Innate Sensing of DNA Virus Genomes

Abstract

DNA viruses are linked to many infectious diseases and contribute significantly to human morbidity and mortality worldwide. Moreover, DNA viral infections are usually lifelong and hard to eradicate. Under certain circumstances, these viruses can cause fatal disease, especially in children and immunocompromised patients. An efficient innate immune response against these viruses is critical, not only as the first line of host defense against viral infection but also for mounting more specific and robust adaptive immunity against the virus. Recognition of the viral DNA genome is the very first step of this whole process and is crucial for understanding viral pathogenesis as well as for preventing and treating DNA virus-associated diseases. This review focuses on the current state of our knowledge on how human DNA viruses are sensed by the host innate immune system and how viral proteins counteract this immune response.

Keywords: AIM2; DNA sensing; DNA sensors; DNA virus; IFI16; RLR; STING; TLR; cGAS; innate immunity.

Figure 1

DNA sensors and related signaling pathway. TLR9 recognizes CpG DNA in the endosome and recruits MyD88 to activate IRF7 and NF-κB, leading to induction of type I interferons (IFNs) and inflammatory cytokines. AT-rich double-stranded DNA (dsDNA) is transcribed by RNA Pol III into 5ʹ-triphosphate double-stranded RNA (5ʹ-ppp-dsRNA), which in turn activates the RIG-I–MAVS pathway. DNA from viruses or bacteria could be detected by cGAS and potentially also by other putative DNA sensors, which are all proposed to activate the endoplasmic reticulum–resident adaptor protein STING. STING translocates from the endoplasmic reticulum to the Golgi to activate TBK1-IRF3 and NF-κB, resulting in robust type I IFN induction and inflammatory cytokine production. Detection of DNA by IFI16 and AIM2 in the nucleus and cytoplasm, respectively, activates the inflammasome via recruitment of ASC and caspase-1, leading to proteolytic cleavage of pro-IL1β and pro-IL18.