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

Voronin, Denis; Schnall, Emily; Grote, Alexandra; Jawahar, Shabnam; Ali, Waleed; Unnasch, Thomas R.; Ghedin, Elodie; Lustigman, Sara

doi:10.1371/journal.ppat.1008085

Cited by 24 publications

(31 citation statements)

References 41 publications

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“…Across the three samples, in both soma and germline, the most expressed wBm genes are involved in transcription and protein synthesis, but also in ATP production and pyruvate catabolism. This last observation is in agreement with pyruvate being at the host-endosymbiont metabolic interface since wBm are unable to perform glycolysis, and both pyruvate phosphate dikinase and pyruvate dehydrogenase complex dihydrolipoamide acetyltransferase are found to be upregulated by in vitro pyruvate supplementation [21,46,47]. The elevated expression of genes involved in ATP production also corroborates the results of previous transcriptomic and proteomic analyses of wOo in the filarial parasite O. ochengi, that suggests a nucleotide provisioning of the host in this symbiosis [23].…”

Section: Plos Neglected Tropical Diseasessupporting

confidence: 89%

Dual RNAseq analyses at soma and germline levels reveal evolutionary innovations in the elephantiasis-agent Brugia malayi, and adaptation of its Wolbachia endosymbionts

Chevignon

Foray²,

Pérez-Jiménez³

et al. 2021

PLoS Negl Trop Dis

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Brugia malayi is a human filarial nematode responsible for elephantiasis, a debilitating condition that is part of a broader spectrum of diseases called filariasis, including lymphatic filariasis and river blindness. Almost all filarial nematode species infecting humans live in mutualism with Wolbachia endosymbionts, present in somatic hypodermal tissues but also in the female germline which ensures their vertical transmission to the nematode progeny. These α-proteobacteria potentially provision their host with essential metabolites and protect the parasite against the vertebrate immune response. In the absence of Wolbachia wBm, B. malayi females become sterile, and the filarial nematode lifespan is greatly reduced. In order to better comprehend this symbiosis, we investigated the adaptation of wBm to the host nematode soma and germline, and we characterized these cellular environments to highlight their specificities. Dual RNAseq experiments were performed at the tissue-specific and ovarian developmental stage levels, reaching the resolution of the germline mitotic proliferation and meiotic differentiation stages. We found that most wBm genes, including putative effectors, are not differentially regulated between infected tissues. However, two wBm genes involved in stress responses are upregulated in the hypodermal chords compared to the germline, indicating that this somatic tissue represents a harsh environment to which wBm have adapted. A comparison of the B. malayi and C. elegans germline transcriptomes reveals a poor conservation of genes involved in the production of oocytes, with the filarial germline proliferative zone relying on a majority of genes absent from C. elegans. The first orthology map of the B. malayi genome presented here, together with tissue-specific expression enrichment analyses, indicate that the early steps of oogenesis are a developmental process involving genes specific to filarial nematodes, that likely result from evolutionary innovations supporting the filarial parasitic lifestyle.

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Section: Plos Neglected Tropical Diseasessupporting

confidence: 89%

Dual RNAseq analyses at soma and germline levels reveal evolutionary innovations in the elephantiasis-agent Brugia malayi, and adaptation of its Wolbachia endosymbionts

Chevignon

Foray²,

Pérez-Jiménez³

et al. 2021

PLoS Negl Trop Dis

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“…7) (NES = 1.61, P = 0.039). Interestingly, data suggest Wolbachia may compete for glycerol-3-phosphate and/or pyruvate from the host for energy, which are metabolites prevalent in our observed downregulated pathways (46,47). Overall, these data reveal that autophagy mutants, when in the presence of Wolbachia, reduce glycolysis and glycerolipid metabolism, which could restrict Wolbachia density through limited accumulation of essential metabolites.…”

Section: Resultsmentioning

confidence: 55%

“…In Wolbachia-infected ovaries with autophagy knocked down, metabolomics analysis revealed a reduction in glycolysis/gluconeogenesis and glycerolipid metabolism. Interestingly, the density of Wolbachia infecting Brugia malayi has been coupled to host glycolysis and pyruvate levels, indicating that autophagy-induced reduction in glycolysis could lead to an unfavorable growth environment for Wolbachia (16,47). It should also be noted that glycerol-3-phosphate is a member of the glycerolipid metabolism pathway, and Wolbachia has a predicted transporter and ability to convert glycerol-3-phosphate into a functional metabolite in Wolbachia glycolysis (46).…”

Section: Discussionmentioning

confidence: 99%

Intracellular Density of Wolbachia Is Mediated by Host Autophagy and the Bacterial Cytoplasmic Incompatibility Gene cifB in a Cell Type-Dependent Manner in Drosophila melanogaster

