The intersection of host in vivo metabolism and immune responses to infection with kinetoplastid and apicomplexan parasites

Abstract

SUMMARYProtozoan parasite infection dramatically alters host metabolism, driven by immunological demand and parasite manipulation strategies. Immunometabolic checkpoints are often exploited by kinetoplastid and protozoan parasites to establish chronic infection, which can significantly impair host metabolic homeostasis. The recent growth of tools to analyze metabolism is expanding our understanding of these questions. Here, we review and contrast host metabolic alterations that occur in vivo during infection with Leishmania, trypanosomes, Toxoplasma, Plasmodium, and Cryptosporidium. Although genetically divergent, there are commonalities among these pathogens in terms of metabolic needs, induction of the type I immune responses required for clearance, and the potential for sustained host metabolic dysbiosis. Comparing these pathogens provides an opportunity to explore how transmission strategy, nutritional demand, and host cell and tissue tropism drive similarities and unique aspects in host response and infection outcome and to design new strategies to treat disease.

Keywords: Cryptosporidium; Leishmania; Plasmodium; Toxoplasma gondii; Trypanosoma; apicomplexan; host-parasite relationship; immunity; kinetoplastida; metabolism.

Fig 1

Amino acids and immune response modulation. (A) Glutamine can fuel the TCA cycle and glycolysis. The latter plays an important role in priming TH1 immunity and B cell responses that clear protozoan and apicomplexan parasites. Glutamine depletion conditions promote regulatory T cell responses (Treg) and limit TH17 responses in the intestine and brain, which can promote tissue pathology. (B) Classical activation upregulates iNOS which converts arginine to nitric oxide (NO), the precursor for reactive nitrogen species (ROS), and ROS which can be directly parasiticidal and cytotoxic. In contrast, “alternatively activated” macrophages are more reliant on beta-oxidation and use arginase to convert arginine to ornithine and urea. Arginase activity can be promoted by cruzipain synthesis in T. cruzi infected phagocytes. Alternative activation is associated with TH2 immunity and wound healing environments regulated by innate and adaptive immune cell cross talk with stromal cells in the tissue that promote fibroblast activation and extracellular matrix development. (C) Indolamine can be metabolized into kynurenine, which is associated with pro-resolution responses and the inhibition of TH1 and TH17 immunity. (D) Tryptophan can also be metabolized into kynurenine by the host or by T. brucei into indolepyruvate to inhibit TH1 and TH17 responses. Tyrosine conversion to hydroxyphenylpyruvate blunts glycolytic metabolism and the “classical activation” of antigen-presenting cells including macrophage (Mo) and dendritic cells (DC). Figure created with BioRender.com.

Fig 2

Nucleoside metabolism in parasite infection. Purines (tan) and pyrimidines (purple) serve as intracellular metabolites and extracellular signaling molecules. Kinetoplastids (A, B, and E) and apicomplexans (C and D) are purine auxotrophs that must acquire these metabolites from the host. Nucleoside balance is frequently dysregulated during infection depending on tissue type and time during infection, which may be related to inflammatory response and/or parasite burden. A2AR, adenosine A2A receptor. Figure created with BioRender.com.

Fig 3

Dysregulation of lipid metabolism during kinetoplastid and apicomplexan parasites infections. Parasitic infections mainly affect host lipolysis/beta oxidation and lipid biosynthesis/lipid scavenging. (A) T. cruzi infection as an example of lipolysis/beta oxidation perturbation. T. cruzi trypomastigotes infect a range of tissues including adipose tissue and cardiomyocytes. Top, infection is associated with elevation of long-chain fatty acids and acylcarnitines in the heart during acute infection, suggesting beta oxidation modulation. Bottom, amastigote replication in host cells leads to infiltration of immune cells and production of inflammatory cytokines including TNFα in adipose tissue which results in increased lipolysis. AAM, alternatively activated macrophages. (B) Parasitic scavenging of host lipids plays an important role in the perturbation of host lipid metabolism. Left, T. gondii and P. falciparum rely on host cholesterol while they can synthesize fatty acids and phospholipids. Intracellular T. gondii uptakes host cholesterol endocytosed by LDL receptor into parasitophorous vacuole. P. falciparum also imports host cholesterol by Niemann–Pick Type C1-Related 1 located in the parasite membrane. Middle, upregulation of cox2 leads to increases in prostaglandin levels in T. gondii, and Leishmania infection, while Plasmodium and T. brucei can also directly produce prostaglandins. Right, although kinetoplastid parasites are able to synthesize their own ergosterol, they uptake other host lipids including triglycerides, diglycerides, and some glycerophosphocholines. Fatty acids are metabolized through the acylcarnitine pathway. NEFA, non-esterified fatty acids. TGA, triglycerides. LCFA, long-chain fatty acids. Figure created with BioRender.com.

Fig 4

Glycolysis and TCA cycle. Glucose, the central fuel of glycolysis (yellow), is necessary to generate robust pro-inflammatory responses. Glucose-6 phosphate (P) can be diverted to the pentose phosphate shunt (blue). The end product of glycolysis, pyruvate, can be converted into acetyl-CoA to power the TCA cycle (gray). B cell generation of antibodies, TH2 immunity, and ROS generation are associated with TCA cycle activity. Kinetoplastids (A–C) and. Apicomplexans (D and E) may benefit from the activation of glycolysis. However, the enrichment or depletion of glycolytic metabolites is dependent on tissue identity and time of infection. Connections from the pentose phosphate pathway back toward glycolytic intermediates are not displayed, for simplicity. Figure created with BioRender.com.