Ten Strategies of Interferon Evasion by Viruses.

Dampened STING-Dependent Interferon Activation in Bats

A novel SARS-related coronavirus (SARS-CoV-2) has recently emerged as a serious pathogen that causes high morbidity and substantial mortality. However, the mechanisms by which SARS-CoV-2 evades host immunity remain poorly understood. Here, we identified SARS-CoV-2 membrane glycoprotein M as a negative regulator of the innate immune response. We found that the M protein interacted with the central adaptor protein MAVS in the innate immune response pathways. This interaction impaired MAVS aggregation and its recruitment of downstream TRAF3, TBK1, and IRF3, leading to attenuation of the innate antiviral response. Our findings reveal a mechanism by which SARS-CoV-2 evades the innate immune response and suggest that the M protein of SARS-CoV-2 is a potential target for the development of SARS-CoV-2 interventions.

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SARS-CoV-2 membrane glycoprotein M antagonizes the MAVS-mediated innate antiviral response.

Double-stranded DNA (dsDNA) sensor cyclic-GMP-AMP synthase (cGAS) along with the downstream stimulator of interferon genes (STING) acting as essential immune-surveillance mediators have become hot topics of research. The intrinsic function of the cGAS-STING pathway facilitates type-I interferon (IFN) inflammatory signaling responses and other cellular processes such as autophagy, cell survival, senescence. cGAS-STING pathway interplays with other innate immune pathways, by which it participates in regulating infection, inflammatory disease, and cancer. The therapeutic approaches targeting this pathway show promise for future translation into clinical applications. Here, we present a review of the important previous works and recent advances regarding the cGAS-STING pathway, and provide a comprehensive understanding of the modulatory pattern of the cGAS-STING pathway under multifarious pathologic states.

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Research Advances in How the cGAS-STING Pathway Controls the Cellular Inflammatory Response.

Cytosolic DNA arising from intracellular pathogens is sensed by cyclic GMP-AMP synthase (cGAS) and triggers a powerful innate immune response. However, herpes simplex virus 1 (HSV-1), a double-stranded DNA virus, has developed multiple mechanisms to attenuate host antiviral machinery and facilitate viral infection and replication. In the present study, we found that HSV-1 tegument protein VP22 acts as an inhibitor of cGAS/stimulator of interferon genes (cGAS/STING)-mediated production of interferon (IFN) and its downstream antiviral genes. Our results showed that ectopic expression of VP22 decreased cGAS/STING-mediated IFN-β promoter activation and IFN-β production. Infection with wild-type (WT) HSV-1, but not VP22-deficient virus (ΔVP22), inhibited immunostimulatory DNA (ISD)-induced activation of the IFN signaling pathway. Further study showed that VP22 interacted with cGAS and inhibited the enzymatic activity of cGAS. In addition, stable knockdown of cGAS facilitated the replication of ΔVP22 virus but not the WT. In summary, our findings indicate that HSV-1 VP22 acts as an antagonist of IFN signaling to persistently evade host innate antiviral responses.IMPORTANCE cGAS is very important for host defense against viral infection, and many viruses have evolved ways to target cGAS and successfully evade the attack by the immune system of their susceptible host. This study demonstrated that HSV-1 tegument protein VP22 counteracts the cGAS/STING-mediated DNA-sensing antiviral innate immunity signaling pathway by inhibiting the enzymatic activity of cGAS. The findings in this study will expand our understanding of the interaction between HSV-1 replication and the host DNA-sensing signaling pathway.

Herpes Simplex Virus 1 Tegument Protein VP22 Abrogates cGAS/STING-Mediated Antiviral Innate Immunity.

