Decoding the enigma of antiviral crisis: Does one target molecule regulate all?. (March 2019) - Mahmud-Al-Rafat, Abdullah
Highlights: IL-6 class switching provides regulation over pro- and anti-inflammatory responses. Unregulated IL-6 trans-signaling promotes uncontrolled pro-inflammatory responses. ADAM-17 regulates class switching between IL-6 trans- and classical-signaling. Selective ADAM-17 blocking restricts overexpression of pro-inflammatory cytokines. ADAM-17 may be an antiviral drug target to reduce immunopathology disease severity. Abstract: Disease fatality associated with Ebola, SARS-CoV and dengue infections in humans is attributed to a cytokine storm that is triggered by excessive pro-inflammatory responses. Interleukin (IL)-6 acts as a mediator between pro- and anti-inflammatory reactivity by initiating trans- and classical-signaling, respectively. Hence, IL-6 is assumed to provide a target for a broad range of antiviral agents. Available immunosuppressive antivirals are directed to control an often exaggerated pro-inflammatory response that gives rise to complex clinical conditions such as lymphocytopenia. It is known that IL-6, via its soluble receptor (sIL-6R), initiates a pro-inflammatory response while an anti-inflammatory response is triggered by the membrane-bound IL-6 receptor (IL-6R). Future antivirals should thus aim to target the mechanism that regulates switching between IL-6 trans- and classical-signaling. In this review, we propose that the tumour necrosis factor-α converting enzyme ADAM-17 could be the master molecule involved in regulating IL-6 class switching and through this in controlling pro- and anti-inflammatory responses to viral antigenic stimuli. Therefore, ADAM-17 should be considered as a potential target molecule for novel antiviral drug discovery that would regulate host reactivity to infection and thereby limit or prevent fatal outcomes.