Alteration in Cellular Signaling and Metabolic Reprogramming during Viral Infection

Pant, Anil; Dsouza, Lara; Yang, Zhilong

doi:10.1128/mbio.00635-21

Cited by 26 publications

(26 citation statements)

References 163 publications

(216 reference statements)

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“…In response to virus infections, the activity of metabolic pathways is often changed reflecting the altered energy and biomolecule demand in infected cells (33). Therefore, we wanted to assess the general transcriptional response of Aag2 cells to CHIKV infection.…”

Section: Resultsmentioning

confidence: 99%

“…For example, the product of the first enzymatic step of glycolysis, glucose-6-phosphate enters the pentose phosphate pathway (PPP), which is responsible for generating pentoses (five-carbon sugars) as well as other RNA and DNA precursors (31). Changes in glycolytic rate are known to occur widely during virus infection presumably as a consequence of a higher energy and/or nucleotide demand enforced by virus replication (32,33,(75)(76)(77). On the other hand, an increased energy metabolism has been shown to activate antiviral defense and glycolytic enhancement is dispensable or even avoided due to triggering of immune responses of the host (31,78,79).…”

Section: Discussionmentioning

confidence: 99%

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The DEAD-box RNA helicase Dhx15 controls glycolysis and arbovirus replication in Aedes aegypti mosquito cells

Miesen

Machado

et al. 2022

Preprint

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Aedes aegypti mosquitoes are responsible for the transmission of arthropod-borne (arbo)viruses including dengue and chikungunya virus (CHIKV), but in contrast to human hosts, arbovirus infected mosquitoes are able to efficiently control virus replication to sub-pathological levels. Yet, our knowledge about the molecular interactions of arboviruses with their mosquito hosts is largely incomplete. Here, we aimed to identify and characterize novel host genes that control arbovirus replication in Aedes mosquitoes. RNA binding proteins (RBPs) are well known to regulate immune signaling pathways in all kingdoms of life. We therefore performed a knockdown screen targeting 461 genes encoding predicted RBPs in Aedes aegypti Aag2 cells and identified 15 genes with antiviral activity against a Sindbis reporter virus. Amongst these, three DEAD-box RNA helicases, AAEL004419/Dhx15, AAEL008728 and AAEL004859 also acted as antiviral factors in dengue and CHIKV infections. Here, we explore the mechanism of Dhx15 in regulating an antiviral transcriptional response in mosquitoes by silencing Dhx15 in Aag2 cells followed by deep-sequencing of poly-A enriched RNAs. Dhx15 knockdown in uninfected or CHIKV-infected cells resulted in differential expression of 856 and 372 genes, respectively. Interestingly, amongst the consistently downregulated genes, glycolytic process was the most strongly enriched GO term as the expression of all core enzymes of the glycolytic pathway was reduced, suggesting that Dhx15 regulates glycolytic function. A decrease in lactate production supported the observation that Dhx15 silencing functionally impaired glycolysis. Modified rates of glycolytic metabolism have been implicated in controlling the replication of several classes of viruses and strikingly, infection of Aag2 cells with CHIKV by itself also resulted in the decrease of several glycolysis genes. Our data suggests that Dhx15 regulates replication of CHIKV, and possibly other arboviruses, by controlling glycolysis in mosquito cells.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The DEAD-box RNA helicase Dhx15 controls glycolysis and arbovirus replication in Aedes aegypti mosquito cells

Miesen

Machado

et al. 2022

Preprint

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“…In addition, viral particles are not expected to secrete L‐lactate by them self. However, the increase of L‐lactate in the group with lower respiratory tract virus infection may result from host cells being infected by virus, since infection of human cells with virus, such as influenza virus, respiratory syncytial virus, or severe acute respiratory syndrome coronavirus 2, may induce metabolic reprogramming of the infected cells resulting in increased secretion of L‐lactate [30]. Our results indicate that sputum L‐lactate should be considered for evaluation as a potential biomarker, which when increased simultaneous with other relevant inflammation biomarkers could strengthen the diagnostics of LRTI.…”

Section: Discussionmentioning

confidence: 99%

Endotracheal lactate reflects lower respiratory tract infections and inflammation in intubated patients

Kolpen

Sørensen

Faurholt‐Jepsen

et al. 2022

APMIS

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The aim of this study was to assess L‐lactate and D‐lactate in endotracheal aspirate from intubated patients hospitalized at the intensive care unit and explore their use as diagnostic biomarkers for inflammation and lower respiratory tract infections (LRTI). Tracheal aspirates from 91 intubated patients were obtained at time of intubation and sent for microbiological analyses, neutrophil count, and colorimetric lactate measurements. We compared the concentration of lactate from patients with microbiological verified LRTI or clinical/radiological suspicion of LRTI with a control group. In addition, associations between inflammation and the lactate isomers were examined by correlating L‐lactate and D‐lactate with sputum neutrophils and clinical assessments. The concentration of L‐lactate was increased in aspirates with verified or suspected LRTI (p < 0.001) relative to the control group at Day 0. Connections between L‐lactate and inflammation were indicated by the correlation between neutrophils and L‐lactate (p < 0.001). We found no increase in sputum D‐lactate from patients with verified or suspected LRTI relative to the control group and D‐lactate was not correlated with neutrophils. L‐lactate was found to be a potential indicator for inflammation and LRTI at the time of intubation. An association was found between neutrophil count and L‐lactate. Interestingly, the increase of L‐lactate in the control group after intubation may suggest that intubation challenges the host response by inflicting tissue damage or by introducing infectious microbes.

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“…More defined are major changes in metabolism occurring during viral infection ( 148 ). Upregulation of different aspects of glycolysis, including glycolytic rates, can favor viral replication.…”

Section: Changes In Mitochondrial Metabolism During Viral Infectionsmentioning

confidence: 99%

Mitochondria and Viral Infection: Advances and Emerging Battlefronts

Sorouri

Chang

Hancks

2022

mBio

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Alteration in Cellular Signaling and Metabolic Reprogramming during Viral Infection

Abstract: Cellular activities are finely regulated by numerous signaling pathways to support specific functions of complex life processes. Viruses are obligate intracellular parasites.

Cited by 26 publications

References 163 publications

The DEAD-box RNA helicase Dhx15 controls glycolysis and arbovirus replication in Aedes aegypti mosquito cells

The DEAD-box RNA helicase Dhx15 controls glycolysis and arbovirus replication in Aedes aegypti mosquito cells

Endotracheal lactate reflects lower respiratory tract infections and inflammation in intubated patients

Mitochondria and Viral Infection: Advances and Emerging Battlefronts

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