Viruses transfer the antiviral second messenger cGAMP between cells

Bridgeman, J. Maelfait, T. Davenne, T. Partridge, Y. Peng, A. Mayer, T. Dong, V. Kaever, P. Borrow, J. Rehwinkel

Science 2015 Sep 11;349(6253):1228-32.

Speaker: Chou-Chen Chang (張肇宸)                                  Time: 13:00~14:00, Sep. 23, 2015

Commentator: Dr. Chih-Peng Chang (張志鵬 老師)          Place: Room 601

Abstract:

Sensing cytosolic DNA produces type I interferons (IFNs) since the cellular factor STING can be activated by recognizing the second messenger, cyclic GMP-AMP (cGAMP), which is synthesized by the cytosolic DNA sensor cGAMP synthase (cGAS). Activation of this STING signaling pathway eventually leads to the activation of transcription factor IRF3 and induction of IFNs [1]. Interestingly, cGAS-synthesized cGAMP can be transferred from producing cells to neighboring cells through gap junctions and then promotes STING activation [2]. Since host factor can be incorporated into the virion of human immunodeficiency virus 1 (HIV-1) [3], the authors were wondering whether virus infection could induce IFN by activating STING even independently of cGAS if the infecting virus can transfer the second messenger by incorporating cGAMP into virion. For this end, the authors produced VSV-G pseudo-typed HIV-1 lentivirus harboring EGFP reporter (HIV-1-GFP). HIV-1-GFP derived from 293T cells overexpressing wild-type mouse cGAS (m-cGAS) could induce IFNs in HEK293 or primary mouse bone marrow derived macrophages; whereas HIV-1-GFP derived from cell expressing catalytically inactive cGAS (m-cGAS-AA) did not. Furthermore, the authors demonstrated that such IFN induction triggered by HIV-1-GFP from cGAS-expressing cells is mediated by virions containing cGAMP and is independent of virus reverse transcription. Taken together, incorporating cGAMP into virion may promote long distance transmission of antiviral signals to cells located far from the initial site of infection. Such transfer of an antiviral mediator may help to speed up the immune response to put the brakes on viral spread. Loading viral vectors with cGAMP therefore holds promise for vaccine development.

References:

1. Sun L, Wu J, Du F, Chen X, Chen ZJ (2013) Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science 339: 786-791.

2. Ablasser A, Schmid-Burgk JL, Hemmerling I, Horvath GL, Schmidt T, et al. (2013) Cell intrinsic immunity spreads to bystander cells via the intercellular transfer of cGAMP. Nature 503: 530-534.

3. Harris RS, Bishop KN, Sheehy AM, Craig HM, Petersen-Mahrt SK, et al. (2003) DNA deamination mediates innate immunity to retroviral infection. Cell 113: 803-809.