Lipid hijacking: A unifying theme in vector-borne diseases
- Department of Microbiology and Immunology, University of Maryland School of Medicine, United States
- Department of Microbiology and Immunology, Indiana University School of Medicine, United States
Figures
Figure 1
Arthropod-borne pathogens and their vectors.
Arthropod vectors transmit various bacteria, viruses, and parasites to mammalian hosts. These pathogens infect hundreds of millions of people each year and are a primary concern of public health efforts (WHO, 2020). (A) Ixodes spp. ticks transmit POWV, Borrelia, Anaplasma, Ehrlichia, and Babesia spp.; (B) Anopheles mosquitoes transmit Plasmodium spp.; (C) Aedes (shown) and Culex mosquitoes transmit various flaviviruses and alphaviruses; (D) Triatoma (shown) and Rhodnius triatomines transmit Trypanosoma cruzi; (E) Glossina tsetse flies transmit Trypanosoma brucei; and (F) Lutzomyia (shown) and Phlebotomus sand flies transmit Leishmania spp.
Figure 2
Classification of membrane lipids.
Lipids structure the membranes of both eukaryotic and prokaryotic cells. (A) Fatty acids are hydrophobic building blocks for many membrane lipids. Common fatty acids include palmitic acid (16:0), oleic acid (18:1), and arachidonic acid (20:4), whose structures differ in the number of carbons and number of double bonds per chain. The presence of double bonds in the chains of certain fatty acids, such as oleic acid and arachidonic acid, makes these lipids unsaturated. (B) Glycerolipids and glycerophospholipids are two classifications of lipids found in eukaryotic and prokaryotic membranes. Glycerolipids (e.g. diacylglycerol) contain a glycerol backbone and at least one fatty acyl chain. Glycerophospholipids, conversely, are glycerolipids that contain a polar head group comprised of phosphate and an alcohol, and are named accordingly (e.g. PG, PE, PI, PS, PC). In the membrane, these lipids largely consist of two fatty acyl chains connected to the glycerol backbone. (C) Sphingolipids are membrane lipids that possess a sphingosine backbone. These include sphingomyelin, which contains a sphingosine backbone, one fatty acyl chain, and either phosphocholine (shown) or phosphoethanolamine. (D) Glycolipids refer to membrane lipids, such as glycerolipids or sphingolipids, that are covalently linked to a sugar residue. (E) Bacterial lipoproteins are membrane molecules that possess an exposed polypeptide chain and either two (diacyl; shown) or three (triacyl) fatty acyl chains. (F) Sterols are essential in eukaryotic physiology and include the animal sterol cholesterol, a critical component of cell membranes. p = phosphate, G = glycerol, E = ethanolamine, I = inositol, S = serine, C = choline, PG = phosphatidylglycerol, PE = phosphatidylethanolamine, PI = phosphatidylinositol, PS = phosphatidylserine, PC = phosphatidylcholine.
Figure 3
Lipid scavenging by extracellular arthropod-borne pathogens.
Certain pathogens can obtain nutrients directly from their environment and may not require host cell invasion for lipid uptake. (A) Borrelia spp. are extracellular bacteria and acquire lipids directly from mammalian cells and the blood. B. burgdorferi also organizes its membrane into eukaryotic-like lipid rafts. (B) Trypanosoma brucei is extracellular in both mammalian and arthropod hosts. These parasites acquire various lipids from the blood and can synthesize their own fatty acids using the type II fatty acid synthase system (FASII) and the microsomal elongase pathway when resources are restricted. In the tsetse fly, the enzyme acetyl coenzyme A carboxylase (ACC) regulates the microsomal elongase pathway based on lipid abundance. (C) Trypanosoma cruzi is extracellular in its trypomastigote and epimastigote forms. Within the triatomine, epimastigotes acquire various lipids from the blood meal. Additional lipids function as signaling molecules and promote the differentiation from epimastigotes into metacyclic trypomastigotes. At this stage, metacyclic trypomastigotes may be deposited in the skin of a mammal before invading cells to become amastigotes. Intracellular amastigotes transform into trypomastigotes, burst out of host cells, and enter the bloodstream. PC = phosphatidylcholine, PG = phosphatidylglycerol, HDL = high density lipoprotein, LDL = low density lipoprotein, LPL = lysophospholipid, TAG = triacylglycerol, SM = sphingomyelin, PL = phospholipid, LPC = lysophosphatidylcholine, OA = oleic acid.
