Prostaglandin E2 As a Modulator of Viral Infections

Sander, Willem J.; O’Neill, Hester G.; Pohl, Carolina H.

doi:10.3389/fphys.2017.00089

Cited by 97 publications

(97 citation statements)

References 159 publications

(178 reference statements)

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“…Quantification of luciferase activity showed that pre-treatment of Calu-3 or Huh7.5 cells with ibuprofen or meloxicam did not significantly affect SARS2-VSVpp or G-VSVpp entry ( Finally, we studied whether inhibition of the COX-2/PGE2 pathway affects SARS-CoV-2 replication. Viruses from several different families have been shown to induce COX-2/PGE2 signaling in host cells (28). The COX-2/PGE2 pathway is pro-viral for viruses such as porcine sapovirus, as PGE2 inhibits nitric oxide production, thus permitting viral replication (9).…”

Section: Resultsmentioning

confidence: 99%

Cyclooxgenase-2 is induced by SARS-CoV-2 infection but does not affect viral entry or replication

Chen

Alfajaro

Jin

et al. 2020

Preprint

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Identifying drugs that regulate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and its symptoms has been a pressing area of investigation during the coronavirus disease 2019 (COVID-19) pandemic. Nonsteroidal anti-inflammatory drugs (NSAIDs), which are frequently used for the relief of pain and inflammation, could modulate both SARS-CoV-2 infection and the host response to the virus. NSAIDs inhibit the enzymes cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), which mediate the production of prostaglandins (PGs). PGE2, one of the most abundant PGs, has diverse biological roles in homeostasis and inflammatory responses. Previous studies have shown that NSAID treatment or inhibition of PGE2 receptor signaling leads to upregulation of angiotensin-converting enzyme 2 (ACE2), the cell entry receptor for SARS-CoV-2, thus raising concerns that NSAIDs could increase susceptibility to infection. COX/PGE2 signaling has also been shown to regulate the replication of many viruses, but it is not yet known whether it plays a role in SARS-CoV-2 replication. The purpose of this study was to dissect the effect of NSAIDs on COVID-19 in terms of SARS-CoV-2 entry and replication. We found that SARS-CoV-2 infection induced COX-2 upregulation in diverse human cell culture and mouse systems. However, suppression of COX-2/PGE2 signaling by two commonly used NSAIDs, ibuprofen and meloxicam, had no effect on ACE2 expression, viral entry, or viral replication. Our findings suggest that COX-2 signaling driven by SARS-CoV-2 may instead play a role in regulating the lung inflammation and injury observed in COVID-19 patients.ImportancePublic health officials have raised concerns about the use of nonsteroidal anti-inflammatory drugs (NSAIDs) for treating symptoms of coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). NSAIDs function by inhibiting the enzymes cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). These enzymes are critical for the generation of prostaglandins, lipid molecules with diverse roles in maintaining homeostasis as well as regulating the inflammatory response. While COX-1/COX-2 signaling pathways have been shown to affect the replication of many viruses, their effect on SARS-CoV-2 infection remains unknown. We found that SARS-CoV-2 infection induced COX-2 expression in both human cell culture systems and mouse models. However, inhibition of COX-2 activity with NSAIDs did not affect SARS-CoV-2 entry or replication. Our findings suggest that COX-2 signaling may instead regulate the lung inflammation observed in COVID-19 patients, which is an important area for future studies.

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Section: Resultsmentioning

confidence: 99%

Cyclooxgenase-2 is induced by SARS-CoV-2 infection but does not affect viral entry or replication

Chen

Alfajaro

Jin

et al. 2020

Preprint

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“…PGE2 is known to have immunomodulatory roles (Kalinski, 2012) and, more particularly in the context of respiratory viral infection (McCarthy and Weinberg, 2012). The modulatory role of PGE2 in several viral infections has recently been reviewed and both inhibitory and activating effects of PGE2 on various immune system pathways identified (Sander et al, 2017). In most of the viral infections studied, PGE2 was reported to increase viral pathogenicity (HSV, CMV, EBV, RV, CVB3, EV71, PSaV, VSV, LCM, RSV, and HTLV-III), which occurred by affecting not only the host immunity, but also viral transcription, translation and/or replication.…”

