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Activation of the endoplasmic reticulum stress sensor IRE1? by the vaccine adjuvant AS03 contributes to its immunostimulatory properties.

ABSTRACT: The oil-in-water emulsion Adjuvant System 03 (AS03) is one of the few adjuvants used in licensed vaccines. Previous work indicates that AS03 induces a local and transient inflammatory response that contributes to its adjuvant effect. However, the molecular mechanisms involved in its immunostimulatory properties are ill-defined. Upon intramuscular injection in mice, AS03 elicited a rapid and transient downregulation of lipid metabolism-related genes in the draining lymph node. In vitro, these modifications were associated with profound changes in lipid composition, alteration of endoplasmic reticulum (ER) morphology and activation of the unfolded protein response pathway. In vivo, treatment with a chemical chaperone or deletion of the ER stress sensor kinase IRE1? in myeloid cells decreased AS03-induced cytokine production and its capacity to elicit high affinity antigen-specific antibodies. In summary, our results indicate that IRE1? is a sensor for the metabolic changes induced by AS03 in monocytic cells and may constitute a canonical pathway that could be exploited for the design of novel vaccine adjuvants.

SUBMITTER: Givord C

PROVIDER: S-EPMC6023910 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Activation of the endoplasmic reticulum stress sensor IRE1α by the vaccine adjuvant AS03 contributes to its immunostimulatory properties.

Givord Charlotte C Welsby Iain I Detienne Sophie S Thomas Séverine S Assabban Assiya A Lima Silva Viviana V Molle Céline C Gineste Romain R Vermeersch Marjorie M Perez-Morga David D Leo Oberdan O Collignon Catherine C Didierlaurent Arnaud M AM Goriely Stanislas S

NPJ vaccines 20180628

The oil-in-water emulsion Adjuvant System 03 (AS03) is one of the few adjuvants used in licensed vaccines. Previous work indicates that AS03 induces a local and transient inflammatory response that contributes to its adjuvant effect. However, the molecular mechanisms involved in its immunostimulatory properties are ill-defined. Upon intramuscular injection in mice, AS03 elicited a rapid and transient downregulation of lipid metabolism-related genes in the draining lymph node. In vitro, these mod ...[more]

PMID: 29977610

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Project description:The unfolded-protein response (UPR) is a signal transduction cascade triggered by perturbation of the homeostasis of the endoplasmic reticulum (ER). UPR resolves ER stress by activating a cascade of cellular responses, including the induction of molecular chaperones, translational attenuation, ER-associated degradation, and other mechanisms. Under prolonged and irremediable ER stress, however, the UPR can also trigger apoptosis. Here, we report that in cells infected with the avian coronavirus infectious bronchitis virus (IBV), ER stress was induced and the IRE1?-XBP1 pathway of UPR was activated. Knockdown and overexpression experiments demonstrated that IRE1? protects infected cells from IBV-induced apoptosis, which required both its kinase and RNase activities. Our data also suggest that splicing of XBP1 mRNA by IRE1? appears to convert XBP1 from a proapoptotic XBP1u protein to a prosurvival XBP1s protein. Moreover, IRE1? antagonized IBV-induced apoptosis by modulating the phosphorylation status of the proapoptotic c-Jun N-terminal kinase (JNK) and the prosurvival RAC-alpha serine/threonine-protein kinase (Akt). Taken together, the data indicate that the ER stress sensor IRE1? is activated in IBV-infected cells and serves as a survival factor during coronavirus infection.Animal coronaviruses are important veterinary viruses, which could cross the species barrier, becoming severe human pathogens. Molecular characterization of the interactions between coronaviruses and host cells is pivotal to understanding the pathogenicity and species specificity of coronavirus infection. It has been well established that the endoplasmic reticulum (ER) is closely associated with coronavirus replication. Here, we report that inositol-requiring protein 1 alpha (IRE1?), a key sensor of ER stress, is activated in cells infected with the avian coronavirus infectious bronchitis virus (IBV). Moreover, IRE1? is shown to protect the infected cells from apoptosis by modulating the unfolded-protein response (UPR) and two kinases related to cell survival. This study demonstrates that UPR activation constitutes a major aspect of coronavirus-host interactions. Manipulations of the coronavirus-induced UPR may provide novel therapeutic targets for the control of coronavirus infection and pathogenesis.

Dataset Information

Activation of the endoplasmic reticulum stress sensor IRE1? by the vaccine adjuvant AS03 contributes to its immunostimulatory properties.

Publications

Activation of the endoplasmic reticulum stress sensor IRE1α by the vaccine adjuvant AS03 contributes to its immunostimulatory properties.

Similar Datasets

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