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JAK/STAT inhibition restores disease tolerance in malaria-infected glucocorticoid receptor knockout mice.

ABSTRACT: Disease tolerance is a defense strategy, whereby the host limits tissue damage, without affecting the pathogen load. In malaria, the disease tolerance mechanisms by which many infected individuals are protected against severe disease, are still incompletely understood. In this study, we show that endogenous glucocorticoids are integral components of disease tolerance in malaria, as genetic deletion of the glucocorticoid receptor in mice resulted in the development of lethal hypoglycemia during Plasmodium chabaudi AS infection. This was paralleled by altered metabolism in liver and spleen, marked by increased glucose uptake, a predominant glycolytic transcriptome, reduced gluconeogenic gene expression and depletion of glycogen stores. Hypoglycemia was highly associated with activation of the JAK/STAT pathway in the liver and spleen. Treatment with ruxolitinib, a JAK1/2 inhibitor, ensured survival by protecting against lethal hypoglycemia. These findings highlight the pivotal role of endogenous glucocorticoids in disease tolerance, and suggest a potential therapeutic role for ruxolitinib in managing malaria-induced hypoglycemia.

ORGANISM(S): Mus musculus

PROVIDER: GSE268268 | GEO | 2025/06/19

REPOSITORIES: GEO

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Project description:The role of the liver for survival of blood-stage malaria is only fragmentary understood. In the experimental blood-stage malaria Plasmodium chabaudi, protective vaccination induces self-healing and, thus, survival of otherwise lethal infections. This study investigates the response of the liver, in terms of mRNA and lincRNA expression, to vaccination-induced self-healing infections and lethal P. chabaudi malaria at early patency on day 4 p.i., when parasitized erythrocytes begin to appear in peripheral blood. Using gene expression microarrays, 23 genes were identified to be induced in the liver by >10-fold at p<0.01. More than one third were genes involved in erythropoiesis, as e.g. Kel, Rhag, Ahsp, Ermap, Slc4a1, Cldn13 Gata1, and Gfi1b. Another group of >10-fold expressed genes contain genes involved in natural cytotoxicity, as those encoding the killer cell lectin-like like receptors Klrb1a, Klrc3, Klrd1, Ncr1 and the granzyme B encoding Gzmb. In addition, there were identified a series of genes involved in the control of cell cycle and mitosis, as Ccnb1, Cdc25c, Ckap2l expressed by >10-fold only in vaccination-protected mice, and 22 genes being at least 100% higher expressed in vaccination-protected mice than the corresponding genes significantly expressed in non-vaccinated mice. Furthermore, distinct lincRNA species were changed by >3-fold in livers of vaccination-protected mice, whereas lethal malaria induced different lincRNAs. Our data suggest that protective vaccination accelerates extramedullary erythropoiesis, generation of liver-resident cytotoxic cells, and regeneration from malaria-induced injuries in the liver at early patency, which may be critical for final survival of otherwise lethal blood-stage malaria of P. chabaudi. Mice: Balb/c mice breeded under specified pathogen-free conditions were delivered from central animal facilities of the University of Düsseldorf. The experiments were performed only with female mice aged 10-12 weeks. They were housed in plastic cages, received a standard diet (Woehrlin, Bad Salzuflen, Germany) and water ad libitum. This study was carried out in strict accordance with the German law on animal protection. The keeping of mice as well as the experimental protocol of the study were officially approved by the State-controlled Committee on the Ethics of Animal Experiments of the State Nordrhein-Westfalen, Germany, and were regularly controlled, without being previously announced, by the local authorities. All efforts were undertaken to minimize suffering of mice. P. chabaudi malaria infection: Blood-stage infections of P. chabaudi were kept in outbred mice under sterile conditions by weekly passages of infected blood. A non-clonal line of P. chabaudi is used in our laboratory since 1982, which resembles to P. chabaudi chabaudi. Challenge of Balb/c mice with 10^6 P. chabaudi-infected erythrocytes, Protective vaccination: As a vaccine, host cell plasma membranes were used, which were isolated in the form of ghosts from P. chabaudi-parasitized erythrocytes Approximately 10^6 ghosts were suspended in 100 µl Freund’s complete adjuvant (FCA) and subcutaneously injected on week 3 and week 1 before infecting with P. chabaudi-parasitized erythrocytes. Control mice were treated in parallel only FCA.

Project description:Disease tolerance is an alternative strategy for acquired immunity to malaria and can be rapidly induced after a single malaria episode - in the absence of improved parasite clearance. Memory of a first malaria episode dampens the inflammatory profile of spleen monocytes and induces mechanisms of stress tolerance to minimise tissue damage. This begs the question how monocytes are instructed to respond in a different way to second compared to first malaria infection. We asked if malaria alters the epigenetic landscape of inflammatory monocytes before their release from the bone marrow - thus testing the compelling innate memory hypothesis. We compared the genome-wide distribution of histone modifications on flow-sorted bone marrow monocytes from mice with memory of severe mosquito transmitted P. chabaudi AJ infection (30 days after drug cure) and drug treated uninfected age-matched controls using ChIPseq. Specifically, we tested whether once-infected mice have long-lived modifications in i) transcription start sites marked with H3K27ac to activate transcription ii) enhancers or superenhancers marked with H3K4me1 to promote gene expression and iii) in H3K9me3 to condense DNA into heterochromatin thereby silencing gene expression. We found no meaningful differences in the histone modification profiles of 2848 genes that define monocyte function in first and second malaria infection using the motif discovery software HOMER. Furthermore, when calling differentially modified regions (DMR) between once-infected mice and uninfected mice to ask whether there were any measurable differences in the epigenetic landscapes of these genes, we found 95% had no detectable modifications. In those rare cases where a DMR was called, HOMER assigned a low peak score, indicating low confidence and minimal biological relevance. Epigenetic reprogramming does therefore not underpin the functional specialisation of inflammatory monocytes in tolerised hosts. Innate memory is thus not induced by malaria infection in vivo. Instead, altered monocyte function and fate are imprinted within the spleen (link to GEO microarray) to promote disease tolerance.

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JAK/STAT inhibition restores disease tolerance in malaria-infected glucocorticoid receptor knockout mice.

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