Dengue Virus Pathogenesis: Innate Immune Signaling and Cell Death Receptor Pathways

The infection caused by the dengue virus (DENV) involves a complicated interaction between viral replication and the body's immune responses. As the first line of defense, the innate immune response limits viral replication but can also lead to immunopathology if it is improperly regulated. The DENV activates several pattern-recognition receptor (PRR) pathways, such as the RIG-I-like receptor (RLR), the Toll-like receptor (TLR), and the cGAS-STING signaling pathway, all of which control interferon and inflammatory responses.

The purpose of this review is to outline the molecular mechanisms involved in the process of innate immune recognition and signaling when DENV infects cells, with a specific focus on the virus's immune-evasion tactics and the relationship between innate immune signaling and programmed cell death; it also examines the possible implications of these pathways for the development of a dengue vaccine and for antiviral approaches.

The RNA of DENV is mainly detected by RNA-sensing pathways such as the RLRs and TLRs, while cGAS-STING signaling can be triggered indirectly as a result of virus-associated cellular stress and the presence of cytosolic DNA. DENV counteracts these antiviral responses by acting on key signaling molecules such as MAVS, STING, TBK1, IRF3, and STAT2, thus promoting viral persistence and replication. At the same time, death-receptor pathways involving tumor necrosis factor receptor (TNFR), Fas (CD95), and TNF-related apoptosis-inducing ligand (TRAIL) receptors control caspase-8-dependent apoptosis and may play a role in the elimination of infected cells as well as in causing tissue injury and immunopathology. The interaction between innate immune signaling, inflammatory responses, and caspase-8-mediated cell death therefore serves as an important factor in determining the balance between antiviral protection and disease progression. If these mechanisms are understood, this could form the basis for developing strategies that boost antiviral immunity while reducing excessive inflammation and pathological cell death.

The way in which dengue disease develops is due to the continuous interaction between the body's antiviral innate immune responses, the virus's ability to evade the immune system, and programmed cell death. It might be possible to enhance control of dengue disease by targeting these closely related pathways, whether by means of vaccine development, antiviral drugs, or therapies that act on the host. Yet any intervention focused on a specific pathway will need to take into account the stage of the disease, the cellular environment, and the possible risk of weakening the protective antiviral immunity.