Hypothyroidism confers tolerance to cerebral malaria

Area of Science:

• Endocrinology
• Infectious Diseases
• Neuroscience

Background:

• Host metabolic modulation can induce disease tolerance to infections, improving survival.
• Thyroid hormones are critical regulators of metabolism.
• Cerebral malaria is a severe complication of malaria, particularly in children.

Purpose of the Study:

• To investigate the role of thyroid hormones in the outcome of experimental cerebral malaria.
• To explore the underlying mechanisms of protection conferred by hypothyroidism.

Main Methods:

• Induction of hypothyroidism in mice.
• Infection with *Plasmodium berghei* ANKA.
• Assessment of survival rates, intracranial pressure, brain damage, pathogen burden, blood-brain barrier integrity, and immune cell infiltration.
• Pharmacological manipulation of Sirtuin 1 activity.

Main Results:

• Hypothyroid mice exhibited increased survival and reduced brain damage and intracranial pressure compared to euthyroid controls.
• Protection was observed without significant changes in parasite load, blood-brain barrier disruption, or immune cell infiltration.
• Sirtuin 1 inhibition reversed the protective effects of hypothyroidism, while Sirtuin 1 activation in euthyroid mice conferred tolerance and reduced lethality.

Conclusions:

• Hypothyroidism confers protection against experimental cerebral malaria via a disease tolerance mechanism.
• Thyroid hormones and Sirtuin 1 are identified as novel therapeutic targets for cerebral malaria.