Interleukin-13 as a target to alleviate severe coronavirus disease 2019 and restore lung homeostasis.

The ongoing coronavirus disease (COVID-19) pandemic urgently requires the availability of interventions that improve outcomes for those with severe disease. Since severe acute respiratory syndrome coronavirus 2 infection is characterized by dysregulated lung mucosae, and that mucosal homeostasis is heavily influenced by interleukin (IL)-13 activity, we explore recent findings indicating that IL-13 production is proportional to disease severity. We propose that excessive IL-13 contributes to the progression of severe/fatal COVID-19 by (1) promoting the recruitment of immune cells that express inflammatory cytokines, causing a cytokine storm that results in widespread destruction of lung tissue, (2) directly facilitating tissue-remodeling that causes airway hyperinflammation and obstruction, and (3) diverting the immune system away from developing high-quality cytotoxic T cells that confer effective anti-viral immunity. These factors may cumulatively result in significant lung distress, multi-organ failure, and death. Here, we suggest repurposing existing IL-13-inhibiting interventions, including antibody therapies routinely used for allergic lung hyperinflammation, as well as viral vector-based approaches, to alleviate disease. Since many of these strategies have previously been shown to be both safe and effective, this could prove to be a highly cost-effective solution. Relevance for Patients: There remains a desperate need to establish medical interventions that reliably improves outcomes for patients suffering from COVID-19. We explore the role of IL-13 in maintaining homeostasis at the lung mucosae and propose that its dysregulation during viral infection may propagate the hallmarks of severe disease - further exploration may provide a platform for invaluable therapeutics.

Unique IL-13Rα2/STAT3 mediated IL-13 regulation detected in lung conventional dendritic cells, 24 h post viral vector vaccination.

This study demonstrates that 24 h following viral vector-based vaccination IL-13Rα2 functions as a master sensor on conventional dendritic cells (cDCs), abetted by high protein stability coupled with minimal mRNA expression, to rapidly regulate DC mediated IL-13 responses at the lung mucosae, unlike IL-13Rα1. Under low IL-13, IL-13Rα2 performs as a primary signalling receptor, whilst under high IL-13, acts to sequester IL-13 to maintain homeostasis, both in a STAT3-dependent manner. Likewise, we show that viral vector-derived IL-13 levels at the vaccination site can induce differential STAT3/STAT6 paradigms in lung cDC, that can get regulated collaboratively or independently by TGF-ß1 and IFN-γ. Specifically, low IL-13 responses associated with recombinant Fowlpox virus (rFPV) is regulated by early IL-13Rα2, correlated with STAT3/TGF-ß1 expression. Whilst, high IL-13 responses, associated with recombinant Modified Vaccinia Ankara (rMVA) is regulated in an IL-13Rα1/STAT6 dependent manner associated with IFN-γR expression bias. Different viral vaccine vectors have previously been shown to induce unique adaptive immune outcomes. Taken together current observations suggest that IL-13Rα2-driven STAT3/STAT6 equilibrium at the cDC level may play an important role in governing the efficacy of vector-based vaccines. These new insights have high potential to be exploited to improve recombinant viral vector-based vaccine design, according to the pathogen of interest and/or therapies against IL-13 associated disease conditions.