Viruses transfer the antiviral second messenger cGAMP between cells

A. Bridgeman1, J. Maelfait1, T. Davenne1, T. Partridge2, Y. Peng1, A. Mayer1, T. Dong1, V. Kaever3, P. Borrow2, J. Rehwinkel1,*

Cyclic GMP-AMP synthase (cGAS) detects cytosolic DNA during virus infection and induces an antiviral state. cGAS signals by synthesis of a second messenger, cyclic GMP-AMP (cGAMP), which activates stimulator of interferon genes (STING). We show that cGAMP is incorporated into viral particles, including lentivirus and herpesvirus virions, when these are produced in cGAS-expressing cells. Virions transferred cGAMP to newly infected cells and triggered a STING-dependent antiviral program. These effects were independent of exosomes and viral nucleic acids. Our results reveal a way by which a signal for innate immunity is transferred between cells, potentially accelerating and broadening antiviral responses. Moreover, infection of dendritic cells with cGAMP-loaded lentiviruses enhanced their activation. Loading viral vectors with cGAMP therefore holds promise for vaccine development.

http://www.sciencemag.org/conten ... cience.aab3632.full

Transmission of innate immune signaling by packaging of cGAMP in viral particles

Matteo Gentili1,2, Joanna Kowal1,2,*, Mercedes Tkach1,2,*, Takeshi Satoh1,2, Xavier Lahaye1,2, Cécile Conrad1,2, Marilyn Boyron3, Bérangère Lombard4, Sylvère Durand5, Guido Kroemer5, Damarys Loew4, Marc Dalod3, Clotilde Théry1,2,6, Nicolas Manel1,2,6,7,†

Infected cells detect viruses through a variety of receptors that initiate cell-intrinsic innate defense responses. Cyclic GMP-AMP synthase (cGAS) is a cytosolic sensor for many DNA viruses and HIV-1. In response to cytosolic viral DNA, cGAS synthesizes the second messenger 2′3′-cyclic GMP-AMP (cGAMP), which activates antiviral signaling pathways. We show that in cells producing virus, cGAS-synthesized cGAMP can be packaged in viral particles and extracellular vesicles. Viral particles efficiently delivered cGAMP to target cells. cGAMP transfer by viral particles to dendritic cells activated innate immunity and antiviral defenses. Finally, we show that cell-free murine cytomegalovirus and the attenuated human poxvirus vaccine Modified Vaccinia Ankara contained cGAMP. Thus transfer of cGAMP by viruses may represent a defense mechanism to propagate immune responses to uninfected target cells.

http://www.sciencemag.org/conten ... cience.aab3628.full