Cytotoxic lymphocytes counteract viral type I interferon immune evasion

Area of Science:

• Immunology
• Virology
• Cell Biology

Background:

• Innate immunity recognizes viral nucleic acids via cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) pathways.
• Many viruses, including human cytomegalovirus (HCMV), possess mechanisms to evade this cGAS-STING-mediated interferon-beta (IFN-β) response.
• Understanding viral immune evasion and host counter-mechanisms is crucial for developing antiviral strategies.

Purpose of the Study:

• To investigate the role of natural killer (NK) cells in counteracting HCMV's evasion of the type I interferon response.
• To elucidate the molecular mechanism by which NK cells restore antiviral immunity during HCMV infection.

Main Methods:

• Comparative analysis of IFN-β response in HCMV-infected cells with wild-type, perforin-knockout, and Granzyme M (GrM)-knockout NK cells.
• Investigation of the interaction between NK cell-derived GrM and the viral pp71 protein.
• Assessment of the impact of pp71 cleavage by GrM on cGAS-STING pathway activation and IFN-β production.

Main Results:

• NK cells significantly enhance the IFN-β response in HCMV-infected cells compared to knockout NK cells.
• Granzyme M (GrM) cleaves the viral pp71 protein into two fragments.
• The second pp71 fragment generated by GrM cleavage augments IFN-β production and overcomes STING inhibition, while the first fragment is rapidly degraded.

Conclusions:

• NK cells utilize Granzyme M (GrM) as a key mechanism to counteract HCMV-induced immune evasion.
• GrM processing of viral pp71 restores the host's cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING)-interferon-beta (IFN-β) innate immune response.
• Targeting the pp71 cleavage site in HCMV can impair NK cell-mediated immune control.