A Family of Dual-Activity Glycosyltransferase-Phosphorylases Mediates Mannogen Turnover and Virulence in Leishmania Parasites

Sernee, M. Fleur; Ralton, Julie E.; Nero, Tracy L.; Sobala, L.F.; Kloehn, Joachim; Vieira-Lara, Marcel A.; Cobbold, Simon A.; Stanton, L.; Pires, Douglas E. V.; Hanssen, Eric; Males, Alexandra; Ward, Tom; Bastidas, L.M.; Peet, Phillip L. van der; Parker, Michael W.; Ascher, David B.; Williams, Spencer J.; Davies, G.J.; McConville, Malcolm J.

doi:10.1016/j.chom.2019.08.009

Cited by 33 publications

(37 citation statements)

References 68 publications

(82 reference statements)

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“…The relevance of LGT for the development of an intracellular life cycle has recently been highlighted by the description of the acquisition and subsequent evolution of a family of dual-activity glycosyltransferase-phosphorylases in Leishmania spp. (54). With respect to DECR, previous studies on LGT in trypanosomatids did not differentiate between DECR and DECR-like proteins.…”

Section: Discussionmentioning

confidence: 81%

Leishmania Encodes a Bacterium-like 2,4-Dienoyl-Coenzyme A Reductase That Is Required for Fatty Acid β-Oxidation and Intracellular Parasite Survival

Semini

Paape

Blume

et al. 2020

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Leishmania spp. are protozoan parasites that cause a spectrum of important diseases in humans. These parasites develop as extracellular promastigotes in the digestive tract of their insect vectors and as obligate intracellular amastigotes that infect macrophages and other phagocytic cells in their vertebrate hosts. Promastigote-to-amastigote differentiation is associated with marked changes in metabolism, including the upregulation of enzymes involved in fatty acid β-oxidation, which may reflect adaptation to the intracellular niche. Here, we have investigated the function of one of these enzymes, a putative 2,4-dienoyl-coenzyme A (CoA) reductase (DECR), which is specifically required for the β-oxidation of polyunsaturated fatty acids. The Leishmania DECR shows close homology to bacterial DECR proteins, suggesting that it was acquired by lateral gene transfer. It is present in other trypanosomatids that have obligate intracellular stages (i.e., Trypanosoma cruzi and Angomonas) but is absent from dixenous parasites with an exclusively extracellular lifestyle (i.e., Trypanosoma brucei). A DECR-green fluorescent protein (GFP) fusion protein was localized to the mitochondrion in both promastigote and amastigote stages, and the levels of expression increased in the latter stages. A Leishmania major Δdecr null mutant was unable to catabolize unsaturated fatty acids and accumulated the intermediate 2,4-decadienoyl-CoA, confirming DECR’s role in β-oxidation. Strikingly, the L. major Δdecr mutant was unable to survive in macrophages and was avirulent in BALB/c mice. These findings suggest that β-oxidation of polyunsaturated fatty acids is essential for intracellular parasite survival and that the bacterial origin of key enzymes in this pathway could be exploited in developing new therapies. IMPORTANCE The Trypanosomatidae are protozoan parasites that infect insects, plants, and animals and have evolved complex monoxenous (single host) and dixenous (two hosts) lifestyles. A number of species of Trypanosomatidae, including Leishmania spp., have evolved the capacity to survive within intracellular niches in vertebrate hosts. The adaptations, metabolic and other, that are associated with development of intracellular lifestyles remain poorly defined. We show that genomes of Leishmania and Trypanosomatidae that can survive intracellularly encode a 2,4-dienoyl-CoA reductase that is involved in catabolism of a subclass of fatty acids. The trypanosomatid enzyme shows closest similarity to the corresponding bacterial enzymes and is located in the mitochondrion and essential for intracellular growth of Leishmania. The findings suggest that acquisition of this gene by lateral gene transfer from bacteria by ancestral monoxenous Trypanosomatidae likely contributed to the development of a dixenous lifestyle of these parasites.

