Rotavirus-Mediated Prostaglandin E2 Production in MA104 Cells Promotes Virus Attachment and Internalisation, Resulting in an Increased Viral Load

Abstract

Rotaviruses are one of the leading causes of severe dehydrating diarrhoea in infants and children under the age of five. Despite the introduction of vaccines, disease burden remains high in sub-Saharan Africa, with no known anti-viral treatments available. During early infection rotavirus attaches to several cellular receptors and enters the cells by either clathrin-dependent or -independent endocytosis. Prostaglandin E2, an abundant eicosanoid, is produced from arachidonic acid during rotavirus infection and inhibition of prostaglandin E2 formation have a deleterious effect on rotavirus infection. In this study, MA104 cells were supplemented with γ-linolenic acid (GLA), a precursor of arachidonic acid. Infection of supplemented cells with rotavirus SA11 led to a depletion in the relative percentages of GLA and arachidonic acid which coincided with an increased production of prostaglandin E2 as monitored by ELISA. Confocal microscopy demonstrated that prostaglandin E2 co-localises with the viroplasm-forming proteins, NSP5 and NSP2. Due to the known association of viroplasms with lipid droplets and the fact that lipid droplets are sites for prostaglandin E2 production, our results indicate a possible role for viroplasms in the production of rotavirus-induced prostaglandin E2. Replication kinetics showed that inhibitors, targeting the biosynthesis of prostaglandin E2, had negative effects on rotavirus yield, especially during the early stages of infection. Using flow cytometry and prostaglandin E2 addback experiments, we show that prostaglandin E2 enhances the attachment and internalisation of rotavirus in MA104 cells indicating a possible role for prostaglandin E2 during clathrin-mediated rotavirus entry. The production of prostaglandin E2 during rotavirus infection could serve as a possible target for anti-viral treatment.

Candida albicans-enteric viral interactions—The prostaglandin E2 connection and host immune responses

“…Interestingly, PGE 2 release from RV-infected cells appears to enhance virus attachment and internalization, possibly through clathrin-mediated endocytosis. 186 Collectively, these results show that PGE 2 plays an important role in RV replication and may influence the severity of RV infections.…”

“… 185 Recently, elevated PGE 2 concentrations were detected in RV-infected MA104 cells following supplementation with γ-linolenic acid, a precursor for AA. 186 Notably, increased levels of PGE 2 correlated with RV replication in a time-and dose-dependent manner, suggesting RV dependence on PGE 2 for proliferation. Interestingly, PGE 2 release from RV-infected cells appears to enhance virus attachment and internalization, possibly through clathrin-mediated endocytosis.…”

“…However, it remains unclear if viral-induced COX2/PGE 2 solely facilitates optimal viral replication or if this expression is also essential for exacerbating viral pathogenesis. The seminal work on PGE 2 promoting RV attachment and internalization in mammalian cells 186 provides a basis for further exploration of viral PGE 2 utilization during infections beyond viral replication. Meanwhile, the outstanding questions regarding how PGE 2 will affect C. albicans -enteric virus co-pathogenesis, transkingdom interactions, host immune modulation during multi-species infections, and the overall viral replication remain to be explored, particularly in the context of gastroenteritis.…”

Advances in the development of antivirals for rotavirus infection

“…Prostaglandin A1 (PGA1) may prevent SA-11 rotavirus maturation in MA-104 cells by inhibiting NSP4 glycosylation or VP4/VP7 synthesis (67). Prostaglandin E 2 inhibitors indomethacin, CAY10502, celecoxib, and SC-560 affect SA11 viral internalization in vitro in early infection and VP6 RNA synthesis in the mid-stage in MA-104 cells (68). Furthermore, prostaglandin E 2 replacement enhances rotavirus infection.…”