed repertoires, individuals are less likely to exhibit throughout all 14 chromosomes, with the majority severe clinical complications and will eventually located near the telomeres (Leech et al. 1984; cease having symptomatic infections, despite being Baruch et al. 1995; Smith et al. 1995;Suet al. parasitemic (Bull et al. 1998). On a population 1995). However, the phenomenon of antigenic vari- level, antigenic variation has explained observations ation was discovered in Plasmodium knowlesi (Brown of reduced incidence of severe disease in older indi- and Brown, 1965). In P. knowlesi, the Schizont viduals living in high transmission settings. Infected Cell Agglutination (SICA) variant antigens Importantly, aside from being the basis, by defini- (Howard et al. 1983) are encoded by the related large tion, of an unhealthy state, chronic parasitemias SICAvar multigene family, which has at least 136 may aid the propagation of the parasite via members that are likewise dispersed on all 14 chro- * Corresponding author: Emory Vaccine Center, Yerkes mosomes, yet more evenly distributed than the P. National Primate Research Center, 954 Gatewood Road, falciparum var genes and without as much concen- Atlanta GA, USA. E-mail: [email protected] tration near the telomeres (Al-Khedery et al. 1999; Parasitology (2018), 145,85–100. © Cambridge University Press 2017. This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted re-use, distribution, and reproduction in any medium, provided the original work is properly cited. Downloaded fromdoi:10.1017/S0031182017001135 https://www.cambridge.org/core. IP address: 170.106.33.14, on 30 Sep 2021 at 07:51:11, subject to the Cambridge Core terms of use, available at https://www.cambridge.org/core/terms. https://doi.org/10.1017/S0031182017001135 M. R. Galinski and others 86 Corredor et al. 2004; Pain et al. 2008; Lapp et al. also undergo antigenic variation and share biological 2017). The initial groundbreaking studies from features akin to P. falciparum, should also be stressed 1965 involved experimental longitudinal infections (Handunnetti et al. 1987; Galinski and Corredor, of P. knowlesi in rhesus macaques, and this work 2004; Chien et al. 2016). In-depth comparative raised a number of critical questions regarding the investigations of these species may be worth pursu- mechanisms of antigenic variation that remain ing in the future, as would be studies of P. knowlesi unanswered today. In contrast to P. falciparum and in the natural macaque hosts from South East P. knowlesi, the var gene family is not present in Asia, Macaca fascicularis and Macaca nemestrina the human malaria species Plasmodium vivax, (Cox-Singh et al. 2008; Divis et al. 2015; Maeno Plasmodium malariae and Plasmodium ovale et al. 2015). It has been predicted that the human (Carlton et al. 2008; Rutledge et al. 2017). Since P. and simian malaria species share regulatory mechan- knowlesi was recognized as a zoonotic parasite and a isms, and it is likely that similar molecular and widespread public health threat in South East Asia immunobiological host factors govern their expres- (Singh et al. 2004; Cox-Singh and Singh, 2008; sion (Barnwell et al. 1983b; Howard, 1984; Cox-Singh et al. 2008), the relative importance of Howard and Barnwell, 1984b; Korir and Galinski, understanding antigenic variation in this species 2006; Arnot and Jensen, 2011). has been escalating. Model systems and advanced technologies have This paper puts forth the overarching hypothesis reached a level of sophistication allowing for the that molecular mechanisms of Plasmodium antigenic realistic characterization of the in vivo dynamics of variation in vivo, regulated by specific host responses Plasmodium antigenic variation, as well as the iden- and factors, can be discovered or computationally tification of specific in vivo host-parasite factors inferred with modern methods of systems biology that regulate antigenic variation. This can be done and possibly result in groundbreaking strategies for by analyzing infected host and parasite blood treating malaria infections. Given the widespread samples from longitudinal infections and conducting implications of antigenic variation in malaria, with high-throughput studies with multi-omic analyses hundreds of millions of cases estimated annually in (e.g., genomics, epigenomics, transcriptomics, pro- about 100 countries, we believe this research area teomics, lipidomics, immunomics and metabolo- should gain increased traction with translational mics). A refined Macaca mulatta genome (Zimin goals in mind. et al. 2014) (Version 7.8) has been available, but a refined P. knowlesi genome (Pain et al. 2008) assem- bly with fully annotated SICAvar sequences has PERSPECTIVES been lacking. To fill this need, over the past year, a Importantly, the dynamics and molecular mechan- high-quality P. knowlesi de novo genome sequence isms of variant antigens in P. knowlesi can be has been generated in the Malaria Host–Pathogen studied in vivo using macaques, with highly syn- Interaction Center (MaHPIC) by combining long- chronous blood-stage infections initiated by estab- read sequences (PacBio) and genome-wide high- lished (or new) SICA[+] and SICA[−] clones, throughput chromosome conformation capture which do or do not express the variant antigens, (Hi-C) data to produce accurate, chromosome-level respectively (Barnwell et al. 1983a). The P. knowlesi scaffolds, followed by automated and manual anno- rhesus macaque model system is the most advanced tation, including for all SICAvar genes. This option for studying the regulatory mechanisms of genome sequence has been named the ‘MaHPIC antigenic variation based on in vivo investigations, Pk Genome Sequence’ and is being reported else- with the use of in vivo derived, well-characterized where in this Special Issue (Lapp et al. 2017). This parasite
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