Figure 4
Immune evasion mechanisms by arthropod-borne pathogens.
(A) Microbial lipids: Borrelia spp. use lipoproteins and other surface lipids to evade immunity and promote disease in humans. Borrelia possess various lipoproteins that inhibit the complement system in the blood. Additionally, antibodies are generated during Borrelia infection that promote anti-phospholipid syndrome, an autoimmune condition that targets phospholipids. Leishmania spp. contain the surface molecule lipophosphoglycan (LPG), which prevents the maturation of the phagosome. (B) Host lipids and metabolism: West Nile Virus (WNV) redistributes cholesterol from the plasma membrane to replication sites at the ER. This phenomenon disrupts lipid rafts, which downregulates JAK/STAT activation and antiviral responses. (C) Surface lipid receptors: Erythrocytes infected with Plasmodium engage the lipid receptor CD36. Infected erythrocytes bind CD36 on endothelial cells and promote cytoadherence, which may lead to severe complications (e.g. cerebral malaria). Flaviviruses and arboviruses have been shown to engage the phosphatidylserine (PS) receptors TIM and TAM. These receptors have known immunosuppressive functions. Engagement of TAM, specifically, has been shown to inhibit type I interferon signaling during infection with other enveloped viruses. (D) Lipid signaling molecules: Eicosanoids, such as prostaglandins and leukotrienes, are formed by the cleavage of arachidonic acid. Eicosanoids may have immunomodulatory roles during trypanosomatid infections. Prostaglandin E2 (PGE2), for example, promotes parasite viability and may be immunosuppressive. Conversely, leukotriene B4 (LTB4) is proinflammatory and recruits neutrophils.
Tables
Table 1
Lipid hijacking by intracellular arthropod-borne pathogens.
| Microbe | Anaplasma and Ehrlichia | Flaviviruses | Alphaviruses |
|---|---|---|---|
| Vector | • Accumulation of lipid transport and absorption proteins from the blood meal in the vector (Villar et al., 2016) | • Increase phospholipid and sphingolipid synthesis (Perera et al., 2012; Melo et al., 2016; Chotiwan et al., 2018; Vial et al., 2019) • Replication occur on ER; form replication vesicles but not convoluted membranes (Junjhon et al., 2014) • Increase aminophospholipid concentrations by regulating AGPAT1 expression in mosquito cells (DENV) (Vial et al., 2019) • Maintain cholesterol levels in mosquito cells by downregulating LRP-1 (DENV) (Tree et al., 2019) • Increase lipid droplets in the cell (Barletta et al., 2016) | • Increase lipid droplets in the cell (Barletta et al., 2016) |
| Mammal | • Accumulate cholesterol in membranes, elevate cellular cholesterol levels and traffic cholesterol to inclusions using flotillins and NPC1-bearing vesicles (A. phagocytophilum) (Xiong et al., 2009; Xiong and Rikihisa, 2012; Xiong et al., 2019) • Manipulate glycerolipid synthesis (A. phagocytophilum) (POPG, PODAG, MPPC) (Shaw et al., 2017) • Recruit membrane phospholipids to bacterial vacuoles (E. chaffeensis) (Lin et al., 2020) | • Viral replication curves the ER lipid bilayer into vesicles and convoluted membranes (Leier et al., 2018) • Increase sphingolipid synthesis and require ceramide for replication vesicles (WNV, ZIKV) (Martín-Acebes et al., 2014; Leier et al., 2020) • Recruit host fatty acid synthase to replication sites for fatty acid synthesis (DENV) (Heaton et al., 2010) • Increase intracellular cholesterol levels (DENV, WNV), induce cholesterol accumulation at the ER (DENV, WNV), and bring in HMGCR to replication sites for cholesterol synthesis (DENV) (Mackenzie et al., 2007; Rothwell et al., 2009; Soto-Acosta et al., 2013; Soto-Acosta et al., 2017) • Interact with lipid droplets on the ER for assembly (DENV) (Samsa et al., 2009) • Lipid droplets are consumed/reabsorbed by the ER for fatty acids and energy (DENV) (Heaton and Randall, 2010; Peña and Harris, 2012; Zhang et al., 2018) | • Require intracellular cholesterol transport (CHIKV) (Wichit et al., 2017) • Nonstructural proteins colocalize with lipid droplets (Remenyi et al., 2017) • Use Akt pathway to drive fatty acid synthesis (SFV) (Mazzon et al., 2018) |
