System-Based Approaches to Delineate the Antiviral Innate Immune Landscape

Figure 1. The antiviral innate immune response is orchestrated by signaling cascades and the synergistic activity of numerous factors that are converging in a complex regulatory network. Pathogen-associated molecular patterns such as viral nucleic acids (viral NAs) are sensed by cytoplasmic pattern recognition receptors (PRRs), which in turn, activate signaling cascades of the innate immune system. This leads to the expression of regulatory function (Regulator) and proteins with antiviral effector proteins (Effector), which is controlled on transcriptional and translational level. Paracrine and autocrine interferon (IFN) signaling synergistically modulate these signaling cascades. The activity of numerous contributing factors puts the cell into an antiviral state, inhibiting virus replication at multiple stages of the viral life cycle. To avoid overshooting immune reactions and adverse effects on cellular fitness, negative regulators eventually shut down the IFN response.

Figure 2. An extensive portfolio of genetic perturbation approaches (1) can be used to modify the protein expression levels to study the contextual function of specific gene products. With a suitable infection model system (2) (e.g., reporter viruses) and a fitting screening format (3), a large number of target genes can be studied on a large scale. Several different methods can then be used as a readout for gene/protein functionality (4). Different datasets can then be merged and fed into meta- and network-analysis algorithms (5). Gathering detailed insights from different experimental settings, a global picture of the innate immunity landscape can be drawn. It is critical to understand virus–host interactions in detail to develop novel antiviral drugs and treatments at the time they are needed.