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.

Bone marrow erythropoiesis is mainly homeostatic and a demand of oxygen in tissues activates stress erythropoiesis in the spleen. Here, we show an increase in the number of circulating erythrocytes in apolipoprotein E−/− mice fed a Western high-fat diet, with similar number of circulating leukocytes and CD41+ events (platelets). Atherogenic conditions increase spleen erythropoiesis with no variations of this cell lineage in the bone marrow. Spleens from atherogenic mice show augmented number of late-stage erythroblasts and biased differentiation of progenitor cells towards the erythroid cell lineage, with an increase of CD71+CD41CD34−CD117+Sca1−Lin− cells (erythroid-primed megakaryocyte-erythroid progenitors), which is consistent with the way in which atherogenesis modifies the expression of pro-erythroid and pro-megakaryocytic genes in megakaryocyte-erythroid progenitors. These data explain the transiently improved response to an acute severe hemolytic anemia insult found in atherogenic mice in comparison to control mice, as well as the higher burst-forming unit-erythroid and colony forming unit-erythroid capacity of splenocytes from atherogenic mice. In conclusion, our work demonstrates that, along with the well stablished enhancement of monocytosis during atherogenesis, stress erythropoiesis in apolipoprotein E−/− mice fed a Western high fat diet results in increased numbers of circulating red blood cells.

Oncogene-immortalized bone marrow-derived macrophages are considered to be a good model for the study of immune cell functions, but the factors required for their survival and proliferation are still unknown. Although the effect of the thyroid hormones on global metabolic and transcriptional responses in macrophages has not yet been examined, there is increasing evidence that they could modulate macrophage functions. We show here that the thyroid hormone T3 is an absolute requirement for the growth of immortal macrophages. The hormone regulates the activity of the main signaling pathways required for proliferation and anabolic processes, including the phosphorylation of ERK and p38 MAPKs, AKT, ribosomal S6 protein, AMPK and Sirtuin-1. T3 also alters the levels of metabolites controlling transcriptional and post-transcriptional actions in macrophages, and causes widespread transcriptomic changes, up-regulating genes needed for protein synthesis and cell proliferation, while down-regulating genes involved in immune responses and endocytosis, among others. This is not observed in primary bone marrow-derived macrophages, where only p38 and AMPK activation is regulated by T3 and in which the metabolic and transcriptomic effects of the hormone are much weaker. However, the response to IFN-γ is reduced by T3 similarly in immortalized macrophages and in the primary cells, confirming previous results showing that the thyroid hormones can antagonize JAK/STAT-mediated signaling. These results provide new perspectives on the relevant pathways involved in proliferation and survival of macrophage cell culture models and on the crosstalk between the thyroid hormones and the immune system.

Metabolic reprogramming is required to fight infections and thyroid hormones are key regulators of metabolism. We have analyzed in hospitalized COVID-19 patients: 40 euthyroid and 39 levothyroxine (LT4)-treated patients in the ward and 29 euthyroid and 9 LT4-treated patients in the intensive care unit (ICU), the baseline characteristics, laboratory data, thyroid-stimulating hormone (TSH), free thyroxine (FT4), free triiodothyronine (FT3), the FT3/FT4 ratio, 11 antiviral cytokines and 74 metabolomic parameters. No evidence for significant differences between euthyroid and LT4-treated patients were found in the biochemical, metabolomic and cytokines parameters analyzed. Only TSH (p=0.009) and ferritin (p=0.031) showed significant differences between euthyroid and LT4-treated patients in the ward, and TSH (p=0.044) and FT4 (p=0.012) in the ICU. Accordingly, severity and mortality were similar in euthyroid and LT4-treated patients. On the other hand, FT3 was negatively related to age (p=0.012), independently of sex and body mass index in hospitalized COVID-19 patients. Patients with low FT3 and older age showed a worse prognosis and higher levels of the COVID-19 severity markers IL-6 and IL-10 than patients with high FT3. IL-6 negatively correlated with FT3 (p=0.023) independently of age, body mass index and sex, whereas IL-10 positively associated with age (p=0.035) independently of FT3, body mass index and sex. A metabolomic cluster of 6 parameters defined low FT3 ward patients. Two parameters, esterified cholesterol (p=4.1x10-4) and small HDL particles (p=6.0x10-5) correlated with FT3 independently of age, body mass index and sex, whereas 3-hydroxybutyrate (p=0.010), acetone (p=0.076), creatinine (p=0.017) and high-density-lipoprotein (HDL) diameter (p=8.3x10-3) were associated to FT3 and also to age, with p-values of 0.030, 0.026, 0.017 and 8.3x10-3, respectively. In conclusion, no significant differences in FT3, cytokines, and metabolomic profile, or in severity and outcome of COVID-19, were found during hospitalization between euthyroid patients and hypothyroid patients treated with LT4. In addition, FT3 and age negatively correlate in COVID-19 patients and parameters that predict poor prognosis were associated with low FT3, and/or with age. A metabolomic cluster indicative of a high ketogenic profile defines non-critical hospitalized patients with low FT3 levels.

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