| Microbe | Plasmodium | Babesia | |
| Vector | Oocysts: • Acquires lipids through lipophorin (Atella et al., 2009; Costa et al., 2018) • Availability of lipophorin-transported lipids impacts growth in the mosquito and infectivity, virulence, quantity, and metabolism of sporozoites (Costa et al., 2018; Werling et al., 2019) | Unknown | |
| Mammal | Liver stage: • Scavenges PC and extracellular and intracellularly synthesized cholesterol (Labaied et al., 2011; Itoe et al., 2014) • Promotes host lipid biosynthesis by inhibiting AMPK pathway (Kluck et al., 2019) • Uses parasite fatty acid synthesis (FAS) II pathway in late liver stage (Yu et al., 2008; Vaughan et al., 2009) Blood stage: • Scavenges fatty acids, choline, ethanolamine, and serine from blood to synthesize phospholipids (PC, PE) (Mikkelsen et al., 1988; Wein et al., 2018; Tanaka et al., 2019) • Uses host Kennedy and PMT pathways to synthesize phospholipids (Ancelin and Vial, 1989; Pessi et al., 2004) • Upregulates triacylglycerol, diacylglycerol, PG, etc. (Gulati et al., 2015) Sexual stages: • PMT pathway is required for making gametocytes (Bobenchik et al., 2013) • Availability of polyunsaturated fatty acids and downregulation of lysophospholipids in the blood triggers gametocytogenesis (Brancucci et al., 2017; Tanaka et al., 2019) • Gametocytes have decreased phospholipids, increased ceramides and sphingolipids (Gulati et al., 2015) | • Causes low HDL levels in patients (Cunha et al., 2000; Bock et al., 2017) • Causes low HDL levels in canines and cattle (Goodger et al., 1990; Milanović et al., 2019) • Synthesizes PC in the blood stage (Florin-Christensen et al., 2000) | |
| Microbe | Leishmania* | Trypanosoma cruzi* | |
| Mammal | • Increases lipid concentrations by regulating expression of lipid metabolism genes (Osorio y Fortéa et al., 2009; Rabhi et al., 2012; Semini et al., 2017) • Sequesters cholesterol in parasitophorous vacuoles and incorporates it in membranes; retains cholesterol using host V-ATPases (Tewary et al., 2006; Semini et al., 2017; Pessoa et al., 2019) • Induces lipid body formation (Rabhi et al., 2016) • Scavenges phospholipids and sphingolipids to make parasite-specific lipids, e.g. the sphingolipid inositol phosphorylceramide (Winter et al., 1994; Henriques et al., 2003; Zhang et al., 2005) • Contains increased cholesterol and free fatty acids, decreased ergosterol and triglycerides (Bouazizi-Ben Messaoud et al., 2017) | • Scavenges long chain fatty acids from pools of triacylglycerols for membranes (Gazos-Lopes et al., 2017) • Upregulates levels of cholesterol and LDL (Johndrow et al., 2014) • Requires host fatty acid oxidation for parasite growth (Caradonna et al., 2013; Li et al., 2016) • Induces lipid body formation (D'Avila et al., 2011) |
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*Extracellular stages in the vector.
Table 2
Requirement of lipid scavenging for microbial growth.
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Lipid hijacking: A unifying theme in vector-borne diseases
eLife 9:e61675.
https://doi.org/10.7554/eLife.61675
