A 5-Lipoxygenase Inhibitor, Zileuton, Modulates Host-Immune Responses and Improves Lung Function in a Model of Severe Acute Respiratory Syndrome (SARS) Induced by Betacoronavirus

Pereira, R.D.; Rabelo, R.A.N.; Oliveira, N.F.M.; Porto, S.L.T.; Andrade, A.C.S.P.; Queiroz-Junior, C.M.; Barbosa, C.L.N.; de Souza-Costa, L.P.; Santos, F.R.S.; Oliveira, F.B.R.; da Silva, B.L.V.; Umezu, H.L.; Ferreira, R.; da Silva, G.S.F.; Cruz, J.S.; Teixeira, M.M.; Costa, V.V.; Machado, F.S. A 5-Lipoxygenase Inhibitor, Zileuton, Modulates Host Immune Responses and Improves Lung Function in a Model of Severe Acute Respiratory Syndrome (SARS) Induced by Betacoronavirus. Viruses 2023, 15, 2049. Pereira, R.D.; Rabelo, R.A.N.; Oliveira, N.F.M.; Porto, S.L.T.; Andrade, A.C.S.P.; Queiroz-Junior, C.M.; Barbosa, C.L.N.; de Souza-Costa, L.P.; Santos, F.R.S.; Oliveira, F.B.R.; da Silva, B.L.V.; Umezu, H.L.; Ferreira, R.; da Silva, G.S.F.; Cruz, J.S.; Teixeira, M.M.; Costa, V.V.; Machado, F.S. A 5-Lipoxygenase Inhibitor, Zileuton, Modulates Host Immune Responses and Improves Lung Function in a Model of Severe Acute Respiratory Syndrome (SARS) Induced by Betacoronavirus. Viruses 2023, 15, 2049.

Abstract

Exacerbated inflammatory responses are a hallmark of severe coronavirus disease 2019 (COVID-19). Zileuton (Zi) is a selective inhibitor of 5-lipoxygenase, an enzyme involved in the production of several inflammatory/pro-resolving lipid mediators. Herein, we investigated the effect of Zi treatment in a severe acute respiratory syndrome (SARS) model. Mouse hepatitis virus (MHV)3-infected mice treated with Zi significantly improved the clinical score, weight loss, cardiopulmonary function, and survival rates compared with infected untreated animals. The protection observed in Zi-treated mice was associated with a lower inflammatory score, reduced dendritic cell-producing tumor necrosis factor (TNF), and increased neutrophil-producing interleukin (IL)-10 in the lungs 3 days after infection (dpi). At 5 dpi, the lungs of treated mice showed an increase in Th2-, Treg CD4+-, and Treg CD8+-producing IL-10 and reduced Th1 infiltrating cells. Furthermore, similar results were found upon Zi treatment after SARS-CoV2 infection in transgenic mice expressing the human angiotensin I-converting enzyme 2 (ACE2) receptor driven by the cytokeratin-18 (K18) gene promoter (K18-hACE2), significantly improving the clinical score, weight loss, and lung inflammatory score compared with untreated animals. Our data suggest that Zi protects against developing severe lung disease during SARS induced by betacoronavirus without affecting the host’s capacity to deal with infection.

Keywords

Zileuton; Viral Infection; MHV; SARS-CoV-2; COVID-19

Subject

Biology and Life Sciences, Immunology and Microbiology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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