Interferons (IFN) are known to play a critical role in the innate immune response to viral infection. The molecular mechanism responsible for eliciting this response has been well studied. It has been shown that IFN production is initiated by signaling pathways activated by molecular sensors in the presence of viral particles including cytosolic DNA sensors. One of these DNA sensors is Cyclic GMP-AMP synthase (cGAS). This enzyme, when activated, catalyzes the synthesis of a second messenger referred to as cyclic GMP-AMP (cGAMP). This messenger subsequently activates transcription factors that “turn on” the genes responsible for the production of IFN (STING).
This cascading sequence of steps occurs within the infected cell. This activation of IFN may also be spread to nearby cells connected via a gap junction. However, Dr. A. Bridgeman and his colleagues from the medical Research Council Human Immunology Unit at the Medical Research Council Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, suspected that this immunity could also be transferred by the viral vector to whatever additional cells it was infecting. They proposed that the infecting virus might actually incorporate and transfer the cGAMP second messenger. This suggestion has some precedence in that the human immunodeficiency virus 1 (HIV-1) has been shown to incorporate host-derived substances. Given this known behavior, the investigators hypothesized that cGAMP could be picked up by infecting virions, incorporated and subsequently passed on to additional host cells and in that way actually inadvertently spread the immune response.
In order to test this proposal, they used modified and attenuated virions to infect a human embryonic kidney cell line that expressed STING and that were able to induce the production of IFN in response to cGAMP. When these same viruses were subsequently exposed to a target cell line, they were shown to have induced the expression of IFN suggesting that their working hypothesis was correct. The investigators painstakingly ruled out other possible variables that might explain this phenomenon. Even virus-like particles stripped of their RNA genome still induced IFN production in target cells. Finally, they went on to demonstrate unambiguously that cGAMP was, in fact, packaged into the virus studied.
This is an interesting finding that may have clinical value. In light of this evidence, the authors suggest that “using viral vectors with cGAMP therefore holds promise for vaccine development.”