Nutrition and Bipartite Metabolism of Intracellular Pathogens

Best, Ashley; Kwaik, Yousef Abu

doi:10.1016/j.tim.2018.12.012

Cited by 37 publications

(35 citation statements)

References 104 publications

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“…In general, there is no clear consensus in literature regarding if T. cruzi infection causes a reduction or an increase in the expression of genes controlling the energy production of the cell. Previous studies showed similar downregulation of oxidative phosphorylation genes in cardiomyocytes infected by distinct T. cruzi strains (Garg et al, 2003;Vyatkina et al, 2004;Manque et al, 2011;Best and Abu Kwaik, 2019). Experiments in vivo using mouse models during early timepoints, are in consistency with our findings that these genes decrease expression over disease progression (Garg et al, 2003;Vyatkina et al, 2004).…”

Section: Discussionsupporting

confidence: 92%

“…In this sense, the inhibition of MAP kinases and the NFκB pathway are mechanisms that pathogenic bacteria can exploit to increase their chances of survival inside a host cell (Cornejo et al, 2017). Additionally, pathogenic bacteria have mechanisms for inhibiting host protein translation to increase the availability of amino acids in the cytosol and can act to augment the uptake of nutrients from the cell (Best and Abu Kwaik, 2019). The data obtained in this study indicates that an unique capability to inhibit translation is also present in some strains of T. cruzi and may be an important mechanism to allow the persistence of the parasite in a specific organ.…”

Section: Discussionmentioning

confidence: 99%

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Differential Modulation of Mouse Heart Gene Expression by Infection With Two Trypanosoma cruzi Strains: A Transcriptome Analysis

et al. 2020

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The causative agent of Chagas disease, Trypanosoma cruzi, retains high genetic diversity, and its populations vary greatly in different geographic locations. T. cruzi mammalian hosts, including humans, also have high genetic variation, making it difficult to predict the disease outcome. Accordingly, this variability must be taken into account in studies aiming to determine the effect of polyparasitism on drug trials, vaccine studies, diagnosis or basic research. Therefore, there is a growing need to consider the interaction between the pathogen and the host immune system in mixed infections. In the present work, we show an in-depth analysis of gene expression in hearts from BALB/c mice infected with either Col1.7G2 or JG alone or a mixture of both strains. Col1.7G2 induced a higher Th1 inflammatory response, while JG produced a weaker activation of immune response genes. Furthermore, JGinfected mice showed a notable reduction in the expression of genes responsible for mitochondrial oxidative phosphorylation and protein synthesis. Interestingly, the mixture-infected group displayed changes in gene expression caused by both strains. Overall, we provided new insights into the host-pathogen interaction in the context of single and dual infection by showing the remarkable differences in the modulation of host gene expression by the two T. cruzi strains.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Differential Modulation of Mouse Heart Gene Expression by Infection With Two Trypanosoma cruzi Strains: A Transcriptome Analysis

et al. 2020

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“…This work illustrates that bacteria adapt their Q salvage strategies to their environments. Bacteria that are located inside a human cell such as C. trachomatis have streamlined their metabolism and rely on import for many nutrients (57)(58)(59)(60). Only q or Q are supposedly available in the intracellular environment, and we show here that Chlamydiae species have evolved to salvage the q base: a YhhQ family member (CT140) imports q, and a bacterial TGT homolog (CT193) catalyzes the base exchange between q and the target guanine in tRNAs.…”

Section: Discussionmentioning

confidence: 83%

Discovery of novel bacterial queuine salvage enzymes and pathways in human pathogens