Section: Viral Infection Ards and Pge2mentioning

confidence: 99%

“…Finally, we hypothesize the age-or proinflammatory disease-related increases in PGE2 might underline the higher severity of COVID-19 in aged and obese populations. It is important to note that several of the downstream products of the PGE2 pathway are required for normal physiological functioning (Sander et al, 2017). Additionally PGE2 had been shown to have both stimulatory and inhibitory effect on the immune system depending on the targeted cell type, inflammatory or physiological context or local concentrations.…”

Section: Viral Infection Ards and Pge2mentioning

confidence: 99%

Hypothesis: mPGES-1-Derived Prostaglandin E2, a So Far Missing Link in COVID-19 Pathophysiology?

Smeitink¹,

Jiang²,

Pecheritsyna³

et al. 2020

Preprint

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With frequencies varying up to 20%, treatment resistant pulmonary failure is a major life-threatening complication in COVID-19 (SARS-CoV-2, HCoV19) disease pathology. Both acute respiratory distress syndrome (ARDS), proposed to be caused by an over-reacting immune system which floods the lung with edema, a liquid consisting of inflammatory cells, and diminished lung perfusion, have been postulated to cause this treatment resistant lung failure. Aging, co-morbidities, male gender and obesity are pre-existing factors associated with the more severe outcome. Thrombosis is more frequently observed than usually seen during ICU admission. Different hypotheses explaining the pathophysiological cascade leading to fast progressing severe COVID-19 disease and how to counteract it have been proposed. A variety of intervention studies to control severity are ongoing or planned. Not suggested so far, we here hypothesize that the inflammatory lipid modulator prostaglandin E2 (PGE2) executes a prominent role in COVID-19 pathophysiology. Based on this we suggest measuring PGE2 in patients and evaluating selective inhibition of the human microsomal prostaglandin E synthase-1 (mPGES-1) as a potential innovative therapeutic approach in this devastating condition for which sonlicromanol, a drug currently in phase 2b studies for mitochondrial disease, is a candidate.

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“…LDs in the host are formed rapidly in response to various infectious agents following PRR signaling [104][105][106]. Given their role in aiding cross-presentation and IFN-signaling, their formation is thought to contribute to the host defense particularly in the context of viral infection [107][108][109].…”

Section: Lipid Dropletsmentioning

confidence: 99%

Pathogens MenTORing Macrophages and Dendritic Cells: Manipulation of mTOR and Cellular Metabolism to Promote Immune Escape

Nouwen

Everts

2020

Cells

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Myeloid cells, including macrophages and dendritic cells, represent an important first line of defense against infections. Upon recognition of pathogens, these cells undergo a metabolic reprogramming that supports their activation and ability to respond to the invading pathogens. An important metabolic regulator of these cells is mammalian target of rapamycin (mTOR). During infection, pathogens use host metabolic pathways to scavenge host nutrients, as well as target metabolic pathways for subversion of the host immune response that together facilitate pathogen survival. Given the pivotal role of mTOR in controlling metabolism and DC and macrophage function, pathogens have evolved strategies to target this pathway to manipulate these cells. This review seeks to discuss the most recent insights into how pathogens target DC and macrophage metabolism to subvert potential deleterious immune responses against them, by focusing on the metabolic pathways that are known to regulate and to be regulated by mTOR signaling including amino acid, lipid and carbohydrate metabolism, and autophagy.

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Prostaglandin E2 As a Modulator of Viral Infections

Cited by 97 publications

References 159 publications

Cyclooxgenase-2 is induced by SARS-CoV-2 infection but does not affect viral entry or replication

Cyclooxgenase-2 is induced by SARS-CoV-2 infection but does not affect viral entry or replication

Hypothesis: mPGES-1-Derived Prostaglandin E2, a So Far Missing Link in COVID-19 Pathophysiology?

Pathogens MenTORing Macrophages and Dendritic Cells: Manipulation of mTOR and Cellular Metabolism to Promote Immune Escape

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