Biology subjects

Jentho, E.

Publications and source records attributed to Jentho, E..

8 recordsLinked to original sources

bioRxiv2026

Age-dependent disease tolerance to SARS-CoV-2 infection

Disease tolerance limits infectious disease severity through tissue damage control mechanisms that do not target pathogens directly. Here we demonstrate that age-dependent decline in adipose tissue lipolysis compromises disease tolerance to SARS-CoV-2 infection. Young adult mice exhibited robust adipocyte lipolysis and 80% survival, whereas old mice showed impaired adipocyte lipolysis and only 20% survival. Genetic repression of adipocyte lipolysis eliminated this age-dependent survival advantage without affecting viral titers, revealing that adipocyte lipolysis is essential for disease tolerance to SARS-CoV-2 in young adults. Impaired adipocyte lipolysis in aged mice was associated with a plasma lipidomic signature that predicts COVID-19 severity and mortality in three independent human cohorts. Mechanistically, adipocyte lipolysis provides free fatty acids (FFA) to support bone marrow emergency myelopoiesis, through CD36- and CPT1-dependent FFA cellular uptake and mitochondrial import, respectively. Bone marrow derived monocytes migrate to the lung via CCL2/CCR2-dependent mechanism where they enforce an immune-metabolic communication network with parenchymal cells to sustain lung structure and function. This circuit is not required to confer protection against influenza infection, revealing pathogen-specific disease tolerance mechanisms. These findings reveal adipose tissue catabolism as a central age-dependent factor responsible for exacerbated COVID-19 mortality in aged populations. One-Sentence SummarySARS-CoV-2 infection induces adipose tissue lipolysis to release fatty acids that drive myelopoiesis and monocyte production for lung protection and COVID-19 disease tolerance, but this protective circuit declines with age, increasing disease severity in the elderly.

immunology↗

bioRxiv2026

Ferroptosis is a Physiologic Vulnerability of Iron-Recycling Macrophages

Iron deficiency anemia affects one-third of the global human population. Paradoxically, the daily iron required to fuel the production red blood cell (RBC) and prevent anemia is provided through its recycling from senescent RBC. This is achieved by splenic red pulp macrophages (RPM) that extract iron from the heme groups of hemoglobin (Hb). How these professional erythrophagocytic macrophages prevent intracellular iron flux from inducing cell death via ferroptosis is unknown. Here we show that SPI-C, the master transcriptional regulator of the erythrophagocytic lineage, orchestrates two redundant anti-ferroptosis pathways. One supports glutathione synthesis, via NF-E2-related factor 2 (NRF2), and the other relies on bilirubin production by biliverdin reductase A (BVRA). Genetic ablation of both pathways, but not either alone, sensitizes erythrophagocytic macrophages to ferroptosis, depletes RPM and increases the severity of iron deficiency anemia in mice. These findings reveal a central physiologic role of ferroptosis in the control of macrophage function, iron homeostasis and iron-deficiency anemia. HighlightsO_LISPI-C enforces the antioxidant metabolic program of RPM. C_LIO_LISPI-C controls bilirubin production by biliverdin reductase A. C_LIO_LIBilirubin protects erythrophagocytic macrophages from ferroptosis. C_LIO_LIFerroptosis protection supports iron-recycling macrophages and limit iron deficiency anemia. C_LI

immunology↗

bioRxiv2025

Biliverdin Reductase Catalytic Activity Is Essential for Malaria Resistance

Jaundice, a condition characterized by elevated levels of circulating bilirubin, is an adaptive response to malaria sustained through bilirubin production by biliverdin reductase A (BVRA). Beyond its enzymatic activity, BVRA acts as a protein kinase and as a transcription factor. To disentangle the contribution of BVRA catalytic activity over its non-canonical functions we generated BlvraG17A and BlvraE97A mice harboring G17A and E97A missense mutations in the BVRA NAD(P)H-binding domain and reductase motif, respectively. Both BlvraG17A and BlvraE97Amice presented a reduction in enzymatic activity and succumbed to malaria, otherwise non-lethal to wild-type (BlvraWT) mice. Quantification of circulating unconjugated bilirubin revealed a dose response effect whereby the mutant strains failed to reach a threshold of circulating bilirubin required to support its protective effect. These findings establish the antimalarial effect of the enzymatic activity of BVRA and define a concentration threshold of bilirubin required for malaria protection, informing therapeutic development and biomarker-guided malaria treatment strategies. Highlights- Establishment of catalytic deficient BVRA mouse mutants; - Anti-malarial effect of BVRA relies on its catalytic activity; - A minimal bilirubin threshold for parasite control; - A minimal bilirubin threshold for malaria resolution;

pathology↗

bioRxiv2025

A bioenergetic basis for multiorgan dysfunction in sepsis

Sepsis is a life-threatening multiorgan dysfunction that develops from a maladaptive host response to infection1. With an estimated 49 million cases per year and [~]11 million related deaths2, sepsis is a global WHO health priority3. Failure to overcome sepsis morbidity and lethality4,5 calls for alternative therapeutic approaches6-8. Here we report that adipocyte lipolysis is vital to prevent the pathogenesis of sepsis in mice. This protective response is evolutionary conserved, producing a plasma lipidomic profile9,10 that reflects on the severity of clinical sepsis. Mechanistically, adipocyte lipolysis fuels energy metabolism to sustain adaptive thermoregulation to infection, via insulin production and insulin receptor (INSR) signaling in adipocytes. This metabolic-based defense strategy does not impact on bacterial burden, establishing disease tolerance to infection11-14. In conclusion, adipocyte lipolysis induces insulin to rewire energy metabolism and support organ function in response to infection.

