ISG15 Is Critical in the Control of Chikungunya Virus Infection Independent of UbE1L Mediated Conjugation

Werneke, Scott; Schilte, Clémentine; Rohatgi, Anjali; Monte, Kristen; Michault, Alain; Arenzana-Seisdedos, Fernando; Vanlandingham, Dana L.; Higgs, Stephen; Fontanet, Arnaud; Albert, Matthew L.; Lenschow, Deborah J.

doi:10.1371/journal.ppat.1002322

Cited by 166 publications

(175 citation statements)

References 63 publications

(101 reference statements)

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“…Among the ISGs analyzed, IRF7, RSAD2, ISG15, ISG54, ISG56, RIG-I, and PKR exhibited expression profiles similar to those of both IFNA and IFNB, which indicates that these ISGs are involved in the innate immune response against CHIKV. ISG15 was also recently shown to play a role in controlling CHIKV infection in mice (35). Notably, our data revealed that CHIKV viral load dictated the induction of IFNA, IFNB, IRF7, and RSAD2 during the acute phase.…”

Section: Discussionsupporting

confidence: 58%

“…Despite extensive documentation about the induction of type I IFNs during CHIKV infection (22)(23)(24)34), only recently have the mechanisms of type I IFN control of CHIKV replication begun to be unraveled (24,25,35,41,50). However, the identities of ISGs that directly control and inhibit CHIKV replication still remain elusive.…”

Section: Discussionmentioning

confidence: 99%

“…The role of type I IFNs in the innate response against CHIKV infection has been demonstrated in vitro in various cell types and animal models (20,21,24,34,35). To further understand their functions in patients, we analyzed the transcriptional profiles of type I IFNs and their associated genes in PBMCs collected longitudinally from 24 CHIKV-infected patients.…”

Section: Transcriptional Profiles Of Chikv-induced Innate Response Inmentioning

confidence: 99%

“…RIG-I and MDA5, which encode for proteins that act as PRRs and detect viruses to modulate signaling pathways in innate immune response, as well as IPS-1, an adaptor molecule involved in RIG-I-and MDA5-mediated signaling (2), were all significantly induced. Furthermore, CHIKV infection also induced ISGs known to inhibit viral protein translation and replication or to induce apoptosis (6,35,37,38), such as ISG15, ISG54, ISG56, and dsRNA-dependent protein kinase (PKR) (Figure 1 and Supplemental Figure 1).…”

Section: Figurementioning

confidence: 99%

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Viperin restricts chikungunya virus replication and pathology

Teng¹,

Foo²,

Simamarta³

et al. 2012

J. Clin. Invest.

167

198

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Chikungunya virus (CHIKV) is a mosquito-borne arthralgia arbovirus that is reemergent in sub-Saharan Africa and Southeast Asia. CHIKV infection has been shown to be self-limiting, but the molecular mechanisms of the innate immune response that control CHIKV replication remain undefined. Here, longitudinal transcriptional analyses of PBMCs from a cohort of CHIKV-infected patients revealed that type I IFNs controlled CHIKV infection via RSAD2 (which encodes viperin), an enigmatic multifunctional IFN-stimulated gene (ISG). Viperin was highly induced in monocytes, the major target cell of CHIKV in blood. Anti-CHIKV functions of viperin were dependent on its localization in the ER, and the N-terminal amphipathic α-helical domain was crucial for its antiviral activity in controlling CHIKV replication. Furthermore, mice lacking Rsad2 had higher viremia and severe joint inflammation compared with wild-type mice. Our data demonstrate that viperin is a critical antiviral host protein that controls CHIKV infection and provide a preclinical basis for the design of effective control strategies against CHIKV and other reemerging arthrogenic alphaviruses.

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Section: Discussionsupporting

confidence: 58%

Section: Discussionmentioning

confidence: 99%

Section: Transcriptional Profiles Of Chikv-induced Innate Response Inmentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

See 2 more Smart Citations

Viperin restricts chikungunya virus replication and pathology

Teng¹,

Foo²,

Simamarta³

et al. 2012

J. Clin. Invest.

167

198

View full text Add to dashboard Cite

show abstract

“…Strong innate immune responses, with high levels of type I IFN, proinflammatory cytokines, and chemokines, have been detected in acute CHIKV-infected patients (64)(65)(66)(82)(83)(84)(85)(86)(87)(88)(89)(90), nonhuman primates (91), and mice (62-64, 66, 92, 93) and might play a critical role in controlling virus replication. Although high levels of some proinflammatory cytokines have been associated with disease severity (82)(83)(84)(85)(87)(88)(89), type I IFN was identified as a key mediator responsible for viral clearance, and IFN-stimulated genes (ISGs) or IFN response factors 3 and 7 have been described to be critical in the control of CHIKV infection (63,64,66,90,94,95). Moreover, IFN-␣/␤ knockout mice (A129 mice) exhibited severe CHIKV disease (62-64, 66, 92), confirming the key role of type I IFNs in the control of CHIKV infection, by restricting virus replication early in the infection, although their effects are not enough to eliminate CHIKV from infected hosts.…”

