Immunogenetic response to a malaria-like parasite in a wild primate

Abstract

Malaria is infamous for the massive toll it exacts on human life and health. In the face of this intense selection, many human populations have evolved mechanisms that confer some resistance to the disease, such as sickle-cell hemoglobin or the Duffy null blood group. Less understood are adaptations in other vertebrate hosts, many of which have a longer history of co-evolution with malaria parasites. By comparing malaria resistance adaptations across host species, we can gain fundamental insight into host-parasite co-evolution. In particular, understanding the mechanisms by which non-human primate immune systems combat malaria may be fruitful in uncovering transferable therapeutic targets for humans. However, most research on primate response to malaria has focused on a single or few loci, typically in experimentally-infected captive primates. Here, we report the first transcriptomic study of a wild primate response to a malaria-like parasite, investigating gene expression response of red colobus monkeys (Piliocolobus tephrosceles) to natural infection with the malaria-like parasite, Hepatocystis. We identified colobus genes with expression strongly correlated with parasitemia, including many implicated in human malaria and suggestive of common genetic architecture of disease response. For instance, the expression of ACKR1 (alias DARC) gene, previously linked to resistance in humans, was found to be positively correlated with parasitemia. Other similarities to human parasite response include induction of changes in immune cell type composition and, potentially, increased extramedullary hematopoiesis and altered biosynthesis of neutral lipids. Our results illustrate the utility of comparative immunogenetic investigation of malaria response in primates. Such inter-specific comparisons of transcriptional response to pathogens afford a unique opportunity to compare and contrast the adaptive genetic architecture of disease resistance, which may lead to the identification of novel intervention targets to improve human health.Author SummaryThe co-evolutionary arms race between humans and malaria parasites has been ongoing for millennia. Fully understanding the evolved human response to malaria is impossible without comparative study of parasites in our non-human primate relatives. Though laboratory primates are fruitful models, the complexity of wild primates infected in a natural transmission system may be a more suitable comparison for contextualizing malaria infections in human patients. Here, we investigate the genetic mechanisms underlying the immune response to Hepatocystis, a close relative of human-infective malaria, in a population of wild Ugandan red colobus monkeys. We find that the genes involved have considerable overlap with those active in human malaria patients. Like Plasmodium, Hepatocystis induces changes in blood cell type and may cause the host to produce blood components outside of the bone marrow or alter metabolism related to the production of lipids. Our work helps to identify the genetic mechanisms underlying the arms race between primates and malaria parasites, providing fundamental evolutionary insight. Such comparative work on the interaction between wild non-human primates and malaria parasites can identify ways in which primates have evolved resistance to malaria parasites, and further investigation of such implicated genes may lead to novel potential therapeutic and vaccine targets.

Search for Selection Signatures Related to Trypanosomosis Tolerance in African Goats

“… Capalbo et al (2012) suggested a role of PDS5A in HIV-1-induced cellular pathogenesis. The gene UBE2K was found associated with the immune response to a malaria-like parasite in a wild primate ( Trujillo and Bergey, 2020 ).…”

Primate malarias as a model for cross-species parasite transmission

“…Studies from multiple African populations have repeatedly found strong signatures of selection in human genomes at the DARC locus, likely because of its function in preventing P. vivax malaria ( McManus et al, 2017 ; Kwiatkowski, 2005 ; Hamid et al, 2021 ; Pierron et al, 2018 ). This gene and its expression levels have also been implicated in parasite invasion or disease in multiple other primates with P. vivax relatives, including South American and African monkeys ( Camargos Costa et al, 2015 ; Tung et al, 2009 ; McHenry et al, 2010 ; Gunalan et al, 2019 ; Trujillo and Bergey, 2020 ).…”

Primate malarias as a model for cross-species parasite transmission

“…Studies from multiple African populations have repeatedly found strong signatures of selection in human genomes at the DARC locus, likely because of its function preventing P. vivax malaria (McManus et al 2017;Kwiatkowski 2005;Hamid et al 2020;Pierron et al 2018). This gene and its expression levels have also been implicated in parasite invasion or disease in multiple other primates with P. vivax relatives, including South American and African monkeys (Costa et al 2015;Tung et al 2009;McHenry et al 2010;Gunalan et al 2019;Trujillo & Bergey 2020). For example, Tung et al (2009) found a regulatory variant that impacts DARC expression in baboons, showing in vitro expression changes and differences in disease burden in a wild baboon population.…”

“…For example, Tung et al (2009) found a regulatory variant that impacts DARC expression in baboons, showing in vitro expression changes and differences in disease burden in a wild baboon population. Recently, Trujillo et al (2020) found evidence for expression differences in Colobus monkeys correlated with parasite levels in individuals' blood. That is, gene families important for host-parasite interaction may be shared across primates, with important insights gained from differences in species-specific variation, including a role for regulatory variation.…”