Lipid hijacking: A unifying theme in vector-borne diseases

O’Neal, Anya J; Butler, L. Rainer; Rolandelli, Agustín; Gilk, Stacey D.; Pedra, Joao H. F.

doi:10.7554/elife.61675

Cited by 44 publications

(39 citation statements)

References 227 publications

(295 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Acylglycerols (triacylglycerol and, secondarily, diacylglycerol) have been found to accumulate in erythrocytes infected with P. falciparum during the late trophozoite and schizont stages (Nawabi et al, 2003). Our findings are consistent with knowledge that Plasmodium parasites often hijack host lipid receptors, to invade other tissues, increasing infection severity (reviewed in Alsultan et al, 2020; Orikiiriza et al, 2017; O’Neal et al, 2020) and a recent study of malaria in Rwandan children which found a metabolic shift to increased production of long-chain unsaturated fatty acid associated triacylglycerols in response to infection with P. falciparum (Orikiiriza et al, 2017). The genes in this module with expression that most strongly correlated to parasitemia included NAGA (logFC = −4.63, p = 2.18 × 10 − 6 , adj.…”

Section: Resultssupporting

confidence: 91%

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

Bergey

2020

Preprint

View full text Add to dashboard Cite

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.

show abstract

Section: Resultssupporting

confidence: 91%

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

Bergey

2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Host lipid remodeling is also observed in vertebrate infection by arboviruses to support their replication ( Ng et al, 2008 ; Fernández de Castro et al, 2016 ; Leier et al, 2020 ). Similar reprogramming events have already been shown in vector cells ( Perera et al, 2012 ; O’neal et al, 2020 ). An increase in the number of lipid droplets has been observed in Aedes albopictus C6/36 cells infected with dengue virus ( Samsa et al, 2009 ).…”

Section: Blood Digestion and Metabolic Signalingsupporting

confidence: 83%

“…In addition to proteins, vertebrate blood is also enriched with lipids. Host lipid usage by pathogens and regulatory changes of lipid metabolism triggered by infection appear as key players in several host-pathogen relationships, being essential determinants for vector competence, as recently revised by O’neal et al (2020) . Digestive lipases, such as TG lipases, are flux generating enzymes for lipid metabolism pathways.…”

Section: Blood Digestion and Metabolic Signalingmentioning

confidence: 99%

Non-immune Traits Triggered by Blood Intake Impact Vectorial Competence

et al. 2021

View full text Add to dashboard Cite

Blood-feeding arthropods are considered an enormous public health threat. They are vectors of a plethora of infectious agents that cause potentially fatal diseases like Malaria, Dengue fever, Leishmaniasis, and Lyme disease. These vectors shine due to their own physiological idiosyncrasies, but one biological aspect brings them all together: the requirement of blood intake for development and reproduction. It is through blood-feeding that they acquire pathogens and during blood digestion that they summon a collection of multisystemic events critical for vector competence. The literature is focused on how classical immune pathways (Toll, IMD, and JAK/Stat) are elicited throughout the course of vector infection. Still, they are not the sole determinants of host permissiveness. The dramatic changes that are the hallmark of the insect physiology after a blood meal intake are the landscape where a successful infection takes place. Dominant processes that occur in response to a blood meal are not canonical immunological traits yet are critical in establishing vector competence. These include hormonal circuitries and reproductive physiology, midgut permeability barriers, midgut homeostasis, energy metabolism, and proteolytic activity. On the other hand, the parasites themselves have a role in the outcome of these blood triggered physiological events, consistently using them in their favor. Here, to enlighten the knowledge on vector–pathogen interaction beyond the immune pathways, we will explore different aspects of the vector physiology, discussing how they give support to these long-dated host–parasite relationships.

show abstract

“…Also, rate-limiting to parasite growth are the diminishing intracellular pools of other nutrients including folate and purines ( Liu et al, 2006 ; Wang et al, 2007 ), and as P. falciparum is unable to synthesize purines, it is dependent upon the salvage of exogenous purines via the purine salvage pathway ( Reyes et al, 1982 ; Downie et al, 2008 ). While P. falciparum has some capacity to synthesize its own lipids (reviewed in O’Neal et al, 2020 ), several classes of lipids are rate-limiting and must also be obtained from an extracellular source ( Gulati et al, 2015 ; O’Neal et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

How Malaria Parasites Acquire Nutrients From Their Host

Counihan

Modak

Koning-Ward

2021

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Plasmodium parasites responsible for the disease malaria reside within erythrocytes. Inside this niche host cell, parasites internalize and digest host hemoglobin to source amino acids required for protein production. However, hemoglobin does not contain isoleucine, an amino acid essential for Plasmodium growth, and the parasite cannot synthesize it de novo. The parasite is also more metabolically active than its host cell, and the rate at which some nutrients are consumed exceeds the rate at which they can be taken up by erythrocyte transporters. To overcome these constraints, Plasmodium parasites increase the permeability of the erythrocyte membrane to isoleucine and other low-molecular-weight solutes it requires for growth by forming new permeation pathways (NPPs). In addition to the erythrocyte membrane, host nutrients also need to cross the encasing parasitophorous vacuole membrane (PVM) and the parasite plasma membrane to access the parasite. This review outlines recent advances that have been made in identifying the molecular constituents of the NPPs, the PVM nutrient channel, and the endocytic apparatus that transports host hemoglobin and identifies key knowledge gaps that remain. Importantly, blocking the ability of Plasmodium to source essential nutrients is lethal to the parasite, and thus, components of these key pathways represent potential antimalaria drug targets.

show abstract

Lipid hijacking: A unifying theme in vector-borne diseases

Cited by 44 publications

References 227 publications

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

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

Non-immune Traits Triggered by Blood Intake Impact Vectorial Competence

How Malaria Parasites Acquire Nutrients From Their Host

Contact Info

Product

Resources

About