# Cytotoxic lymphocytes counteract viral type I interferon immune evasion

## TL;DR

Natural killer cells help fight human cytomegalovirus by cutting a viral protein that normally blocks the immune response, turning a defense into a weakness.

## Contribution

NK cells use granzyme M to counteract HCMV immune evasion by cleaving the viral pp71 protein.

## Key findings

- Granzyme M cleaves pp71 into fragments, one of which enhances the interferon-β response.
- NK cells cannot enhance IFN-β when HCMV pp71 lacks a granzyme M cleavage site.
- Cleaved pp71 fragments flip the viral immune evasion strategy into an antiviral signal.

## Abstract

Viruses are recognized by host cell innate immunity through viral RNA/DNA sensing by cyclic GMP-AMP synthase (cGAS) stimulator of interferon genes (STING). However, many viruses evade cGAS-STING signaling and antiviral IFN-β response. Here, we show that natural killer (NK) cells counteract immune evasion of type I interferon response upon human cytomegalovirus (HCMV) infection. NK cells enhance IFN-β response in virus-infected cells more efficiently than perforin-knockout and GrM-knockout NK cells. Mechanistically, GrM cleaves viral pp71 into two fragments, the first, like full-length pp71, still inhibits cGAS-STING-IFN-β response but is rapidly degraded by the proteasome, and the second fragment that rather augments IFN-β and outperforms full-length pp71 inhibition of STING. NK cells cannot enhance IFN-β response in cells infected with HCMV that harbors a pp71 with a mutated GrM cleavage site. We conclude that NK cells use GrM to counteract cytomegaloviral innate immune evasion through pp71-mediated inhibition of cGAS-STING-IFN-β innate immune response.

Human cytomegalovirus (HCMV) is a common virus that can cause severe disease in newborns and people with weakened immune systems. To survive in the body, HCMV blocks an important early-warning system in infected cells called the cGAS-STING pathway, which normally triggers production of interferon-β to stop viral spread. We found that natural killer (NK) cells can overcome this viral defense. NK cells release an enzyme called granzyme M that cuts a viral protein, pp71, which is responsible for shutting down the interferon response. Once pp71 is cut, one piece is quickly destroyed and the other actually helps restore the antiviral signal. When the virus is engineered so pp71 cannot be cut, NK cells lose this ability to enhance interferon-β production. These results show that NK cells can “flip” a viral immune-evasion strategy and strengthen the body’s antiviral defenses, suggesting new ways to improve immunity against HCMV.