Ivermectin reduces in vivo coronavirus infection in a mouse experimental model

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.Fil: Arevalo, A. P.. Instituto Pasteur de Montevideo; UruguayFil: Pagotto, R.. Instituto Pasteur de Montevideo; UruguayFil: Pórfido, Jorge Luis. Instituto Pasteur de Montevideo; Uruguay. Universidad de la República; Uruguay. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Daghero, H.. Instituto Pasteur de Montevideo; UruguayFil: Segovia, Alcira Mercedes. Instituto Pasteur de Montevideo; Uruguay. Universidad de la República; UruguayFil: Yamasaki, K.. Universidad de la Republica. Facultad de Veterinaria.; UruguayFil: Varela, B. Universidad de la Republica. Facultad de Veterinaria.; UruguayFil: Hill, Marcelo. Instituto Pasteur de Montevideo; Uruguay. Universidad de la República; UruguayFil: Verdes, J. M.. Universidad de la Republica. Facultad de Veterinaria.; UruguayFil: Duhalde Vega, Maite. Instituto Pasteur de Montevideo; Uruguay. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; ArgentinaFil: Bollati Fogollin, M.. Instituto Pasteur de Montevideo; UruguayFil: Crispo, Martina. Instituto Pasteur de Montevideo; Urugua

Role of inflammasome activation in tumor immunity triggered by immune checkpoint blockers

Immune checkpoint blockers improve the overall survival of a limitednumber of patients among different cancers. Identifying pathways thatinfluence the immunological and clinical response to treatment is criticalto improve the therapeutic efficacy and predict clinical responses. Recently,a key role has been assigned to innate immune mechanisms in checkpointblockade-driven anti-tumor responses. However, inflammatory pathwayscan both improve and impair anti-tumor immunity. In this review, wediscuss how different inflammatory pathways, particularly inflammasomeactivation, can influence the clinical outcome of immune checkpoint blockers.Inflammasome activation may reinforce anti-tumor immunity by boostingCD8+ T cell priming as well as by enhancing T helper type 17 (Th17)responses. In particular, we focus on the modulation of the cation channeltransmembrane protein 176B (TMEM176B) and the ectonucleotidase CD39as potential targets to unleash inflammasome activation leading to reinforcedanti-tumor immunity and improved efficacy of immune checkpointblockers. Future studies should be aimed at investigating the mechanismsand cell subsets involved in inflammasome-driven anti-tumor responses.Fil: Segovia, Alcira Mercedes. Instituto Pasteur de Montevideo; UruguayFil: Russo, Sofia. Instituto Pasteur de Montevideo; UruguayFil: Girotti, Maria Romina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Rabinovich, Gabriel Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Hill, Marcelo. Instituto Pasteur de Montevideo; Urugua