Hypothyroidsm increases tolerance to experimental cerebral malaria


In a model of experimental cerebral malaria in mice infected with Plasmodium berghei, we have observed that hypothyroid mice show a greater survival than euthyroid mice and that hyperthyroid mice die earlier than euthyroid mice. When infected animals are placed in metabolic boxes, before and during the first 4 days after infection euthyroid mice show higher energy expenditure due to their higher basal metabolism, more movement and higher food intake than hypothyroid mice. However, from the fourth night of infection, euthyroid mice drastically decrease their energy expenditure, dying on day 6 with symptoms of cerebral malaria including paralysis and coma. In contrast, hypothyroid mice maintain similar levels of energy expenditure during the 6 days-experiment, although differences between day and night are lost. Hypothyroid mice eventually die of anemia, some of they even one month after infection. In contrast with the increased survival of hypothyroid mice, both groups of mice have very similar levels of parasitemia up to day 6. All these data indicate that hypothyroidism increases tolerance to cerebral malaria. The analysis of the immune response to infection indicates that hypothyroid mice, despite showing a strong spleen atrophy before infection, display a significant splenomegaly with a much greater increase in the number of the different types of myeloid and lymphoid cells than euthyroid animals. Hypothyroidism neither protects from the breaking of the blood-brain barrier, a hallmark of cerebral malaria, nor decreases the number of infiltrated leukocytes, including CD8 lymphocytes, in the brain. However, histological and magnetic resonance analysis demonstrate tha hypothyroidism decreases the number of microhemorrages and abolishes the increase in brain volume and the compression of the brain. Cerebral angiographies show a dramatic decrease in blood flow in infected euthyroid mice with a lower arterial blood signal that is not observed in infected hypothyroid mice. Tolerance to infections has been related to metabolic changes, in which regulation of the activity of AMPK and sirtuins plays a key role. We have verified that hypothyroid mice present - at least in the liver - an increase in AMPK and SIRT1 activity. We have observed that treatment of euthyroid mice with a SIRT1 activator increases survival and decreases compression of the brain vessels, while hypothyroid mice treated with a SIRT1 inhibitor show reduced survival accompanied by decreased cerebral blood supply. In summary, the metabolic changes induce by hypothyroidism result in increased tolerance to cerebral malaria by a mechanism that involves the regulation of sirtuin activity. Interestingly, the circulating levels of thyroid hormones strongly decrease in the infected euthyroid animals, suggesting that this reduction could constitute a defense mechanism against cerebral malaria. This mechanism could also operate in the areas of endemic malaria in humans, which could be superimposed with areas of iodine deficiency in which thyroid hormone synthesis is reduced.

Alemany de la Peña, Susana
Investigador Científico