Deehan

Lin

Blum

et al. 2021

mBio

119

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Autophagy is an intracellular degradation pathway involved in innate immunity. Pathogenic bacteria have evolved several mechanisms to escape degradation or exploit autophagy to acquire host nutrients. In the case of endosymbionts, which often have commensal or mutualistic interactions with the host, autophagy is not well characterized. We utilized tissue-specific autophagy mutants to determine if Wolbachia, a vertically transmitted obligate endosymbiont of Drosophila melanogaster, is regulated by autophagy in somatic and germ line cell types. Our analysis revealed core autophagy proteins Atg1 and Atg8 and a selective autophagy-specific protein Ref(2)p negatively regulate Wolbachia in the hub, a male gonad somatic cell type. Furthermore, we determined that the Wolbachia effector protein, CifB, modulates autophagy-Wolbachia interactions, identifying a new host-related pathway which these bacterial proteins interact with. In the female germ line, the cell type necessary for inheritance of Wolbachia through vertical transmission, we discovered that bulk autophagy mediated by Atg1 and Atg8 positively regulates Wolbachia density, whereas Ref(2)p had no effect. Global metabolomics of fly ovaries deficient in germ line autophagy revealed reduced lipid and carbon metabolism, implicating metabolites from these pathways as positive regulators of Wolbachia. Our work provides further understanding of how autophagy affects bacteria in a cell type-dependent manner. IMPORTANCE Autophagy is a eukaryotic intracellular degradation pathway which can act as an innate immune response to eliminate pathogens. Conversely, pathogens can evolve proteins which modulate the autophagy pathway to subvert degradation and establish an infection. Wolbachia, a vertically transmitted obligate endosymbiont which infects up to 40% of insect species, is negatively regulated by autophagy in whole animals, but the specific molecular mechanism and tissue which govern this interaction remain unknown. Our studies use cell type-specific autophagy mutants to reveal that Wolbachia is negatively regulated by selective autophagy in the soma, while nonselective autophagy positively regulates Wolbachia in the female germ line. These data provide evidence that cell type can drive different basal autophagy programs which modulate intracellular microbes differently. Additionally, we identified that the Wolbachia effector CifB acts in the selective autophagy pathway to aid in intracellular bacterial survival, providing a new function for CifB beyond its previously identified role in reproductive manipulation.

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“…In the mutually exclusive association between Wolbachia and filarial nematodes, evidence indicates that Wolbachia plays a role in heme provisioning [ 27 , 28 ], while directly relying on host pyruvate production, through glycolysis, for its own survival. Removal of Wolbachia via antibiotic treatment led to increased host levels of glucose and glycogen [ 29 , 30 ].…”

Section: Introductionmentioning

confidence: 99%

Wolbachia and Sirtuin-4 interaction is associated with alterations in host glucose metabolism and bacterial titer

2020

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Wolbachia is an intracellular bacterial symbiont of arthropods notorious for inducing many reproductive manipulations that foster its dissemination. Wolbachia affects many aspects of host biology, including metabolism, longevity and physiology, being described as a nutrient provisioning or metabolic parasite, depending on the host-microbe association. Sirtuins (SIRTs) are a family of NAD + -dependent post-translational regulatory enzymes known to affect many of the same processes altered by Wolbachia , including aging and metabolism, among others. Despite a clear overlap in control of host-derived pathways and physiology, no work has demonstrated a link between these two regulators. We used genetically tractable Drosophila melanogaster to explore the role of sirtuins in shaping signaling pathways in the context of a host-symbiont model. By using transcriptional profiling and metabolic assays in the context of genetic knockouts/over-expressions, we examined the effect of several Wolbachia strains on host sirtuin expression across distinct tissues and timepoints. We also quantified the downstream effects of the sirtuin x Wolbachia interaction on host glucose metabolism, and in turn, how it impacted Wolbachia titer. Our results indicate that the presence of Wolbachia is associated with (1) reduced sirt-4 expression in a strain-specific manner, and (2) alterations in host glutamate dehydrogenase expression and ATP levels, key components of glucose metabolism. We detected high glucose levels in Wolbachia- infected flies, which further increased when sirt-4 was over-expressed. However, under sirt-4 knockout, flies displayed a hypoglycemic state not rescued to normal levels in the presence of Wolbachia . Finally, whole body sirt-4 over-expression resulted in reduced Wolbachia ovarian titer. Our results expand knowledge of Wolbachia -host associations in the context of a yet unexplored class of host post-translational regulatory enzymes with implications for conserved host signaling pathways and bacterial titer, factors known to impact host biology and the symbiont’s ability to spread through populations.

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

Cited by 24 publications

References 41 publications

Dual RNAseq analyses at soma and germline levels reveal evolutionary innovations in the elephantiasis-agent Brugia malayi, and adaptation of its Wolbachia endosymbionts

Dual RNAseq analyses at soma and germline levels reveal evolutionary innovations in the elephantiasis-agent Brugia malayi, and adaptation of its Wolbachia endosymbionts

Intracellular Density of Wolbachia Is Mediated by Host Autophagy and the Bacterial Cytoplasmic Incompatibility Gene cifB in a Cell Type-Dependent Manner in Drosophila melanogaster

Wolbachia and Sirtuin-4 interaction is associated with alterations in host glucose metabolism and bacterial titer

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