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

Abstract

Infected cells detect viruses through a variety of receptors that initiate cell-intrinsic innate defense responses. Cyclic guanosine monophosphate (GMP)-adenosine monophosphate (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 Modified Vaccinia Ankara virus contained cGAMP. Thus, transfer of cGAMP by viruses may represent a defense mechanism to propagate immune responses to uninfected target cells.

cGAS-STING Signaling Regulates Initial Innate Control of Cytomegalovirus Infection

“…The effectiveness of STING sensing of MCMV despite M48 counteraction may be due to cGAMP, which has been shown to traffic to neighboring cells (45). Two recent reports show that cGAMP can also be directly incorporated into MCMV virions, serving to activate STING virtually immediately upon virus entry into the cytosol (46,47), and perhaps, this pathway supersedes the M48 blockade (or an analogous/parallel viral strategy targeting STING). Taken together, our results and those of others highlight cGAS-STING as a fundamental mechanism for cell-intrinsic sensing of various herpesviruses and the downstream control of viral infection and pathogenesis.…”

Snapin promotes HIV ‐1 transmission from dendritic cells by dampening TLR 8 signaling

“…Within the cytosol, HIV‐1 encounters the deoxyribose nucleoside triphosphate hydrolase SAMHD1, which limits the efficiency of HIV reverse transcription and inhibits replication (Goldstone et al , 2011; Hrecka et al , 2011; Laguette et al , 2011). This prevents detection of reverse‐transcribed viral DNA and activation of interferon responses (Gao et al , 2013; Bridgeman et al , 2015; Gentili et al , 2015). Other factors contributing to HIV‐1 escape in DCs have been described and include TREX1, an exonuclease that degrades reverse‐transcribed HIV DNA in the cytoplasm (Yan et al , 2010), and APOBEC3G/3F (A3G/3F) whose knockdown enhances HIV‐1 infection of DCs associated with G‐to‐A hypermutation of the HIV genome (Pion et al , 2006).…”

Extracellular vesicles and viruses: Are they close relatives?

“…Some data indicate that EVs, although less effectively than virions themselves, can transfer cytosolic proteins involved in antiviral responses, such as APOBEC3G and cGAMP (33)(34)(35)(36), to recipient cells. However, the relative efficiency of virions and EVs in transferring these proteins may be dependent on cell type and environmental conditions.…”

“…Similarly, recent data indicate that the second messenger cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) (induced by cGAMP synthase) is enclosed both in HIV particles and in EVs that are released from infected cells. Intercellular transfer of cGAMP, although accomplished more efficiently by viruses than by EV, triggers antiviral IFN responses in newly infected cells in a stimulator of interferon genes (STING)-dependent manner (35,36).…”