Yuan

Zallot

Grove

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Queuosine (Q) is a complex tRNA modification widespread in eukaryotes and bacteria that contributes to the efficiency and accuracy of protein synthesis. Eukaryotes are not capable of Q synthesis and rely on salvage of the queuine base (q) as a Q precursor. While many bacteria are capable of Q de novo synthesis, salvage of the prokaryotic Q precursors preQ0 and preQ1 also occurs. With the exception of Escherichia coli YhhQ, shown to transport preQ0 and preQ1, the enzymes and transporters involved in Q salvage and recycling have not been well described. We discovered and characterized 2 Q salvage pathways present in many pathogenic and commensal bacteria. The first, found in the intracellular pathogen Chlamydia trachomatis, uses YhhQ and tRNA guanine transglycosylase (TGT) homologs that have changed substrate specificities to directly salvage q, mimicking the eukaryotic pathway. The second, found in bacteria from the gut flora such as Clostridioides difficile, salvages preQ1 from q through an unprecedented reaction catalyzed by a newly defined subgroup of the radical-SAM enzyme family. The source of q can be external through transport by members of the energy-coupling factor (ECF) family or internal through hydrolysis of Q by a dedicated nucleosidase. This work reinforces the concept that hosts and members of their associated microbiota compete for the salvage of Q precursors micronutrients.

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“…An emerging concept in bacterial pathogenesis is nutritional virulence, whereby intracellular bacteria are specifically adapted to obtain essential nutrients by exploiting host metabolic processes (37). Several bacteria, including Anaplasma phagocytophilum and Francisella tularensis, utilize host autophagy for nutrient acquisition (6). Investigators have speculated that C. burnetii can also obtain nutrients from the host via CCV fusion with autophagosomes (6, 9).…”

Section: Discussionmentioning

confidence: 99%

“…transporting nutrients through a vacuole membrane barrier. Legionella pneumophila is phylogenetically related to C. burnetii and exploits the host's neutral amino acid transporter, solute carrier (SLC) 1A5, to obtain amino acids from the cytoplasm (6)(7)(8). Unlike other vacuolar bacteria, C. burnetii resides within a harsh phagolysosome-like compartment that is thought to be a rich source of nutrients delivered by fusion with endocytic and autophagic vesicles (9,10).…”

mentioning

confidence: 99%

Replication of Coxiella burnetii in a Lysosome-Like Vacuole Does Not Require Lysosomal Hydrolases

2019

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Coxiella burnetii is an intracellular bacterium that causes query, or Q fever, a disease that typically manifests as a severe flu-like illness. The initial target of C. burnetii is the alveolar macrophage. Here, it regulates vesicle trafficking pathways and fusion events to establish a large replication vacuole called the Coxiella-containing vacuole (CCV). Similar to a phagolysosome, the CCV has an acidic pH and contains lysosomal hydrolases obtained via fusion with late endocytic vesicles. Lysosomal hydrolases break down various lipids, carbohydrates, and proteins; thus, it is assumed C. burnetii derives nutrients for growth from these degradation products. To investigate this possibility, we utilized a GNPTAB−/− HeLa cell line that lacks lysosomal hydrolases in endocytic compartments. Unexpectedly, examination of C. burnetii growth in GNPTAB−/− HeLa cells revealed replication and viability are not impaired, indicating C. burnetii does not require by-products of hydrolase degradation to survive and grow in the CCV. However, although bacterial growth was normal, CCVs were abnormal, appearing dark and condensed rather than clear and spacious. Lack of degradation within CCVs allowed waste products to accumulate, including intraluminal vesicles, autophagy protein LC3, and cholesterol. The build-up of waste products coincided with an altered CCV membrane, where LAMP1 was decreased and CD63 and LAMP1 redistributed from a punctate to uniform localization. This disruption of CCV membrane organization may account for the decreased CCV size due to impaired fusion with late endocytic vesicles. Collectively, these results demonstrate lysosomal hydrolases are not required for C. burnetii survival and growth but are needed for normal CCV development. These data provide insight into mechanisms of CCV biogenesis while raising the important question of how C. burnetii obtains essential nutrients from its host.

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Nutrition and Bipartite Metabolism of Intracellular Pathogens

Cited by 37 publications

References 104 publications

Differential Modulation of Mouse Heart Gene Expression by Infection With Two Trypanosoma cruzi Strains: A Transcriptome Analysis

Differential Modulation of Mouse Heart Gene Expression by Infection With Two Trypanosoma cruzi Strains: A Transcriptome Analysis

Discovery of novel bacterial queuine salvage enzymes and pathways in human pathogens

Replication of Coxiella burnetii in a Lysosome-Like Vacuole Does Not Require Lysosomal Hydrolases

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