Innate immune sensing of DNA viruses

Abstract

DNA viruses are a significant contributor to human morbidity and mortality. The immune system protects against viral infections through coordinated innate and adaptive immune responses. While the antigen-specific adaptive mechanisms have been extensively studied, the critical contributions of innate immunity to anti-viral defenses have only been revealed in the very recent past. Central to these anti-viral defenses is the recognition of viral pathogens by a diverse set of germ-line encoded receptors that survey nearly all cellular compartments for the presence of pathogens. In this review, we discuss the recent advances in the innate immune sensing of DNA viruses and focus on the recognition mechanisms involved.

Figure 1

Cell surface and endosomal recognition of DNA viruses. A majority of DNA viruses such as CMV, HSV, vaccinia virus and adenovirus are recognized at the cell surface by TLR2. Vaccinia virus is also detected by TLR4. The stimulation of TLR2 and TLR4 leads to the activation of NF-κ B and IRF-3 dependent immune responses. In contrast the recognition of adenovirus by β3-integrins at the cell surface leads to post-translational processing of proIL-1α to IL-1α. The recognition of DNA viruses in the endosomes is exclusively mediated by TLRs such as TLR3, 7, 8, and 9 which sense nucleic acids. The activation the endosomal TLRs results in a strong activation of IRF3/7-dependent type I interferon responses as well as NF-κB-dependent cytokine expression.

Figure 2

Detection of DNA viruses by interferon-inducing cytosolic sensors. Cytosolic sensing DNA viruses is a complex phenomenon involving a plethora of receptors including IFI16, RNA polymerase III and MDA5. These receptors sense viral nucleic acids and activate type I interferon responses through a common signaling platform consisting of STING and TBK1.

Figure 3

Inflammasome-dependent recognition of DNA viruses. NLRP3 and AIM2 sense DNA viral infections and form caspase 1-containing inflammasome complexes through the adapter protein ASC. The activation of caspase 1 results in the proteolytic processing of proIL-1β and proIL-18 to IL-1β and IL-18, respectively. The DNA viruses sensed by the inflammasome pathways include adenovirus, modified Ankara vaccinia virus (MAV), mCMV, and vaccinia virus (VV).