Francisella tularensis Exploits AMPK Activation to Harvest Host-Derived Nutrients Liberated from Host Lipolysis

Dominguez, Sedelia; Whiles, Shannon; Deobald, Kelly; Kawula, Thomas H.

doi:10.1128/iai.00155-22

Cited by 3 publications

(3 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…infection at 48 hours, indicative of an increased bioenergetic potential ( S6F Fig ). The combination of increased NADPH/NADP+ ratio and bioenergetic potential are conducive of increased anabolic functions, including fatty acid synthesis which has been reported to be an energy source for FTT replication [ 22 , 23 ]. Conversely, the ear had higher baseline reduced/oxidized glutathione and NADH/NAD+ ratios that decreased with time, suggesting elevated redox stress ( S4F and S5A Figs).…”

Section: Resultsmentioning

confidence: 99%

“…A convenient virulence strategy would be to manipulate host metabolic hubs to achieve both requirements. For example, FTT is reported to primarily rely on host amino acids, fatty acids, and glycerol for replication [ 22 , 23 , 36 ]. Coincidently, maintaining mitochondrial function, limiting pro-inflammatory glycolysis, and increasing cellular bioenergetics could meet both demands [ 12 , 15 ].…”

Section: Discussionmentioning

confidence: 99%

“…For example, increased amino acid depletion was evident in the pulmonary compartment relative to the intradermal compartment over time, potentially indicating increased amino acid consumption by FTT ( Fig 4A ). Additionally, a high NADPH/NADP+ ratio, which occurred in the lungs after FTT infection, could be a manifestation of either increased pentose phosphate pathway flux and/or lipogenesis, both of which provide essential fuel sources [ 22 , 23 , 36 , 38 ]. The observation that FTT maintains or limits modulation of the NADPH/NADP+ ratio and pentose phosphate pathway in the lungs even under extrinsic metabolic pressures provided by preconditioning with LPS further support the involvement of these networks.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Route of Francisella tularensis infection informs spatiotemporal metabolic reprogramming and inflammation in mice

Jessop,

Schwarz,

Bohrnsen

et al. 2023

PLoS ONE

View full text Add to dashboard Cite

Route of exposure to pathogens can inform divergent disease pathogenesis and mortality rates. However, the features that contribute to these differences are not well established. Host metabolism has emerged as a critical element governing susceptibility and the metabolism of tissue exposure sites are unique. Therefore, specific metabolic niches may contribute to the course and outcome of infection depending on route of infection. In the current study, we utilized a combination of imaging and systems metabolomics to map the spatiotemporal dynamics of the host response to intranasal (i.n.) or intradermal (i.d.) infection of mice using the bacterium Francisella tularensis subsp tularensis (FTT). FTT causes lethal disease through these infection routes with similar inoculation doses and replication kinetics, which allowed for isolation of host outcomes independent of bacterial burden. We observed metabolic modifications that were both route dependent and independent. Specifically, i.d. infection resulted in early metabolic reprogramming at the site of infection and draining lymph nodes, whereas the lungs and associated draining lymph nodes were refractory to metabolic reprogramming following i.n. infection. Irrespective of exposure route, FTT promoted metabolic changes in systemic organs prior to colonization, and caused massive dysregulation of host metabolism in these tissues prior to onset of morbidity. Preconditioning infection sites towards a more glycolytic and pro-inflammatory state prior to infection exacerbated FTT replication within the lungs but not intradermal tissue. This enhancement of replication in the lungs was associated with the ability of FTT to limit redox imbalance and alter the pentose phosphate pathway. Together, these studies identify central metabolic features of the lung and dermal compartments that contribute to disease progression and identify potential tissue specific targets that may be exploited for novel therapeutic approaches.

show abstract

Section: Resultsmentioning

confidence: 99%