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Section: Discussionmentioning

confidence: 81%

Leishmania Encodes a Bacterium-like 2,4-Dienoyl-Coenzyme A Reductase That Is Required for Fatty Acid β-Oxidation and Intracellular Parasite Survival

Semini

Paape

Blume

et al. 2020

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“…to colonize new host niches and are essential for thermotolerance and the infection of the mammalian host (Sernee et al, 2019). Genomic evidence has demonstrated that HGT is not uncommon between bacterial species and parasitic protists (Nixon et al, 2003;Sernee et al, 2019) and the role this can play in human infections emphasizes the need to understand these relationships, especially to assess whether HGT is the result of protist predation over bacteria, or one of the possible outcomes of a hypothetical symbiotic relationship (Sibbald et al, 2020). An active investigation on the possibility that protists other than T.vaginalis and Acanthamoeba, especially Giardia spp., Leishmania spp., and E. histolytica, may have bacterial symbionts should be taken into account by parasitologists and bacteriologists alike.…”

Section: T Vaginalis/m Hominis Symbiosis and Cancermentioning

confidence: 99%

Paradigms of Protist/Bacteria Symbioses Affecting Human Health: Acanthamoeba species and Trichomonas vaginalis

et al. 2021

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Ever since the publication of the seminal paper by Lynn Margulis in 1967 proposing the theory of the endosymbiotic origin of organelles, the study of the symbiotic relationships between unicellular eukaryotes and prokaryotes has received ever-growing attention by microbiologists and evolutionists alike. While the evolutionary significance of the endosymbiotic associations within protists has emerged and is intensively studied, the impact of these relationships on human health has been seldom taken into account. Microbial endosymbioses involving human eukaryotic pathogens are not common, and the sexually transmitted obligate parasite Trichomonas vaginalis and the free-living opportunistic pathogen Acanthamoeba represent two unique cases in this regard, to date. The reasons of this peculiarity for T. vaginalis and Acanthamoeba may be due to their lifestyles, characterized by bacteria-rich environments. However, this characteristic does not fully explain the reason why no bacterial endosymbiont has yet been detected in unicellular eukaryotic human pathogens other than in T. vaginalis and Acanthamoeba, albeit sparse and poorly investigated examples of morphological identification of bacteria-like microorganisms associated with Giardia and Entamoeba were reported in the past. In this review article we will present the body of experimental evidences revealing the profound effects of these examples of protist/bacteria symbiosis on the pathogenesis of the microbial species involved, and ultimately their impact on human health.

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“…More recent evidence indicates that cytokines influence macrophage metabolic states, with consequences for the amastigote's access to required nutrients. Specific metabolic countermeasures may have evolved to combat these stresses and ensure long lived parasitism [23].…”

Section: Macrophage Activationmentioning

confidence: 99%

Leishmaniasis immunopathology—impact on design and use of vaccines, diagnostics and drugs

et al. 2020

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Leishmaniasis is a disease complex caused by 20 species of protozoan parasites belonging to the genus Leishmania. In humans the it has two main clinical forms, visceral leishmaniasis (VL) and cutaneous or tegumentary leishmaniasis (CL), as well as several other cutaneous manifestations in a minority of cases. In the mammalian host Leishmania infect different populations of macrophages where they multiply and survive in the phagolysosomal compartment. The progression of both VL and CL depends on the maintenance of a parasite-specific immunosuppressive state based upon this host macrophage infection. The complexity and variation of immune responses and immunopathology in humans and the different host interactions of the different Leishmania species has an impact upon the effectiveness of vaccines, diagnostics and drugs. Powered by Edit orial Manager® and ProduXion Manager® from Aries Syst em s Corporat ion Leishmaniasis immunopathologyimpact on design and use of vaccines, diagnostics and drugs

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A Family of Dual-Activity Glycosyltransferase-Phosphorylases Mediates Mannogen Turnover and Virulence in Leishmania Parasites

Cited by 33 publications

References 68 publications

Leishmania Encodes a Bacterium-like 2,4-Dienoyl-Coenzyme A Reductase That Is Required for Fatty Acid β-Oxidation and Intracellular Parasite Survival

Leishmania Encodes a Bacterium-like 2,4-Dienoyl-Coenzyme A Reductase That Is Required for Fatty Acid β-Oxidation and Intracellular Parasite Survival

Paradigms of Protist/Bacteria Symbioses Affecting Human Health: Acanthamoeba species and Trichomonas vaginalis

Leishmaniasis immunopathology—impact on design and use of vaccines, diagnostics and drugs

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