key: cord-353742-k4gxww2c authors: Arévalo, AP; Pagotto, R; Pórfido, J; Daghero, H; Segovia, M; Yamasaki, K; Varela, B; Hill, M; Verdes, JM; Duhalde Vega, M; Bollati-Fogolín, M; Crispo, M title: Ivermectin reduces coronavirus infection in vivo: a mouse experimental model date: 2020-11-02 journal: bioRxiv DOI: 10.1101/2020.11.02.363242 sha: doc_id: 353742 cord_uid: k4gxww2c SARS-CoV2 is a single strand RNA virus member of the type 2 coronavirus family, responsible for causing COVID-19 disease in humans. The objective of this study was to test the ivermectin drug in a murine model of coronavirus infection using a type 2 family RNA coronavirus similar to SARS-CoV2, the mouse hepatitis virus (MHV). BALB/cJ female mice were infected with 6,000 PFU of MHV-A59 (Group Infected; n=20) and immediately treated with one single dose of 500 μg/kg of ivermectin (Group Infected + IVM; n=20), or were not infected and treated with PBS (Control group; n=16). Five days after infection/treatment, mice were euthanized to obtain different tissues to check general health status and infection levels. Overall results demonstrated that viral infection induces the typical MHV disease in infected animals, with livers showing severe hepatocellular necrosis surrounded by a severe lymphoplasmacytic inflammatory infiltration associated with a high hepatic viral load (52,158 AU), while ivermectin administration showed a better health status with lower viral load (23,192 AU; p<0.05) and few livers with histopathological damage (p<0.05), not showing statistical differences with control mice (P=NS). Furthermore, serum transaminase levels (aspartate aminotransferase and alanine aminotransferase) were significantly lower in treated mice compared to infected animals. In conclusion, ivermectin seems to be effective to diminish MHV viral load and disease in mice, being a useful model for further understanding new therapies against coronavirus diseases. Immediately after necropsy, liver and spleen were fixed in 10% neutral buffered formalin 120 (pH 7.4) for further processing. For evaluation, they were embedded in paraffin, sectioned 121 at 4 µm and stained with hematoxylin-eosin (H&E), according to (Kyuwa et al., 2002) . Control group (p<0.05). Results are shown in Figure 6A , B, C and D. Mouse Hepatitis Virus Infection, Liver, Mouse Digestive System The FDA-416 approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro A Role for Neutrophils in Viral Respiratory Disease New Insights About Albumin and Liver Disease, 421 Annals of Hepatology Avermectin exerts 423 anti-inflammatory effect by downregulating the nuclear transcription factor 424 kappa-B and mitogen-activated protein kinase activation pathway Ivermectin, 'Wonder drug' from Japan: the human use 428 perspective The Immunobiology of SARS* Modelos lineales generalizados 434 mixtos: aplicaciones en InfoStat Cryo-EM analysis of the post-fusion 436 structure of the SARS-CoV spike glycoprotein Molecular pathology analyses of two fatal human 440 19 infections of avian influenza A(H7N9) virus Zhong 446 NS; China Medical Treatment Expert Group for Covid-19. Clinical 447 Characteristics of Coronavirus Disease 2019 in China Ivermectin: a systematic review from antiviral 451 effects to COVID-19 complementary regimen Ivermectin as a Broad-Spectrum Host Antiviral: The Real Deal? Cells 9 Animal and translational models of SARS-CoV-2 infection Of Mice and Men: 464 The Coronavirus MHV and Mouse Models as a Translational Approach Understand SARS-CoV-2 The importin 467 alpha/beta-specific inhibitor Ivermectin affects HIF-dependent hypoxia response 468 pathways Acute 470 hepatic failure in IFN-γ-deficient BALB/c mice after murine coronavirus 471 infection Acute and chronic changes 474 in the microcirculation of the liver in inbred strains of mice following infection 475 with mouse hepatitis virus type 3 Pathogenesis of coronavirus-induced infections. Review of 478 pathological and immunological aspects Hematological 480 parameters in the early phase of influenza A virus infection in differentially 481 susceptible inbred mouse strains Liver immunology and its role in 484 inflammation and homeostasis Immunomodulatory effect of 488 various anti-parasitics: a review Ivermectin, a new candidate therapeutic against SARS-CoV-2/COVID-19 Toxicology Testing. In: Haschek and Rousseaux's Handbook of Toxicologic 497 Nuclear/nucleolar localization properties of 502 C-terminal nucleocapsid protein of SARS coronavirus Ivermectin is a specific inhibitor of importin α/β-mediated nuclear import able to 506 inhibit replication of HIV-1 and dengue virus Coronavirus Pathogenesis Advances in Virus 510 513 Nucleocytoplasmic transport of nucleocapsid proteins of enveloped RNA 514 viruses Ivermectin inhibits LPS-induced production of inflammatory cytokines and 517 improves LPS-induced survival in mice