Priming and Activation of Inflammasome by Canarypox Virus Vector ALVAC via the cGAS/IFI16–STING–Type I IFN Pathway and AIM2 Sensor

Abstract

Viral vectors derived from different virus families, including poxvirus (canarypox virus vector ALVAC) and adenovirus (human Ad5 vector), have been widely used in vaccine development for a range of human diseases including HIV/AIDS. Less is known about mechanisms underlying host innate response to these vectors. Increasing evidence from clinical vaccine trials testing different viral vectors has suggested the importance of understanding basic elements of host-viral vector interactions. In this study, we investigated the innate interactions of antigen presenting cells (APCs) with two commonly used HIV vaccine vectors, ALVAC and Ad5, and herein reported identification of AIM2 as an innate sensor for ALVAC triggering strong inflammasome activation in both human and mouse APCs. Microarray and comprehensive gene knockout analyses (CRISPR/Cas9) identified that ALVAC stimulated the cGAS/IFI16-STING-Type I IFN pathway to prime AIM2, which was functionally required for ALVAC-induced inflammasome activation. We also provided evidence that different from ALVAC, Ad5 vector itself was unable to induce inflammasome activation, which was related to its inability to stimulate STING-Type I IFN pathway and to provide inflammasome priming signals. In pre-conditioned APCs, Ad5 vector could stimulate inflammasome activation through AIM2-independent mechanism. Therefore, our study identifies AIM2 inflammasome and cGAS/IFI16-STING-Type I IFN pathway as novel mechanism for host innate immunity to ALVAC vaccine vector.

Inhibition of double‐strand DNA‐sensing cGAS ameliorates brain injury after ischemic stroke

“…However, the weakness of this experiment may be that it is not expected that reduced infarct volume of microglial cGAS‐deficient mice presented to be reduced further in the experimental model; the effect of cGAS inhibition in these mice may be therefore difficult to interpret. Although the precise molecular mechanism of cGAS on neuroinflammation after ischemic stroke remains elusive and needs to be further investigated, we suspect that the interaction of downstream NF‐κB with GSDMD or type I IFN with AIM2 may be involved in this process (Liu et al , ,b).…”

Structure-guided drug design identifies a BRD4-selective small molecule that suppresses HIV

“…CRISPR/Cas9 KO of BRD4 and BRD2. BRD4 and BRD2 gene editing was carried out using CRISPR/Cas9, as we previously reported (51). Gene-specific guide RNA sequences targeting human BRD2 or BRD4 were designed using an online tool (http://crispr.mit.edu/) (Supplemental Table 6).…”

Common Differences: The Ability of Inflammasomes to Distinguish Between Self and Pathogen Nucleic Acids During Infection

“…Finally, adenoviruses (AdVs) are non-enveloped linear double-stranded DNA viruses often used for viral transduction or for pseudotyping as vaccines. Interestingly, AdVs do not activate the AIM2 inflammasome unless the cells are first primed through the type I IFN pathway (Liu et al, 2017). Instead, AdVs activate the NLRP3 inflammasome (Barlan et al, 2011a;Barlan et al, 2011b;Muruve et al, 2008).…”

“…Instead, AdVs activate the NLRP3 inflammasome (Barlan et al, 2011a;Barlan et al, 2011b;Muruve et al, 2008). Alternatively, the adenovirus based canarypox virus vector was able to activate the AIM2 inflammasome due to simultaneous type I IFN pathway activation (Liu et al, 2017). Additionally, antibody binding to AdVs following repeated AdV exposure facilitates virus uptake by dendritic cells and subsequent AIM2 inflammasome activation (Eichholz et al, 2016).…”