Retroviruses, including HIV, can activate innate immune responses, but the host sensors for retroviruses are largely unknown. Here we show that HIV infection activates cyclic-GMP-AMP (cGAMP) synthase (cGAS) to produce cGAMP, which binds to and activates the adaptor protein STING to induce type-I interferons and other cytokines. Inhibitors of HIV reverse transcriptase, but not integrase, abrogated interferon-β induction by the virus, suggesting that the reverse transcribed HIV DNA triggers the innate immune response. Knockout or knockdown of cGAS in mouse or human cell lines blocked cytokine induction by HIV, murine leukemia virus (MLV) and Simian immunodeficiency virus (SIV). These results indicate that cGAS is an innate immune sensor of HIV and other retroviruses.

RNA virus infections are detected by the RIG-I family of receptors, which induce type-I interferons through the mitochondrial protein MAVS. MAVS forms large prion-like polymers that activate the cytosolic kinases IKK and TBK1, which in turn activate NF-κB and IRF3, respectively, to induce interferons. Here we show that MAVS polymers recruit several TRAF proteins, including TRAF2, TRAF5, and TRAF6, through distinct TRAF-binding motifs. Mutations of these motifs that disrupted MAVS binding to TRAFs abrogated its ability to activate IRF3. IRF3 activation was also abolished in cells lacking TRAF2, 5, and 6. These TRAF proteins promoted ubiquitination reactions that recruited NEMO to the MAVS signaling complex, leading to the activation of IKK and TBK1. These results delineate the mechanism of MAVS signaling and reveal that TRAF2, 5, and 6, which are normally associated with NF-κB activation, also play a crucial role in IRF3 activation in antiviral immune responses.DOI: http://dx.doi.org/10.7554/eLife.00785.001

The gut microbiota was emerging as critical regulatory elements in shaping the outcome of cancer immunotherapy. However, the underlying mechanisms by which the gut commensal species enhance antitumor immunity remain largely unexplored. Here, we show that the gut microbiota from healthy individuals conferred considerable sensitivity to anti-PD-1 in the colorectal cancer (CRC) tumor-bearing mice, whereas gut microbiota from CRC patients failed to do so. By 16S rRNA gene sequencing, we identified Lactobacillus that was significantly increased in the mice with good response to anti-PD-1, and significantly correlated with anti-tumor immunity. After a series of screening, we isolated a novel Lacticaseibacillus strain, named L. paracasei sh2020. L. paracasei sh2020 showed the most notable anti-tumor immunity in the mice with gut dysbiosis. Mechanistically, the antitumor immune response elicited by L. paracasei sh2020 was dependent on CD8 + T cell. In vitro and in vivo studies revealed that L. paracasei sh2020 stimulation triggered the upregulated expression of CXCL10 in the tumors and subsequently enhanced CD8 + T cell recruitment. Meanwhile, the modulation of gut microbiota caused by L. paracasei sh2020 enhanced its antitumor effect and gut barrier function. Overall, our study offered novel insights into the mechanism by which gut microbiota shaped the outcome of cancer immunotherapy and, more importantly, the novel strain L. paracasei sh2020 might serve as an easy and effective way to promote anti-PD-1 effect in clinical practice.

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