A Proteomics Perspective on Viral DNA Sensors in Host Defense and Viral Immune Evasion Mechanisms

Abstract

The sensing of viral DNA is an essential step of cellular immune response to infections with DNA viruses. These human pathogens are spread worldwide, triggering a wide range of virus-induced diseases, and are associated with high levels of morbidity and mortality. Despite similarities between DNA molecules, mammalian cells have the remarkable ability to distinguish viral DNA from their own DNA. This detection is carried out by specialized antiviral proteins, called DNA sensors. These sensors bind to foreign DNA to activate downstream immune signaling pathways and alert neighboring cells by eliciting the expression of antiviral cytokines. The sensing of viral DNA was shown to occur both in the cytoplasm and nucleus of infected cells, disproving the notion that sensing occurred by simple spatial separation of viral and host DNA. A number of omic approaches, in particular mass spectrometry-based proteomic methods, have significantly contributed to the constantly evolving field of viral DNA sensing. Here, we review the impact of omic methods on the identification of viral DNA sensors, as well as on the characterization of mechanisms involved in host defense or viral immune evasion.

Diverse mechanisms evolved by DNA viruses to inhibit early host defenses

“…The recognition of viral DNA by host PRRs constitutes a core mechanism through which cells initiate innate immune responses (Crow, Javitt, and Cristea, 2015). Not surprisingly, viruses have acquired means to target PRRs for degradation to inhibit their DNA sensing functions, i.e., binding to viral DNA and stimulation of IFNs or pro-inflammatory cytokines.…”

“…This expression further induces the amplification of IFNs and interferon-stimulated genes (ISGs), which occurs several steps after the initial sensing event (reviewed in (Haller, Kochs, and Weber, 2006). The presence of viral DNA can be recognized by PRRs in multiple subcellular compartments, including the cytosol, endosomes, and the nucleus (as reviewed in (Crow, Javitt, and Cristea, 2015)). This sensing event signals through adaptor molecules in a sensor-dependent manner and leads to one of several outcomes—either transcription of type I and type II interferons or other cytokines (through translocation of IRFs and NF-κB), or cleavage of cytokines to produce their mature forms as exemplified by the function of inflammasomes (reviewed in (Crow, Javitt, and Cristea, 2015)).…”