pathology↗

bioRxiv2025

Monocyte control of organismal energy homeostasis

Multicellular organisms rely on inter-organ communication networks to maintain vital parameters within a dynamic physiological range. Macrophages are central to this homeostatic control system, sensing deviations of those parameters and responding accordingly to support tissue function and organismal homeostasis. Here we demonstrate that dysregulation of iron metabolism in parenchyma cells, imposed by the deletion of ferritin H chain, is sensed by monocyte-derived macrophages. In response, macrophages derived from circulating monocytes support tissue function, energy metabolism and thermoregulation, as demonstrated in bone marrow chimeric and parabiotic mice. This salutary effect is contingent on a transcriptional program, controlled in macrophages by the transcription factor A mitochondria. This transcriptional response acts in a non-cell autonomous manner to support the mitochondria of parenchyma cells, irrespectively of mitochondrial transfer. In conclusion, monocyte-derived macrophages cross-regulate Fe and energy metabolism to support tissue function and organismal homeostasis.

immunology↗

bioRxiv2025

A Metabolite-Based Resistance Mechanism Against Malaria

Whether jaundice, a common presentation of Plasmodium (P.) falciparum malaria (1-3) arising from the accumulation of circulating bilirubin, represents an adaptive or maladaptive response to Plasmodium spp. infection is not understood (1-3). We found that asymptomatic P. falciparum infection was associated with a >10-fold higher ratio of unconjugated bilirubin over parasite burden, compared to symptomatic malaria. Genetic suppression of bilirubin synthesis by biliverdin reductase A (BVRA) (4) increased parasite virulence and malaria mortality in mice. Accumulation of unconjugated bilirubin in plasma, via genetic inhibition of hepatic conjugation by UDP glucuronosyltransferase family 1 member A1 (UGT1A1) (5), was protective against malaria in mice. Unconjugated bilirubin inhibited P. falciparum proliferation in red blood cells (RBC) via a mechanism that suppressed mitochondrial pyrimidine synthesis. Moreover, unconjugated bilirubin inhibited hemozoin (Hz) crystallization and compromised the parasites food vacuole. In conclusion, jaundice represents a metabolic response to Plasmodium spp. infection that limits malaria severity.

immunology↗

bioRxiv2021

A HYPOMETABOLIC DEFENSE STRATEGY AGAINST PLASMODIUM INFECTION

Hypoglycemia is a clinical hallmark of severe malaria, the often-lethal presentation of Plasmodium falciparum infection of humans. Here we report that mice reduce blood glucose levels in response to Plasmodium infection via a coordinated response whereby labile heme, an alarmin produced via hemolysis, induces anorexia and represses hepatic glucose production (HGP). While protective against unfettered immune-mediated inflammation, organ damage and anemia, when sustained over time heme-driven repression of HGP can progress towards hypoglycemia, compromising host energy expenditure and thermoregulation. This hypometabolic state arrests the development of asexual stages of Plasmodium spp., which undergo pyknosis and develop mitochondrial dysfunction. In response, Plasmodium activates a transcriptional program reducing its virulence and inducing sexual differentiation towards the production of transmissible gametocytes. We infer that malaria-associated hypoglycemia represents a trade-off of an evolutionarily conserved defense strategy restricting Plasmodium spp. from accessing host-derived glucose and balancing parasite virulence and transmission.

immunology↗

bioRxiv2019

Heme induces innate immunity memory

Trained immunity defines long-lasting adaptive responses of innate immunity, mediated by transcriptional and epigenetic modifications of myeloid cells. Here, we report that labile heme, an alarmin released extracellularily upon tissue damage and hemolysis, induces trained immunity in human and murine primary cells and in mice. Heme-trainning in monocytes is associated with epigenetic and transcriptional profiles that overlap to some extent with those seen in {beta}-glucan-training, the prototype agonist of trained immunity. In sharp contrast to {beta}-glucan training however, heme-training relied on activation of the Syk/JNK-pathway. Heme training in mice was associated with long-lasting expansion of myeloid-biased progenitor cells as well as with altered chromatin accessibility in hematopoietic stem and progenitor cells. Finally, heme-induced training was protective against bacterial sepsis in mice. In conclusion, we reveal that heme, a bona fide alarmin, induces innate immune memory regulating host response to infection.

immunology↗