Section: Discussionmentioning

confidence: 99%

A Novel Poxvirus-Based Vaccine, MVA-CHIKV, Is Highly Immunogenic and Protects Mice against Chikungunya Infection

García-Arriaza

Cepeda

Holzmann

et al. 2014

J Virol

106

127

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There is a need to develop a single and highly effective vaccine against the emerging chikungunya virus (CHIKV), which causes a severe disease in humans. Here, we have generated and characterized the immunogenicity profile and the efficacy of a novel CHIKV vaccine candidate based on the highly attenuated poxvirus vector modified vaccinia virus Ankara (MVA) expressing the CHIKV C, E3, E2, 6K, and E1 structural genes (termed MVA-CHIKV). MVA-CHIKV was stable in cell culture, expressed the CHIKV structural proteins, and triggered the cytoplasmic accumulation of Golgi apparatus-derived membranes in infected human cells. Furthermore, MVA-CHIKV elicited robust innate immune responses in human macrophages and monocyte-derived dendritic cells, with production of beta interferon (IFN-␤), proinflammatory cytokines, and chemokines. After immunization of C57BL/6 mice with a homologous protocol (MVA-CHIKV/MVA-CHIKV), strong, broad, polyfunctional, and durable CHIKVspecific CD8؉ T cell responses were elicited. The CHIKV-specific CD8 ؉ T cells were preferentially directed against E1 and E2 proteins and, to a lesser extent, against C protein. CHIKV-specific CD8؉ memory T cells of a mainly effector memory phenotype were also induced. The humoral arm of the immune system was significantly induced, as MVA-CHIKV elicited high titers of neutralizing antibodies against CHIKV. Remarkably, a single dose of MVA-CHIKV protected all mice after a high-dose challenge with CHIKV. In summary, MVA-CHIKV is an effective vaccine against chikungunya virus infection that induced strong, broad, highly polyfunctional, and long-lasting CHIKV-specific CD8 ؉ T cell responses, together with neutralizing antibodies against CHIKV. These results support the consideration of MVA-CHIKV as a potential vaccine candidate against CHIKV. IMPORTANCEWe have developed a novel vaccine candidate against chikungunya virus (CHIKV) based on the highly attenuated poxvirus vector modified vaccinia virus Ankara (MVA) expressing the CHIKV C, E3, E2, 6K, and E1 structural genes (termed MVA-CHIKV). Our findings revealed that MVA-CHIKV is a highly effective vaccine against chikungunya virus, with a single dose of the vaccine protecting all mice after a high-dose challenge with CHIKV. Furthermore, MVA-CHIKV is highly immunogenic, inducing strong innate responses: high, broad, polyfunctional, and long-lasting CHIKV-specific CD8 ؉ T cell responses, together with neutralizing antibodies against CHIKV. This work provides a potential vaccine candidate against CHIKV.

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Evidence for an involvement of the ubiquitin‐like modifier ISG15 in MHC class I antigen presentation

et al. 2020

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The IFN stimulated gene 15 (ISG15) encodes a 15‐kDa ubiquitin‐like protein, that is induced by type I IFNs and is conjugated to the bulk of newly synthesized polypeptides at the ribosome. ISG15 functions as an antiviral molecule possibly by being covalently conjugated to viral proteins and disturbing virus particle assembly. Here, we have investigated the effect of ISGylation on degradation and antigen presentation of viral and cellular proteins. ISGylation did not induce proteasomal degradation of bulk ISG15 target proteins neither after overexpressing ISG15 nor after induction by IFN‐β. The MHC class I cell surface expression of splenocytes derived from ISG15‐deficient mice or mice lacking the catalytic activity of the major de‐ISGylating enzyme USP18 was unaltered as compared to WT mice. Fusion of ubiquitin or FAT10 to the long‐lived nucleoprotein (NP) of lymphocytic choriomeningitis virus accelerated the proteasomal degradation of NP while fusion to ISG15 did not detectably speed up NP degradation. Nevertheless, MHC‐I restricted presentation of two epitopes of NP were markedly enhanced when it was fused to ISG15 similarly to fusion with ubiquitin or FAT10. Thus, we provide evidence that ISG15 can enhance the presentation of antigens on MHC‐I most likely by promoting co‐translational antigen processing.

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ISG15 Is Critical in the Control of Chikungunya Virus Infection Independent of UbE1L Mediated Conjugation

Cited by 166 publications

References 63 publications

Viperin restricts chikungunya virus replication and pathology

Viperin restricts chikungunya virus replication and pathology

A Novel Poxvirus-Based Vaccine, MVA-CHIKV, Is Highly Immunogenic and Protects Mice against Chikungunya Infection

Evidence for an involvement of the ubiquitin‐like modifier ISG15 in MHC class I antigen presentation

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