The teams of Ana Aranda and Susana Alemany from the Instituto de Investigaciones Biomédicas "Alberto Sols", a joint center of the Consejo Superior de Investigaciones Científicas (CSIC) and the Universidad Autónoma de Madrid (UAM) have demonstrated that hypothyroidism protects against cerebral malaria, reducing neurological symptoms and significantly increasing survival in mice infected by the Plasmodium parasite.
The results, published in the journal Science Advances, open the door to a possible new therapeutic target against cerebral malaria in children, a disease that kills several hundred thousand children annually in endemic areas.
A team of Spanish researchers led by Drs. Ana Aranda and Susana Alemany from the Instituto de Investigaciones Biomédicas "Alberto Sols" (IIBM) -a joint center of the Universidad Autónoma de Madrid (UAM) and the Consejo Superior de Investigaciones Científicas (CSIC)-, in collaboration with other teams from the UAM, the Universidad Complutense de Madrid (UCM) and the Centro Nacional de Investigaciones Cardiovasculares (CNIC) has demonstrated that hypothyroidism protects against cerebral malaria in children, which is the most severe manifestation of the disease. These results have been published in the journal Science Advances
Malaria is a disease transmitted to humans by a mosquito infected by Plasmodium parasites. Cerebral malaria is the most severe form of the disease and mainly affects children under 5 years of age. Only last year cerebral malaria killed hundreds of thousands of children in developing countries. The areas of endemic malaria partially overlap, mainly in Africa, with areas of low iodine intake. Iodine is needed for the production of the thyroid hormones, and when the amount of iodine in the diet is not sufficient the thyroid gland does not produce enough thyroid hormones, causing hypothyroidism. Although both cerebral malaria and hypothyroidism are important health problems, the influence of hypothyroidism in the development or outcome of cerebral malaria has not yet been studied.
In our laboratory we have addressed this issue using an experimental model of cerebral malaria in mice that faithfully recapitulates the neurological symptoms and death caused by cerebral malaria in humans. We compared the response to infection with Plasmodium of mice fed with a normal diet and mice fed a low iodine diet supplemented with anti-thyroidal drugs for one month prior to the infection. We found that hypothyroidism increases survival in mice infected with Plasmodium. While mice with a normal thyroid function die 6-7 days after infection with the parasite, hypothyroid mice die much later and almost half of them survive the disease.
The parasite causes breakdown of the blood-brain barrier that allows the entry of parasites and immune cells into the brain. This in turn induces brain swelling, which increases intracranial pressure and compression of cerebral arteries, which causes neurological symptoms and ultimately death. At day 5 post-infection, all normal mice presented neurological symptoms, including paralysis and ataxia. At day 6 they usually suffered convulsions and coma previous to death, while infected hypothyroid mice presented no clear symptoms of cerebral malaria. Although hypothyroid mice have a normal immune response and a broken blood brain barrier after the infection, brain swelling is not produced in these animals.
Possible new therapeutic target
These results suggest that children in endemic areas of iodine deficiency should not be exposed to a higher risk of dying from cerebral malaria, but they could rather be protected from severe disease. These results also suggest that anti-thyroidal drugs could represent a therapeutic approach to fight cerebral malaria. However, hypothyroidism is detrimental to health, especially in very young children, as thyroid hormones are essential for brain development and thyroid hormone deficiency during this period causes mental retardation.
When analyzing the mechanism by which hypothyroidism protects against cerebral malaria we observed that this protection is at least partially mediated by the activity of the enzyme Sirtuin 1. We demonstrated that treatment of mice with normal thyroid function with a Sirtuin 1 activator mimics the effect of hypothyroidism decreasing neurological symptoms and reducing lethality. Infection with Plasmodium causes a marked reduction of the cerebral blood flow in the brains of normal mice, as a consequence of brain swelling, but cerebral blood flow is restored when infected mice were treated with a compound named SRT-1720, a sirtuin 1 activator.
The identification of Sirtuin 1 as a mediator of thyroid hormone action in the outcome of cerebral malaria points out to a beneficial role of Sirtuin 1 activators for treatment of this disease. In this context, clinical trials with Sirtuin 1 activators for different pathologies are ongoing and we believe that these drugs in combination with the antimalarial drugs used to inhibit parasite replication might help to reduce the high intrinsic mortality due to cerebral malaria.
Thus, the activation of the Sirtuin 1 protein could be a new therapeutic target against cerebral malaria in children, conclude the authors of this encouraging study.
Cerebral circulation in an uninfected mouse, in a mouse infected with Plasmodium in which a strong decrease in blood flow is observed, and in an infected mouse treated with SRT1720, an activator of Sirtuin 1, which significantly recovers cerebral circulation /Rodríguez Muñoz et al.