Human Cytomegalovirus Tegument Protein UL82 Inhibits STING-Mediated Signaling to Evade Antiviral Immunity

Cyclic GMP-AMP synthase (cGAS) senses viral DNA in the cytosol and then catalyzes synthesis of the second messenger cGAMP, which activates the ER-localized adaptor protein Mediator of IRF3 Activator (MITA) to initiate innate antiviral response. Human cytomegalovirus (HCMV) proteins can antagonize host immune responses to promote latent infection. Here, we identified HCMV UL42 as a negative regulator of cGAS/MITA-dependent antiviral response. UL42-deficiency enhances HCMV-induced production of type I interferons (IFNs) and downstream antiviral genes. Consistently, wild-type HCMV replicates more efficiently than UL42-deficient HCMV. UL42 interacts with both cGAS and MITA. UL42 inhibits DNA binding, oligomerization and enzymatic activity of cGAS. UL42 also impairs translocation of MITA from the ER to perinuclear punctate structures, which is required for MITA activation, by facilitating p62/LC3B-mediated degradation of translocon-associated protein β (TRAPβ). These results suggest that UL42 can antagonize innate immune response to HCMV by targeting the core components of viral DNA-triggered signaling pathways.

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Human cytomegalovirus protein UL42 antagonizes cGAS/MITA-mediated innate antiviral response.

Innate immunity is the first line of host defense against viral invasion. The induction of type I interferons (IFNs) and inflammatory cytokines is essential to host antiviral immune responses, which are also key targets of viral immune evasion. Human cytomegalovirus (HCMV) can establish long-term latent infections, in which immune evasion is a pivotal step. In this study, we identified HCMV protein UL44, a DNA polymerase processivity factor, as an inhibitor of the interferon regulatory factor 3 (IRF3)- and NF-κB-dependent antiviral response. Ectopic expression of UL44 inhibited HCMV-triggered induction of downstream effector genes and enhanced viral replication. Conversely, knockdown of UL44 potentiated HCMV-triggered induction of downstream antiviral genes. UL44 interacted with IRF3 and p65, and it inhibited the binding of IRF3 and NF-κB to the promoters of their downstream antiviral genes. These findings reveal an important mechanism of immune evasion by HCMV at the transcriptional level.IMPORTANCE Induction of type I IFNs and inflammatory cytokines plays pivotal roles in host antiviral innate immune responses. Viruses have evolved various mechanisms to interfere with these processes. HCMV causes severe ailments in immunodeficient populations and is a major cause of birth defects. It has been shown that HCMV antagonizes host innate immune defenses, which is important for establishing immune evasion and latent infection. In this study, we identified the HCMV DNA polymerase subunit UL44 as a suppressor of antiviral innate immune responses. Overexpression of UL44 impaired HCMV-triggered induction of type I IFNs and other antiviral genes and thus potentiated viral replication, whereas UL44 deficiency showed opposite effects. Mechanistic studies indicated that UL44 acts by inhibiting the binding of IRF3 and NF-κB to the promoters of downstream antiviral genes. These findings defined an important mechanism of HCMV immune evasion at the transcriptional level, which may provide a therapeutic target for the treatment of HCMV infection.

Human Cytomegalovirus DNA Polymerase Subunit UL44 Antagonizes Antiviral Immune Responses by Suppressing IRF3- and NF-κB-Mediated Transcription.

Abstract Whether and how innate antiviral response is regulated by humoral metabolism remains enigmatic. We show that viral infection induces progesterone via the hypothalamic-pituitary-adrenal axis in mice. Progesterone induces downstream antiviral genes and promotes innate antiviral response in cells and mice, whereas knockout of the progesterone receptor PGR has opposite effects. Mechanistically, stimulation of PGR by progesterone activates the tyrosine kinase SRC, which phosphorylates the transcriptional factor IRF3 at Y107, leading to its activation and induction of antiviral genes. SARS-CoV-2-infected patients have increased progesterone levels, and which are co-related with decreased severity of COVID-19. Our findings reveal how progesterone modulates host innate antiviral response, and point to progesterone as a potential immunomodulatory reagent for infectious and inflammatory diseases. 

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Shan Su

Papers

Human Cytomegalovirus Tegument Protein UL82 Inhibits STING-Mediated Signaling to Evade Antiviral Immunity

Human cytomegalovirus protein UL42 antagonizes cGAS/MITA-mediated innate antiviral response.

Human Cytomegalovirus DNA Polymerase Subunit UL44 Antagonizes Antiviral Immune Responses by Suppressing IRF3- and NF-κB-Mediated Transcription.

Modulation of innate immune response to viruses including SARS-CoV-2 by progesterone

β-adrenoreceptor-triggered PKA activation negatively regulates the innate antiviral response