Mouse liver transcriptome under the condition of fasting, Heme induction and plasmodium infection
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB47568 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR6748010.fastq.gz | Fastqsanger.gz | |||
| ERR6748020.fastq.gz | Fastqsanger.gz | |||
| ERR6748030.fastq.gz | Fastqsanger.gz | |||
| ERR6748040.fastq.gz | Fastqsanger.gz | |||
| ERR6748050.fastq.gz | Fastqsanger.gz |
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Project description:Hypoglycemia is a clinical hallmark of severe malaria, the often-lethal outcome of Plasmodium falciparum infection. Yet, the underlying mechanisms driving the pathogenesis of malaria-associated hypoglycemia remain poorly understood. Here we report that labile heme, an alarmin generated as a byproduct of hemolysis during the blood stage of Plasmodium spp. infection, plays a central role in the development of malaria-associated hypoglycemia. Labile heme recapitulated the hypometabolic response to Plasmodium (chabaudi chabaudi; Pcc) infection in mice, including the development of anorexia, transcriptional repression of hepatic glucose production (HGP) and reduction of glycemia, energy expenditure (EE) as well as core body temperature. While this hypometabolic response is protective against immune-mediated liver damage and anemia, when sustained over time it can lead to hypoglycemia and compromise EE as well as thermoregulation. In response, asexual stages of Plasmodium spp. activate a transcriptional program that reduces virulence in favor of sexual commitment and presumably malaria transmission. In conclusion, malaria-associated hypoglycemia represents a trade-off of a hypometabolic defense strategy against Plasmodium infection.
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Project description:Transcription profiling of P. gingivalis W50 grown in continuous culture under conditions of heme-excess and heme-limitation. Reference design (using Cy5 labelled genomic DNA as the reference) to compare two conditions: heme-excess vs heme-limitation. Three samples for each condition, independently grown.
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Project description:Severe presentations of malaria emerge as parasites from Plasmodium spp. proliferate and lyse red blood cells (RBC), producing extracellular hemoglobin (HB). The heme prosthetic groups are released upon HB oxidation generating circulating labile heme. Here we asked whether scavenging of extracellular HB and/or labile heme, by haptoglobin (HP) and/or hemopexin (HPX), respectively, is protective against severe presentations of malaria. We found that circulating labile heme is an independent risk factor for cerebral and non-cerebral severe presentations of P. falciparum malaria. Labile heme was negatively correlated with HP and HPX, which were however, not risk factors for severe P. falciparum malaria. Genetic HP and/or HPX deletion in mice led to accumulation of labile heme in plasma and kidneys in response to Plasmodium (chabaudi chabaudi) infection. This was associated with increased mortality and acute kidney injury (AKI) in ageing but not adult mice, corroborated in P. falciparum malaria by a an inverse correlation between HPX and heme with serological markers of AKI. In conclusion, HP and HPX exert an age-dependent protective effect against malaria that counters the pathogenesis of AKI in mice and presumably in humans.
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Project description:Hypoglycemia is a clinical hallmark of severe malaria, the often-lethal outcome of Plasmodium falciparum infection. Yet, the underlying mechanisms driving the pathogenesis of malaria-associated hypoglycemia remain poorly understood. Here we report that labile heme, an alarmin generated as a byproduct of hemolysis during the blood stage of Plasmodium spp. infection, plays a central role in the development of malaria-associated hypoglycemia. Labile heme recapitulated the hypometabolic response to Plasmodium (chabaudi chabaudi; Pcc) infection in mice, including the development of anorexia, transcriptional repression of hepatic glucose production (HGP) and reduction of glycemia, energy expenditure (EE) as well as core body temperature. While this hypometabolic response is protective against immune-mediated liver damage and anemia, when sustained over time it can lead to hypoglycemia and compromise EE as well as thermoregulation. I response, asexual stages of Plasmodium spp. activate a transcriptional program that reduces virulence in favor of sexual commitment and presumably malaria transmission. In conclusion, malaria-associated hypoglycemia represents a trade-off of a hypometabolic defense strategy against Plasmodium infection.
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