Pyruvate produced by Brugia spp. via glycolysis is essential for maintaining the mutualistic association between the parasite and its endosymbiont, Wolbachia

Autor: Sara Lustigman, Waleed Ali, Shabnam Jawahar, Alexandra Grote, Thomas R. Unnasch, Elodie Ghedin, Emily Schnall, Denis Voronin
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Metabolic Processes
Male
Nematoda
Pathology and Laboratory Medicine
Biochemistry
Brugia pahangi
Brugia malayi
chemistry.chemical_compound
Drug Discovery
Pyruvic Acid
Medicine and Health Sciences
Glycolysis
Brugia Malayi
Biology (General)
Genes
Helminth
2. Zero hunger
0303 health sciences
biology
030302 biochemistry & molecular biology
Eukaryota
Ketones
Filariasis
3. Good health
Chemistry
Intracellular Pathogens
Physical Sciences
Female
Wolbachia
Pathogens
Research Article
Pyruvate
Drug Research and Development
QH301-705.5
Immunology
Microbiology
Host-Parasite Interactions
03 medical and health sciences
Virology
parasitic diseases
Brugia
Parasitic Diseases
Genetics
Animals
Humans
Symbiosis
Molecular Biology
030304 developmental biology
Pharmacology
Hexokinase
Bacteria
Host Microbial Interactions
Intracellular parasite
Chemical Compounds
Organisms
Biology and Life Sciences
RC581-607
biology.organism_classification
Invertebrates
Citric acid cycle
Metabolism
Gluconeogenesis
chemistry
Parasitology
Immunologic diseases. Allergy
Acids
Pyruvate kinase
Zdroj: PLoS Pathogens, Vol 15, Iss 9, p e1008085 (2019)
PLoS Pathogens
ISSN: 1553-7374
1553-7366
Popis: Human parasitic nematodes are the causative agents of lymphatic filariasis (elephantiasis) and onchocerciasis (river blindness), diseases that are endemic to more than 80 countries and that consistently rank in the top ten for the highest number of years lived with disability. These filarial nematodes have evolved an obligate mutualistic association with an intracellular bacterium, Wolbachia, a symbiont that is essential for the successful development, reproduction, and survival of adult filarial worms. Elimination of the bacteria causes adult worms to die, making Wolbachia a primary target for developing new interventional tools to combat filariases. To further explore Wolbachia as a promising indirect macrofilaricidal drug target, the essential cellular processes that define the symbiotic Wolbachia-host interactions need to be identified. Genomic analyses revealed that while filarial nematodes encode all the enzymes necessary for glycolysis, Wolbachia does not encode the genes for three glycolytic enzymes: hexokinase, 6-phosphofructokinase, and pyruvate kinase. These enzymes are necessary for converting glucose into pyruvate. Wolbachia, however, has the full complement of genes required for gluconeogenesis starting with pyruvate, and for energy metabolism via the tricarboxylic acid cycle. Therefore, we hypothesized that Wolbachia might depend on host glycolysis to maintain a mutualistic association with their parasitic host. We did conditional experiments in vitro that confirmed that glycolysis and its end-product, pyruvate, sustain this symbiotic relationship. Analysis of alternative sources of pyruvate within the worm indicated that the filarial lactate dehydrogenase could also regulate the local intracellular concentration of pyruvate in proximity to Wolbachia and thus help control bacterial growth via molecular interactions with the bacteria. Lastly, we have shown that the parasite’s pyruvate kinase, the enzyme that performs the last step in glycolysis, could be a potential novel anti-filarial drug target. Establishing that glycolysis is an essential component of symbiosis in filarial worms could have a broader impact on research focused on other intracellular bacteria-host interactions where the role of glycolysis in supporting intracellular survival of bacteria has been reported.
Author summary Wuchereria bancrofti, Brugia malayi, Brugia timori, and Onchocerca volvulus are human parasitic nematodes and causative agents of lymphatic filariasis (LF, elephantiasis) and onchocerciasis (river blindness). These neglected tropical diseases are ranked in the top ten for the highest years lived with disability. In 2016, the global prevalence of LF was between 24.8 to 36.1 million while for onchocerciasis it was 9.5 to 24.2 million. These nematodes have evolved a mutualistic association with an intracellular bacterium, Wolbachia, an obligatory symbiont that is essential for the successful development, reproduction, and survival of adult filarial worms. Consequently, these bacteria are a target of interest for developing new interventional tools to combat the filariases. To develop macrofilaricidal drug targets, we must identify the cellular processes that define the symbiotic relationship between the bacteria and their filarial hosts. Here, we evaluated the role of glycolysis—a pathway that is incomplete in Wolbachia—in the symbiotic relationship. We found that glycolysis is an essential metabolic pathway that supports the symbiosis between the filarial worm and Wolbachia, and demonstrated that this pathway, on which Wolbachia rely, can be exploited to discover new or repurposed drugs, and thus facilitate anti-filarial elimination goals.
Databáze: OpenAIRE
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