Hypothyroidism confers tolerance to cerebral malaria

Rodríguez-Muñoz, Diego; Sánchez, Á.; Pérez-Benavente, Susana; Contreras‐Jurado, Constanza; Montero-Pedrazuela, Ana; Toledo-Castillo, Marta; Gutiérrez-Hernández, María; Rodrigues‐Díez, Raquel; Folgueira, Cintia; Briones, Ana M.; Sabio, Guadalupe; Cobeta, Ignacio Monedero; Chávez-Coira, Irene; Castejón, David; Fernández-Valle, Encarnación; Regadera, Javier; Bautista, José M.; Aranda, Ana; Alemany, Susana

doi:10.1126/sciadv.abj7110

Cited by 5 publications

(4 citation statements)

References 66 publications

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“…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.…”

Section: Discussionsupporting

confidence: 90%

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

Oelschlegel,

Bhattacharjee,

Wenk

et al. 2024

Nat Commun

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Sequestration of infected red blood cells (iRBCs) in the microcirculation is a hallmark of cerebral malaria (CM) in post-mortem human brains. It remains controversial how this might be linked to the different disease manifestations, in particular brain swelling leading to brain herniation and death. The main hypotheses focus on iRBC-triggered inflammation and mechanical obstruction of blood flow. Here, we test these hypotheses using murine models of experimental CM (ECM), SPECT-imaging of radiolabeled iRBCs and cerebral perfusion, MR-angiography, q-PCR, and immunohistochemistry. We show that iRBC accumulation and reduced flow precede inflammation. Unexpectedly, we find that iRBCs accumulate not only in the microcirculation but also in large draining veins and sinuses, particularly at the rostral confluence. We identify two parallel venous streams from the superior sagittal sinus that open into the rostral rhinal veins and are partially connected to infected skull bone marrow. The flow in these vessels is reduced early, and the spatial patterns of pathology correspond to venous drainage territories. Our data suggest that venous efflux reductions downstream of the microcirculation are causally linked to ECM pathology, and that the different spatiotemporal patterns of edema development in mice and humans could be related to anatomical differences in venous anatomy.

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Section: Discussionsupporting

confidence: 90%

“…In these mice the flow in the large vessels, as determined with TOF-MRA, was maintained. Although angiographies were not analyzed at the single-vessel level, the flow in the sinuses is clearly visible in these TOF-MRA images 37 .…”

Section: Discussionmentioning

confidence: 99%

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

Oelschlegel,

Bhattacharjee,

Wenk

et al. 2024

Nat Commun

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“…Malaria is a life-threatening infection caused by the genus Plasmodium . A recent study using a mouse model of cerebral malaria showed that hypothyroidism promotes mouse survival, with protection attenuated by the SIRT1 inhibitor EX-527, whereas in mice with normal thyroid function the SIRT1 activator SRT1720 confers host protection [ 83 ], thus suggesting SIRT1 as a therapeutic target in cerebral malaria.…”

Section: Function Of Sirt1 During Infectionsmentioning

confidence: 99%

Sirtuin 1 in Host Defense during Infection

Kim

Silwal

2022

Cells

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Sirtuins (SIRTs) are members of the class III histone deacetylase family and epigenetically control multiple target genes to modulate diverse biological responses in cells. Among the SIRTs, SIRT1 is the most well-studied, with a role in the modulation of immune and inflammatory responses following infection. The functions of SIRT1 include orchestrating immune, inflammatory, metabolic, and autophagic responses, all of which are required in establishing and controlling host defenses during infection. In this review, we summarize recent information on the roles of SIRT1 and its regulatory mechanisms during bacterial, viral, and parasitic infections. We also discuss several SIRT1 modulators, as potential antimicrobial treatments. Understanding the function of SIRT1 in balancing immune homeostasis will contribute to the development of new therapeutics for the treatment of infection and inflammatory disease.

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“…Thermoregulation is a key feature in the maintenance of homeostasis that allows organ processes to work effectively, and its close connection with thyroid hormones is well-documented 1 , 2 . With an increase in metabolic diseases in recent years, thyroid dysfunctions, especially hypothyroidism, represent the most common endocrine disorders and are a major healthcare issue that affects ~4–10% of the population worldwide 3 , 4 .…”

Section: Introductionmentioning

confidence: 99%

Yijung-tang improves thermogenesis and reduces inflammation associated with gut microbiota in hypothyroid rats

Khakisahneh

Zhang

Han

et al. 2023

npj Biofilms Microbiomes

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Currently, considerable attention is focused on exploring the potential relationship between herbal medicine (HM) and the gut microbiome in terms of thermoregulation, which is an important aspect of human health, in modern system biology. However, our knowledge of the mechanisms of HM in thermoregulation is inadequate. Here, we demonstrate that the canonical herbal formula, Yijung-tang (YJT), protects against hypothermia, hyperinflammation, and intestinal microbiota dysbiosis in PTU-induced hypothyroid rats. Notably, these properties were associated with alterations in the gut microbiota and signaling crosstalk between the thermoregulatory and inflammatory mediators in the small intestine and brown adipose tissue (BAT). In contrast to the conventional drug L-thyroxine for curing hypothyroidism, YJT has an efficacy for attenuating systematic inflammatory responses, related with depression in intestinal TLR4 and Nod2/Pglyrp1 signaling pathways. Our findings suggest that YJT could promote BAT thermogenesis and prevent systemic inflammation in PTU-induced hypothyroid rats, which was associated with its prebiotic effect on modulating of the gut microbiota and gene expression with relevance in the enteroendocrine function and innate immune systems. These findings may strengthen the rationale of the microbiota–gut–BAT axis for a paradigm shift to enable holobiont-centric medicine.

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Hypothyroidism confers tolerance to cerebral malaria

Cited by 5 publications

References 66 publications

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

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

Sirtuin 1 in Host Defense during Infection

Yijung-tang improves thermogenesis and reduces inflammation associated with gut microbiota in hypothyroid rats

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