Hypothyroidism confers tolerance to cerebral malaria

Abstract

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.

Beyond the microcirculation: sequestration of infected red blood cells and reduced flow in large draining veins in experimental cerebral malaria

“…Our interpretation is supported by a recent study 37 on protective effects of hypothyroidism in ECM. In hypothyroid C57BL/6 wt mice, PbA infections did not result in increased intracranial pressure and edema despite inflammation and BBB-breakdown.…”

Beyond the microcirculation: sequestration of infected red blood cells and reduced flow in large draining veins in experimental cerebral malaria

“…Our interpretation is supported by a recent study 37 on protective effects of hypothyroidism in ECM. In hypothyroid C57BL/6 wt mice, PbA infections did not result in increased intracranial pressure and edema despite inflammation and BBB-breakdown.…”

Thyroid hormone deficiency worsens outcomes in vaccinia virus infection

“…Of note, uninfected hypothyroid mice also displayed spleen hypotrophy in homeostasis when compared with euthyroid and hyperthyroid animals ( Fig. 2A and B ), as previously described ( 17 , 26 ). Histological examination indicated an important increase in the splenic lymphoid nodules, often presenting germinal centers in euthyroid mice, even more marked in hyperthyroid mice, while hypothyroid spleens were atretic, showing smaller and fewer white pulp nodules ( Fig.…”

“…Uninfected hypothyroid mice display reduced body weight, as expected ( 17 ), while hyperthyroid mice have normal body weight ( Fig. 1B ).…”

“…Thus, further studies are needed to determine whether thyroid hormone supplementation, either alone or as adjunctive therapy, might be favorable for the outcome of respiratory infections. However, hypothyroidism is beneficial in cerebral malaria ( 17 ), reinforcing the idea that NTIS may be advantageous or detrimental for a proper immune response, depending on the disease type, pathogen, and affected organ ( 12 ).…”

IFNγ-inducible Gbp4 and Irgb6 contribute to experimental cerebral malaria pathology in the olfactory bulb

“…Despite prolonged survival, Irgb6 −/− Gbp4 −/− mice exhibited elevated serum levels of IFN-γ, IFN-ɑ, and CCL2. CCL2, a key chemoattractant for monocytes and T cells, is known to drive immune cell infiltration into the brain during ECM and other neuroinflammatory conditions (36,(45)(46)(47)(48)(49)(50). Notably, Gbp4 −/− deficient mice alone showed increased serum IFN-α, consistent with Gbp4's reported role in negatively regulating IFN-α via IRF7 during viral infection (24).…”

Beyond the microcirculation: sequestration of infected red blood cells and reduced flow in large draining veins in experimental cerebral malaria

“…Our interpretation is supported by a recent study 37 on protective effects of hypothyroidism in ECM. In hypothyroid C57BL/6 wt mice, PbA infections did not result in increased intracranial pressure and edema despite inflammation and BBB-breakdown.…”

Thyroid hormone deficiency worsens outcomes in vaccinia virus infection

“…Of note, uninfected hypothyroid mice also displayed spleen hypotrophy in homeostasis when compared with euthyroid and hyperthyroid animals ( Fig. 2A and B ), as previously described ( 17 , 26 ). Histological examination indicated an important increase in the splenic lymphoid nodules, often presenting germinal centers in euthyroid mice, even more marked in hyperthyroid mice, while hypothyroid spleens were atretic, showing smaller and fewer white pulp nodules ( Fig.…”

“…Uninfected hypothyroid mice display reduced body weight, as expected ( 17 ), while hyperthyroid mice have normal body weight ( Fig. 1B ).…”

“…Thus, further studies are needed to determine whether thyroid hormone supplementation, either alone or as adjunctive therapy, might be favorable for the outcome of respiratory infections. However, hypothyroidism is beneficial in cerebral malaria ( 17 ), reinforcing the idea that NTIS may be advantageous or detrimental for a proper immune response, depending on the disease type, pathogen, and affected organ ( 12 ).…”

IFNγ-inducible Gbp4 and Irgb6 contribute to experimental cerebral malaria pathology in the olfactory bulb

“…Despite prolonged survival, Irgb6 −/− Gbp4 −/− mice exhibited elevated serum levels of IFN-γ, IFN-ɑ, and CCL2. CCL2, a key chemoattractant for monocytes and T cells, is known to drive immune cell infiltration into the brain during ECM and other neuroinflammatory conditions (36,(45)(46)(47)(48)(49)(50). Notably, Gbp4 −/− deficient mice alone showed increased serum IFN-α, consistent with Gbp4's reported role in negatively regulating IFN-α via IRF7 during viral infection (24).…”

Beyond the microcirculation: sequestration of infected red blood cells and reduced flow in large draining veins in experimental cerebral malaria

“…Our interpretation is supported by a recent study 37 on protective effects of hypothyroidism in ECM. In hypothyroid C57BL/6 wt mice, PbA infections did not result in increased intracranial pressure and edema despite inflammation and BBB-breakdown.…”

Thyroid hormone deficiency worsens outcomes in vaccinia virus infection

“…Of note, uninfected hypothyroid mice also displayed spleen hypotrophy in homeostasis when compared with euthyroid and hyperthyroid animals ( Fig. 2A and B ), as previously described ( 17 , 26 ). Histological examination indicated an important increase in the splenic lymphoid nodules, often presenting germinal centers in euthyroid mice, even more marked in hyperthyroid mice, while hypothyroid spleens were atretic, showing smaller and fewer white pulp nodules ( Fig.…”

“…Uninfected hypothyroid mice display reduced body weight, as expected ( 17 ), while hyperthyroid mice have normal body weight ( Fig. 1B ).…”

“…Thus, further studies are needed to determine whether thyroid hormone supplementation, either alone or as adjunctive therapy, might be favorable for the outcome of respiratory infections. However, hypothyroidism is beneficial in cerebral malaria ( 17 ), reinforcing the idea that NTIS may be advantageous or detrimental for a proper immune response, depending on the disease type, pathogen, and affected organ ( 12 ).…”

IFNγ-inducible Gbp4 and Irgb6 contribute to experimental cerebral malaria pathology in the olfactory bulb

“…Despite prolonged survival, Irgb6 −/− Gbp4 −/− mice exhibited elevated serum levels of IFN-γ, IFN-ɑ, and CCL2. CCL2, a key chemoattractant for monocytes and T cells, is known to drive immune cell infiltration into the brain during ECM and other neuroinflammatory conditions (36,(45)(46)(47)(48)(49)(50). Notably, Gbp4 −/− deficient mice alone showed increased serum IFN-α, consistent with Gbp4's reported role in negatively regulating IFN-α via IRF7 during viral infection (24).…”