Disulfiram inhibits neutrophil extracellular trap formation and protects rodents from acute lung injury and SARS-CoV-2 infection
Jose M. Adrover, Lucia Carrau, Juliane Daßler-Plenker, Yaron Bram, Vasuretha Chandar, Sean Houghton, David Redmond, Joseph R. Merrill, Margaret Shevik, Benjamin R. tenOever, Scott K. Lyons, Robert E. Schwartz, Mikala Egeblad
Jose M. Adrover, Lucia Carrau, Juliane Daßler-Plenker, Yaron Bram, Vasuretha Chandar, Sean Houghton, David Redmond, Joseph R. Merrill, Margaret Shevik, Benjamin R. tenOever, Scott K. Lyons, Robert E. Schwartz, Mikala Egeblad
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Research Article COVID-19 Immunology

Disulfiram inhibits neutrophil extracellular trap formation and protects rodents from acute lung injury and SARS-CoV-2 infection

Abstract

Severe acute lung injury has few treatment options and a high mortality rate. Upon injury, neutrophils infiltrate the lungs and form neutrophil extracellular traps (NETs), damaging the lungs and driving an exacerbated immune response. Unfortunately, no drug preventing NET formation has completed clinical development. Here, we report that disulfiram — an FDA-approved drug for alcohol use disorder — dramatically reduced NETs, increased survival, improved blood oxygenation, and reduced lung edema in a transfusion-related acute lung injury (TRALI) mouse model. We then tested whether disulfiram could confer protection in the context of SARS-CoV-2 infection, as NETs are elevated in patients with severe COVID-19. In SARS-CoV-2–infected golden hamsters, disulfiram reduced NETs and perivascular fibrosis in the lungs, and it downregulated innate immune and complement/coagulation pathways, suggesting that it could be beneficial for patients with COVID-19. In conclusion, an existing FDA-approved drug can block NET formation and improve disease course in 2 rodent models of lung injury for which treatment options are limited.

Authors

Jose M. Adrover, Lucia Carrau, Juliane Daßler-Plenker, Yaron Bram, Vasuretha Chandar, Sean Houghton, David Redmond, Joseph R. Merrill, Margaret Shevik, Benjamin R. tenOever, Scott K. Lyons, Robert E. Schwartz, Mikala Egeblad

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Figure 5

Disulfiram improves lung histology in a golden hamster SARS-CoV-2 infection model.

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Disulfiram improves lung histology in a golden hamster SARS-CoV-2 infect...
(A) Representative images from whole mount cleared SARS-CoV-2–infected lungs from hamsters treated with disulfiram or vehicle. Arrows point to NETs, defined as triple colocalization events of DNA, MPO, and citH3. Representative of 5 independent whole mounts per group. (B) Quantification of NETs in the lungs of SARS-CoV-2–infected hamsters. A group was started on daily disulfiram treatment 24 hours prior to infection (pretreat.), while disulfiram was initiated in the other group one day post infection (post.). n = 10 lung volumes from 5 hamsters per group. (C and D) Representative images (showing MPO in cyan) and quantification of neutrophil infiltration to the lungs of SARS-CoV-2–infected hamsters. n = 30 random fields from 5 lungs per group. (E) Quantification of SARS-CoV-2 nucleocapsid signal normalized to β-actin (both proteins detected in lung lysates by Western blot) in disulfiram- and vehicle-treated hamsters, showing that disulfiram does not affect viral load. n = 5 Western blots from 3 uninfected hamsters, 5 Western blots from 5 infected and vehicle-treated hamsters, and 10 Western blots from infected and disulfiram-treated hamsters (5 from the pretreatment and 5 from the posttreatment groups). (F and G) Representative images (left, original image; right, detection overlay showing infiltrated area in violet) and quantification of the heavily immune-infiltrated areas from H&E-stained lungs of disulfiram- or vehicle-treated hamsters infected with SARS-CoV-2. n = 5 (vehicle) and 10 (disulfiram) lungs per group. (H and I) Quantification (mean value of 10 independent measurements per lung) and representative images of perivascular fibrosis in the Masson trichrome–stained lungs of infected hamsters treated with disulfiram or vehicle. n = 5 (vehicle) and 10 (disulfiram) lungs per group. Data are shown as mean ± SEM. *P < 0.05, ***P < 0.001 as determined by 1-way ANOVA with Tukey’s multiple comparison test (A) or unpaired 2-tailed t test analysis (D, E, G, and H). Scale bars: (A) 25 μm, (C) 50 μm, (F and I) 1 mm.