Diego Rodriguez-Muñoz, Ángela Sánchez, Susana Pérez-Benavente, Constanza Contreras-Jurado, Ana Montero-Pedrazuela, Marta Toledo-Castillo, María Gutiérrez-Hernández, Raquel Rodrigues-Díez, Cintia Folgueira, Ana M. Briones, Guadalupe Sabio, Ignacio Monedero-Cobeta, Irene Chávez-Coira, David Castejón, Encarnación Fernández-Valle, Javier Regadera, José M. Bautista, Ana Aranda, Susana Alemany, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Comunidad de Madrid, Centro de Investigación Biomédica en Red Cáncer (España), Instituto de Salud Carlos III, Ministerio de Economía y Competitividad (España), Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF), Comunidad de Madrid (España), Centro de Investigación Biomédica en Red - CIBERONC (Cáncer), UAM. Departamento de Farmacología, UAM. Departamento de Fisiología, and UAM. Departamento de Medicina
The modulation of the host’s metabolism to protect tissue from damage induces tolerance to infections increasing survival. Here, we examined the role of the thyroid hormones, key metabolic regulators, in the outcome of malaria. Hypothyroidism confers protection to experimental cerebral malaria by a disease tolerance mechanism. Hypothyroid mice display increased survival after infection with Plasmodium berghei ANKA, diminishing intracranial pressure and brain damage, without altering pathogen burden, blood-brain barrier disruption, or immune cell infiltration. This protection is reversed by treatment with a Sirtuin 1 inhibitor, while treatment of euthyroid mice with a Sirtuin 1 activator induces tolerance and reduces intracranial pressure and lethality. This indicates that thyroid hormones and Sirtuin 1 are previously unknown targets for cerebral malaria treatment, a major killer of children in endemic malaria areas., This work was funded by grants SAF2017-83289-R to S.A. and A.A., SAF2017-90604REDT to A.A. supported by the The European Regional Development Fund (FEDER) and BIO2016-77430-R to J.M.B. from the Ministerio de Economía y Competitividad; B2017/BMD-3724 to S.A. and A.A. from the Comunidad de Madrid; and CIBERONC CB/16/00228 to A.A. from the Instituto de Salud Carlos III.