Targeting potential drivers of COVID-19: Neutrophil extracellular traps

Barnes, Betsy J.; Adrover, Jose M.; Baxter-Stoltzfus, Amelia; Borczuk, Alain; Cools-Lartigue, Jonathan; Crawford, James M.; Daßler-Plenker, Juliane; Guerci, Philippe; Huynh, Caroline; Knight, Jason S.; Loda, Massimo; Looney, Mark R.; McAllister, Florencia; Rayes, Roni; Renaud, Stephane; Rousseau, Simon; Salvatore, Steven; Schwartz, Robert E.; Spicer, Jonathan D.; Yost, Christian C.; Weber, Andrew; Zuo, Yu; Egeblad, Mikala

Due to the clear similarities between the clinical presentation of severe COVID-19 and known NETopathies-ARDS and microthrombosis-we propose that excess NETs may play a major role in the disease. Our understanding of NET formation and function is incomplete, but drugs that target NETs exist or are in development (Fig. 4) . These drugs include inhibitors of the molecules required for NET formation: NE, PAD4, and gasdermin D. For example, endogenous inhibitors of NET formation, which may function by inhibiting PAD4, have been isolated from umbilical cord plasma (Yost et al., 2016) , and these are in development for the treatment of inflammatory syndromes such as COVID-19. Clinical development of inhibitors against NE is the most advanced, and importantly, they could inhibit both the formation of NETs, where NE activity is part of the signaling mechanism, and the toxic activities of NE on the NETs. The NE inhibitor sivelestat was approved to treat ARDS in Japan and South Korea, but it did not increase survival after ARDS in a meta-analysis of clinical trials (Tagami et al., 2014) . However, a new generation of potent NE inhibitors, including lonodelestat (POL6014), alvelestat, CHF6333, and elafin, have undergone Phase I testing. As a result, it may be possible to expedite their development as treatments for COVID-19. Gasdermin D inhibitors remain in preclinical development, but an existing drug-disulfiram, used to treat alcoholism-has been reported to inhibit gasdermin D and limit lung injury in animal models (Hu et al., 2018 Preprint) . Finally, colchicine is another existing drug that could inhibit both neutrophil recruitment to sites of inflammation and the secretion of IL1β, and trials using colchicine in COVID-19 are underway (ClinicalTrials.gov identifiers: NCT04326790, NCT04328480, NCT04322565, NCT04322682).