Common host variation drives malaria parasite fitness in healthy human red cells

Ebel, Emily R.; Kuypers, Frans A.; Lin, Carrie; Petrov, Dmitri A.; Egan, Elizabeth S.

doi:10.1101/2020.10.08.332494

Cited by 3 publications

(2 citation statements)

References 96 publications

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“…For instance, in mice vaccinated with erythrocyte ghosts isolated from P. chaubaudi -infected erythrocytes, RHAG , SPTA1 , KLF1 , and SLC4A1 were among the erythropoiesis-involved genes that were significantly upregulated in response to infection with blood stage Plasmodium chabaudi (Delic et al, 2020). Furthermore, variation in SPTA1 , which encodes a component of the RBC plasma membrane, was recently found to impact P. falciparum growth in cultured human RBCs (Ebel et al, 2020). Lastly, heterozygous deletion in SLC4A1 causes South Asian hereditary ovalocytosis, which confers protection in humans against many Plasmodium species (Jarolim et al, 1991; Paquette et al, 2015), and this gene has been found to be under differential selection pressure in other primate species (Steiper et al, 2012).…”

Section: Resultsmentioning

confidence: 99%

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

Bergey

2020

Preprint

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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.

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Section: Resultsmentioning

confidence: 99%

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

Bergey

2020

Preprint

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“…HBSS contains salts at the same concentration as RPMI 1640, but lacks amino acids and trace elements found in RPMI. Red blood cells from different donors may have a large influence on P. falciparum growth rates (32): we therefore used a single donor (O+) for all experiments.…”

Section: Methodsmentioning

confidence: 99%

Nutrient limitation magnifies fitness costs of antimalarial drug resistance mutations

Nair

Arya

et al. 2021

Preprint

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Drug resistance mutations tend to disrupt key physiological processes, and therefore carry a fitness cost. The size of these fitness costs is a central determinant of the rate of spread of these mutations in natural populations so are important to quantify. Head-to-head competition assays provide a standard approach to measuring differential fitness, and have been used extensively for malaria parasites. These assays typically use standardized culture media, containing RPMI 1640, which has a 1.4 to 5.5-fold (mean: 2.6-fold) higher concentration of amino acids than human blood. In this rich media we predict that fitness costs will be underestimated because resource competition is weak. We tested this prediction using an artemisinin sensitive parasite edited to contain kelch-C580Y or R561H mutations conferring resistance to artemisinin or synonymous control mutations. We examined the impact of these single amino acid mutations on fitness, using replicated head-to head competition experiments conducted in media containing (i) normal RPMI, (ii) modified RPMI with reduced amino acid concentration, (iii) RPMI containing only isoleucine, or (iv) 3-fold diluted RPMI. We found a significant 1.3 to 1.4-fold increase in fitness costs measured in modified and isoleucine-only media relative to normal media, while fitness costs were 2.5-fold higher in diluted media. We conclude that fitness costs are strongly affected by media composition and will be significantly underestimated in normal RPMI. Elevated fitness costs in nature will limit spread of ART-resistance but will also promote evolution of compensatory mutations that restore fitness, and can be exploited to maximize selection in laboratory experiments.

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Primate malarias as a model for cross-species parasite transmission

Voinson

Nunn

Goldberg

2022

eLife

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Parasites regularly switch into new host species, representing a disease burden and conservation risk to the hosts. The distribution of these parasites also gives insight into characteristics of ecological networks and genetic mechanisms of host-parasite interactions. Some parasites are shared across many species, whereas others tend to be restricted to hosts from a single species. Understanding the mechanisms producing this distribution of host specificity can enable more effective interventions and potentially identify genetic targets for vaccines or therapies. As ecological connections between human and local animal populations increase, the risk to human and wildlife health from novel parasites also increases. Which of these parasites will fizzle out and which have the potential to become widespread in humans? We consider the case of primate malarias, caused by Plasmodium parasites, to investigate the interacting ecological and evolutionary mechanisms that put human and nonhuman primates at risk for infection. Plasmodium host switching from nonhuman primates to humans led to ancient introductions of the most common malaria-causing agents in humans today, and new parasite switching is a growing threat, especially in Asia and South America. Based on a wild host-Plasmodium occurrence database, we highlight geographic areas of concern and potential areas to target further sampling. We also discuss methodological developments that will facilitate clinical and field-based interventions to improve human and wildlife health based on this eco-evolutionary perspective.

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Common host variation drives malaria parasite fitness in healthy human red cells

Cited by 3 publications

References 96 publications

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

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

Nutrient limitation magnifies fitness costs of antimalarial drug resistance mutations

Primate malarias as a model for cross-species parasite transmission

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