Emerging Proviral Roles of Caspases during Lytic Replication of Gammaherpesviruses

Tabtieng, Tate; Gaglia, Marta Maria

doi:10.1128/jvi.01011-17

Cited by 5 publications

(3 citation statements)

References 60 publications

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“…Several viruses, including EBV and KSHV, hijack caspase activity to facilitate viral replication ( 76 ). Similar to HPV, KSHV commandeers caspase-8 activity to suppress a type I IFN response during lytic replication ( 26 ).…”

Section: Discussionmentioning

confidence: 99%

Apoptotic caspases suppress an MDA5-driven IFN response during productive replication of human papillomavirus type 31

Huang

Groover

Damania

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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Human papillomaviruses (HPVs) infect the basal proliferating cells of the stratified epithelium, but the productive phase of the life cycle (consisting of viral genome amplification, late gene expression, and virion assembly) is restricted to the highly differentiated suprabasal cells. While much is known regarding the mechanisms that HPVs use to block activation of an innate immune response in undifferentiated cells, little is known concerning how HPV prevents an interferon (IFN) response upon differentiation. Here, we demonstrate that high-risk HPVs hijack a natural function of apoptotic caspases to suppress an IFN response in differentiating epithelial cells. We show that caspase inhibition results in the secretion of type I and type III IFNs that can act in a paracrine manner to induce expression of interferon-stimulated genes (ISGs) and block productive replication of HPV31. Importantly, we demonstrate that the expression of IFNs is triggered by the melanoma differentiation-associated gene 5 (MDA5)–mitochondrial antiviral-signaling protein (MAVS)–TBK1 (TANK-binding kinase 1) pathway, signifying a response to double-stranded RNA (dsRNA). Additionally, we identify a role for MDA5 and MAVS in restricting productive viral replication during the normal HPV life cycle. This study identifies a mechanism by which HPV reprograms the cellular environment of differentiating cells through caspase activation, co-opting a nondeath function of proteins normally involved in apoptosis to block antiviral signaling and promote viral replication.

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Section: Discussionmentioning

confidence: 99%

Apoptotic caspases suppress an MDA5-driven IFN response during productive replication of human papillomavirus type 31

Huang

Groover

Damania

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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“…The results emphasize the relationship of apical periodontitis with reactivated EBV. EBV lytic infection is crucial for the innate immune response and the development of disease (Farina et al , Tabtieng & Gaglia ). Thus, lytic replication of EBV could affect periapical inflammation.…”

Section: Discussionmentioning

confidence: 99%

Epstein–Barr virus reactivation by persistent apical periodontal pathogens

et al. 2019

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Aim To assess whether Epstein–Barr virus (EBV) reactivation is triggered by persistent apical periodontitis‐related microbes using in vitro and ex vivo methodologies. Methodology Surgically removed human periapical granulomas (n = 50) and healthy gingival tissues (n = 10) were analysed to determine the presence of EBV and seven persistent apical periodontitis‐related microbes. In addition, real‐time polymerase chain reaction was used to detect the mRNA expression of BZLF‐1, an immediate–early gene of EBV. Expression of latent membrane protein (LMP)‐1 and ZEBRA, an early lytic protein of EBV encoded by BZLF‐1, was also examined using triple‐colour immunofluorescence staining. n‐Butyric acid produced by the microbes was quantified, and luciferase assays were performed in association with bacterial lysates. In addition, Daudi cells were cultured with bacterial lysates, and the expression levels of BZLF‐1 mRNA and ZEBRA protein were determined. Results EBV DNA and BZLF‐1 mRNA were detected in 47 out of 50 periapical granulomas, but not in healthy gingival tissues. The EBV DNA copy number and the number of Fusobacterium nucleatum were significantly positively correlated with BZLF‐1 expression in periapical granulomas. The number of Prevotella intermedia was slightly correlated with BZLF‐1 expression; however, the other microbes were not. CD79a‐positive B cells in periapical granulomas, but not those in healthy gingival tissues, expressed both LMP‐1 and ZEBRA. n‐Butyric acid production was the highest in F. nucleatum and the lowest in P. intermedia. Enterococcus faecalis, Candida albicans and the other tested microbes did not produce n‐butyric acid. An F. nucleatum lysate exhibited significantly increased BZLF‐1‐luciferase activity in the same manner of commercial butyric acid, whereas P. intermedia did not. F. nucleatum also induced the expression of BZLF‐1 mRNA and ZEBRA protein by Daudi cells, indicating that EBV reactivation was induced. Conclusion Among the persistent apical periodontitis‐related bacteria that were tested, F. nucleatum most strongly reactivated latent EBV, whereas E. faecalis and C. albicans as well as the other microbes did not.

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“…However, innate immunity is a double-edge sword as the induction of pro-inflammatory responses and activation of programmed cell death might release a burst of virions and may therefore facilitate the spread of infection [12]. Furthermore, activation of caspases might serve a proviral role in the lytic replication of EBV through proteolytic cleavage of critical cellular and viral proteins [13]. Further investigations are required to elucidate how inflammasome activation, programmed cell death, and caspase activation fulfill their proviral function in the context of EBV infection.…”

Section: Introductionmentioning

confidence: 99%

Epstein–Barr Virus and Innate Immunity: Friends or Foes?

et al. 2019

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Epstein–Barr virus (EBV) successfully persists in the vast majority of adults but causes lymphoid and epithelial malignancies in a small fraction of latently infected individuals. Innate immunity is the first-line antiviral defense, which EBV has to evade in favor of its own replication and infection. EBV uses multiple strategies to perturb innate immune signaling pathways activated by Toll-like, RIG-I-like, NOD-like, and AIM2-like receptors as well as cyclic GMP-AMP synthase. EBV also counteracts interferon production and signaling, including TBK1-IRF3 and JAK-STAT pathways. However, activation of innate immunity also triggers pro-inflammatory response and proteolytic cleavage of caspases, both of which exhibit proviral activity under some circumstances. Pathogenic inflammation also contributes to EBV oncogenesis. EBV activates NFκB signaling and induces pro-inflammatory cytokines. Through differential modulation of the proviral and antiviral roles of caspases and other host factors at different stages of infection, EBV usurps cellular programs for death and inflammation to its own benefits. The outcome of EBV infection is governed by a delicate interplay between innate immunity and EBV. A better understanding of this interplay will instruct prevention and intervention of EBV-associated cancers.

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Emerging Proviral Roles of Caspases during Lytic Replication of Gammaherpesviruses

Cited by 5 publications

References 60 publications

Apoptotic caspases suppress an MDA5-driven IFN response during productive replication of human papillomavirus type 31

Apoptotic caspases suppress an MDA5-driven IFN response during productive replication of human papillomavirus type 31

Epstein–Barr virus reactivation by persistent apical periodontal pathogens

Epstein–Barr Virus and Innate Immunity: Friends or Foes?

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