Activation of COX-2/PGE
            <sub>2</sub>
            Promotes Sapovirus Replication via the Inhibition of Nitric Oxide Production

Alfajaro, Mia Madel; Choi, Jong‐Soon; Kim, Deok-Song; Seo, Ja-Young; Kim, Jiyun; Park, Jun-Gyu; Soliman, Mahmoud; Baek, Yeong-Bin; Cho, Eun-Hyo; Kwon, Joseph; Kwon, Hyung Jun; Park, Su‐Jin; Lee, Woo Song; Kang, Mun-Il; Hosmillo, Myra; Goodfellow, Ian; Cho, Kyoung-Oh

doi:10.1128/jvi.01656-16

Cited by 23 publications

(32 citation statements)

References 44 publications

(58 reference statements)

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“…The same study also suggested that increased COX-2 expression in 5-LOX and 15-LOX deficient macrophages was responsible for the defect in M2 polarization. Indeed, several recent studies have implicated COX-2 derived PGs in detrimental immune responses during viral infection, including virus-induced immunosuppression (Chen et al, 2015;Gandhi et al, 2015;Alfajaro et al, 2017).…”

Section: Viral Infectionmentioning

confidence: 99%

Immune-regulation and -functions of eicosanoid lipid mediators

Bieren¹

2017

Biological Chemistry

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Bioactive lipids regulate most physiological processes, from digestion to blood flow and from hemostasis to labor. Lipid mediators are also involved in multiple pathologies including cancer, autoimmunity or asthma. The pathological roles of lipid mediators are based on their intricate involvement in the immune system, which comprises source and target cells of these mediators. Based on their biosynthetic origin, bioactive lipids can be grouped into different classes [e.g. sphingolipids, formed from sphingosine or eicosanoids, formed from arachidonic acid (AA)]. Owing to the complexity of different mediator classes and the prominent immunological roles of eicosanoids, this review will focus solely on the immune-regulation of eicosanoids. Eicosanoids do not only control key immune responses (e.g. chemotaxis, antigen presentation, phagocytosis), but they are also subject to reciprocal control by the immune system. Particularly, key immunoregulatory cytokines such as IL-4 and IFN-γ shape the cellular eicosanoid profile, thus providing efficient feedback regulation between cytokine and eicosanoid networks. For the purpose of this review, I will first provide a short overview of the most important immunological functions of eicosanoids with a focus on prostaglandins (PGs) and leukotrienes (LTs). Second, I will summarize the current knowledge on immunological factors that regulate eicosanoid production during infection and inflammation.

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Section: Viral Infectionmentioning

confidence: 99%

Immune-regulation and -functions of eicosanoid lipid mediators

Bieren¹

2017

Biological Chemistry

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“…NSAIDs could also affect a later stage of the SARS-CoV-2 life cycle. For porcine sapovirus, feline calicivirus, murine norovirus, and mouse coronavirus, COX inhibition impaired viral replication (6,9,10). COX inhibition was found to impair mouse coronavirus infection at a post-binding step early in the replication cycle, potentially entry or initial genome replication (6).…”

Section: Introductionmentioning

confidence: 98%

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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“…The cytotoxicity test for the different chemicals used was carried out by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay as described previously [ 34 , 63 ]. Briefly, monolayers of RAW264.7 and CRFK cells grown in 96-well plates were incubated for 24 h with different concentrations of chemicals.…”

Section: Methodsmentioning

confidence: 99%

“…To evade this, viruses devise strategies to subvert cellular pathways for their own benefit such as via COXs/prostaglandin E 2 (PGE 2 ) signaling, which participates in the modulation of the host response to infection and the life cycle of several viruses [ 32 – 33 ]. Representatives from at least eleven different virus families are known to activate COXs/PGE 2 signaling or to enhance the expression levels of PGE 2 : Caliciviridae [ 34 ], Arteriviridae [ 35 ], Herpesviridae [ 36 ], Rhabdoviridae [ 37 ], Retroviridae [ 38 ], Picornaviridae [ 39 – 40 ], Flaviviridae [ 41 ], Orthomyxoviridae [ 42 – 43 ], Adenoviridae [ 44 ], and Paramyxoviridae [ 45 ].…”

Section: Introductionmentioning

confidence: 99%

“…Previously, we reported that infection of PSaV strain Cowden induced strong COX-2/PGE 2 signaling with only a transient COX-1/PGE 2 signal during late stage infection [ 34 ]. Pharmacological inhibitors or siRNAs against COX-1 and COX-2 significantly reduced PSaV replication, which was restored by the addition of PGE 2 , indicating that COXs/PGE 2 acts as a proviral signal [ 34 ]. However, the role of COXs/PGE 2 signaling is unknown for other members within the Caliciviridae family.…”

Section: Introductionmentioning

confidence: 99%

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Feline calicivirus- and murine norovirus-induced COX-2/PGE2 signaling pathway has proviral effects

et al. 2018

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Cyclooxygenases (COXs)/prostaglandin E2 (PGE2) signaling pathways are known to modulate a variety of homeostatic processes and are involved in various pathophysiological conditions. COXs/PGE2 signaling pathways have also been demonstrated to have proviral or antiviral effects, which appeared different even in the same virus family. A porcine sapovirus Cowden strain, a member of genus Sapovirus within the Caliciviridae family, induces strong COX-2/PGE2 but transient COX-1/PGE2 signaling to enhance virus replication. However, whether infections of other viruses in the different genera activate COXs/PGE2 signaling, and thus affect the replication of viruses, remains unknown. In the present study, infections of cells with the feline calicivirus (FCV) F9 strain in the genus Vesivirus and murine norovirus (MNV) CW-1 strain in the genus Norovirus only activated the COX-2/PGE2 signaling in a time-dependent manner. Treatment with pharmacological inhibitors or transfection of small interfering RNAs (siRNAs) against COX-2 enzyme significantly reduced the production of PGE2 as well as FCV and MNV replications. The inhibitory effects of these pharmacological inhibitors against COX-2 enzyme on the replication of both viruses were restored by the addition of PGE2. Silencing of COX-1 via siRNAs and inhibition of COX-1 via an inhibitor also decrease the production of PGE2 and replication of both viruses, which can be attributed to the inhibition COX-1/PGE2 signaling pathway. These data indicate that the COX-2/PGE2 signaling pathway has proviral effects for the replication of FCV and MNV, and pharmacological inhibitors against these enzymes serve as potential therapeutic candidates for treating FCV and MNV infections.

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Activation of COX-2/PGE ₂ Promotes Sapovirus Replication via the Inhibition of Nitric Oxide Production

Cited by 23 publications

References 44 publications

Immune-regulation and -functions of eicosanoid lipid mediators

Immune-regulation and -functions of eicosanoid lipid mediators

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

Feline calicivirus- and murine norovirus-induced COX-2/PGE2 signaling pathway has proviral effects

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Activation of COX-2/PGE 2 Promotes Sapovirus Replication via the Inhibition of Nitric Oxide Production

Cited by 23 publications

References 44 publications

Immune-regulation and -functions of eicosanoid lipid mediators

Immune-regulation and -functions of eicosanoid lipid mediators

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

Feline calicivirus- and murine norovirus-induced COX-2/PGE2 signaling pathway has proviral effects

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Activation of COX-2/PGE ₂ Promotes Sapovirus Replication via the Inhibition of Nitric Oxide Production