Avian oncogenic herpesvirus antagonizes the cGAS-STING DNA-sensing pathway to mediate immune evasion

Abstract

The cellular DNA sensor cGMP-AMP synthase (cGAS) detects cytosolic viral DNA via the stimulator of interferon genes (STING) to initiate innate antiviral response. Herpesviruses are known to target key immune signaling pathways to persist in an immune-competent host. Marek’s disease virus (MDV), a highly pathogenic and oncogenic herpesvirus of chickens, can antagonize host innate immune responses to achieve persistent infection. With a functional screen, we identified five MDV proteins that blocked beta interferon (IFN-β) induction downstream of the cGAS-STING pathway. Specifically, the MDV major oncoprotein Meq impeded the recruitment of TANK-binding kinase 1 and IFN regulatory factor 7 (IRF7) to the STING complex, thereby inhibiting IRF7 activation and IFN-β induction. Meq overexpression markedly reduced antiviral responses stimulated by cytosolic DNA, whereas knockdown of Meq heightened MDV-triggered induction of IFN-β and downstream antiviral genes. Moreover, Meq-deficient MDV induced more IFN-β production than wild-type MDV. Meq-deficient MDV also triggered a more robust CD8+ T cell response than wild-type MDV. As such, the Meq-deficient MDV was highly attenuated in replication and lymphoma induction compared to wild-type MDV. Taken together, these results revealed that MDV evades the cGAS-STING DNA sensing pathway, which underpins the efficient replication and oncogenesis. These findings improve our understanding of the virus-host interaction in MDV-induced lymphoma and may contribute to the development of novel vaccines against MDV infection.

PRV UL13 inhibits cGAS–STING-mediated IFN-β production by phosphorylating IRF3

“…Moreover, Marek’s disease virus (MDV) VP23 inhibits the DNA-sensing pathway by suppressing IRF7 activation [ 17 ]. The MDV major oncoprotein Meq impedes the recruitment of TBK1 and IRF7 to the STING complex and inhibits IRF7 activation and IFN-β induction [ 18 ].…”

Latest Insights into Marek’s Disease Virus Pathogenesis and Tumorigenesis

“…CVI stocks also encode at least two isoforms of the multifunctional Meq protein that fundamentally differ in their oncogenic potential [102]. Moreover, Meq has been reported to modulate intrinsic immune responses, including p53-mediated apoptosis [103] and the cGAS-STING pathway [104], but more work is needed to understand the molecular mechanisms of this key virulence factor.…”

Conserved strategies for pathogen evasion of cGAS–STING immunity

“…The KSHV vIRF1 protein blocks this process, preventing association of TBK1 [62]. Mareck's disease virus is an avian oncogenic herpesvirus, and its oncoprotein Meq functions in a similar way, blocking recruitment of TBK1 to STING in chicken cells [63 ]. Interestingly, the oncoproteins E1A and E7 from adenovirus and human papillomavirus also bind and inhibit STING, however the mechanistic consequences of binding have not yet been elucidated [64].…”