Trends in Parasitology I Parasite of the Month Hepatocystis Imran Ejotre,1'2 DeeAnn M. Reeder,3 Kai Matuschewski,1 and Juliane Schaer1'4* department of Molecular Parasitology, Humboldt University, Berlin, Germany 2Muni University, Arua, Uganda department of Biology, Bucknell University, Lewisburg, PA, USA department of Biological Sciences, Macquarie University, North Ryde, NSW, Australia Blood infection limited to sexual stages oA- Gametes 9 / Early gametocyte \ f Ring stage Erythrocyte Gamogony 4 I Merozoites & Early o gametocyte Ring stage Fertilization in midgut Culicoides Zygote \ Ookinete Mature y merocyst Merogony Sporogony in head and thorax Oocyst Early merocyst ^ tla3§] Young Hepatocyte Sporozoites Trends In Parasitology Hepatocystis parasites are the closest relatives of Plasmodium species of mammals. They infect monkeys, bats, squirrels, and ungulates in Africa, Asia, and Australia. A prevalence of up to 100% has been documented in fruit bats and monkeys. Twenty-five morphospecies have been described, and cross-species transmission, divergent Hepatocystis lineages, and species complexes are reported in primate and bat hosts. Biting midges (Culicoides) are the only known vectors. In the vertebrate, merogony occurs exclusively in the liver, resulting in formation of macroscopic merocysts. Merozoites invade erythrocytes and transform directly into sexual gametocytes, thereby omitting asexual replication and associated health conditions. Gametocytes can persist for several weeks and fertilize after a bloodmeal in the Culicoides midgut. The Hepatocystis genome features unique gene families, a low number of Plasmodium interspersed repeat {pit) genes, and an absence of the reticulocyte-binding protein family. Phylogeny Distribution map ■ Erythrocytic schizogony Plasmodium (Plasmodium) {monkeys, humans) Plasmodium tyinckeia) (rodents, bats) Hepatocystis (monkeys, bats, rodents, ungulates) Plasmodium {Laverania) (apes, humans) Nycterla (bets) Plasmodium (birds and squamates) Plasmodium odoco//e7(dser) Polychromophllus (bats) HaemocysffoVufn Haemoprotaus catharu' Parahaemoproteus Haemoprotaus Leucocytozoon Degenerating merocysts surrounded by a layer of giant cells (fused macrophages) and collagen fibers (fibroblasts) Trends in Parasitology KEY FACTS:: Hepatocystis is phylogenetically nested within (paraphyletic) mammalian Plasmodium clades. Vector Culicoides adetsi has been confirmed for primate-infecting species Hepatocystis kochi; experimental infection of Culicoides nubeculosus was reported with Hepatocystis of Australian bats. Liver merocysts differ in size and structure among Hepatocystis species and mature within 2 months. Merozoites are discharged into sinusoids, while a small proportion likely reinvades hepatocytes for a secondary merogony. Ookinetes penetrate the midgut and transform to oocysts in the thorax and head of Culicoides. Sporozoites accumulate in the hemocoel. Three genomes in the nucleus (19.95 Mb encoding 5341 genes), mitochondrion (6.6 kb), and apicoplast (27 kb). Adaptations to the Culicoides vector are recognizable in the genome/transcriptome. DISEASE FACTS:: Infections rarely cause disease, but anemia has been documented. Cyclical fevers do not occur as blood stages are limited to gametocytes that do not provoke cytokine responses. Liver merocyst maturation leads to cellular infiltration and inflammation, followed by granuloma formation. Hemozoin pigment is deposited in liver and spleen. Identification of apparent selection of resistance alleles in the promoter region of the Duffy blood group antigen/chemo-kine receptor DARC in H. kochi-infected monkeys. TAXONOMY AND CLASSIFICATION: PHYLUM: Apicomplexa CLASS: Aconoidasida ORDER: Haemosporida FAMILY: Plasmodiidae/ Haemoproteidae GENUS: Hepatocystis 456 Trends in Parasitology, May 2021, 37, No. 5 © 2020 Elsevier Ltd. All rights reserved. https://doi.Org/10.1016/j.pt.2020.07.015 ^ CelPress Trends in Parasitology I Parasite of the Month Acknowledgments I.E. is supported by a PhD scholarship of the German Academic Exchange Service (DAAD). J.S. is funded by an individual research grant from the German Research Foundation (DFG; project number 437846632). We acknowledge Dr Werner Stenzel (Charite, Universitatsmedizin Berlin) for his contribution to the liver histology. Resources www.ebi.ac.uk/ena https://github.com/adamjamesreid/hepatocystis-genome Literature 1. Laveran, A. (1899) Les hematozoaires endoglobulaires (haemocytozoa), Societe Paris, Volume jubilaire, pp. 124-133 2. Garnham, P.C.C. etal. (1961) The vector of Hepatocystis (= Plasmodium) kochi; the successful conclusion of observations in many parts of tropical Africa. Trans. ft Soc. Trop. Med. Hyg. 55, 497-502 3. Garnham, P.C.C. (1966) Malaria Parasites and Other Haemosporidia, Blackwell Scientific Publications 4. Tung, J. ef a/. (2009) Evolution of a malaria resistance gene in wild primates. Nature 460, 388-391 5. Thurber, M.I. etal. (2013) Co-infection and cross-species transmission of divergent Hepatocystis lineages in a wild African primate community. Int. J. Parasitol. 43, 613-619 6. Schaer, J. ef a/. (2017) Epauletted fruit bats display exceptionally high infections with a Hepatocystis species complex in South Sudan. Sci. Rep. 7, 6928 7. Schaer, J. ef a/. (2018) Phylogeny of Hepatocystis parasites of Australian flying foxes reveals distinct parasite clade. Int. J. Parasitol. Parasit. Wildl. 7, 207-212 8. Boundenga, L. ef a/. (2018) Extensive diversity of malaria parasites circulating in Central African bats and monkeys. Ecol. Evol. 8, 10578-10586 9. Galen, S. ef a/. (2018) The polyphyly of Plasmodium: Comprehensive phylogenetic analyses of the malaria parasites (order Haemosporida) reveal widespread taxonomic conflict, ft Soc. Open Sci. 5, 171780 10. Aunin, E. etal. (2020) Genomic and transcriptomic evidence for descent from Plasmodium and loss of blood schizogony in Hepatocystis parasites from naturally infected red colobus monkeys. PLoS Pathog. 16, e1008717 Trends in Parasitology, May 2021, 37, No. 5 ©2020 Elsevier Ltd. All rights reserved. https://doi.Org/10.1016/j.pt.2020.07.015 4 57