Metabolic profiling during malaria reveals the role of the aryl hydrocarbon receptor in regulating kidney injury

Abstract

Systemic metabolic reprogramming induced by infection exerts profound, pathogen-specific effects on infection outcome. Here, we detail the host immune and metabolic response during sickness and recovery in a mouse model of malaria. We describe extensive alterations in metabolism during acute infection, and identify increases in host-derived metabolites that signal through the aryl hydrocarbon receptor (AHR), a transcription factor with immunomodulatory functions. We find that Ahr-/- mice are more susceptible to malaria and develop high plasma heme and acute kidney injury. This phenotype is dependent on AHR in Tek-expressing radioresistant cells. Our findings identify a role for AHR in limiting tissue damage during malaria. Furthermore, this work demonstrates the critical role of host metabolism in surviving infection.

Metabolomic analysis of diverse mice reveals hepatic arginase-1 as source of plasma arginase in Plasmodium chabaudi infection

“…Kynurenine and phenylalanine were elevated in all individuals, mouse and human. Kynurenine is a tryptophan breakdown product and ligand of the aryl hydrocarbon receptor (AhR), which protects the host in multiple models of malaria and sepsis (Lissner et al 2020, Brant et al 2014, Bessede et al 2014. Phenylalanine is also elevated during infection, as in other malaria studies (Enwonwu et al 1999, Lopansri et al 2006, Leopold et al 2019a.…”

“…To uncover metabolic processes that are important during Plasmodium infection, we recently identified hundreds of plasma metabolites that change significantly when C57BL/6 mice are infected with P. chabaudi (Lissner et al 2020). Many of these also change in human malaria (Gupta et al 2017, Surowiec et al 2015, Leopold et al 2019a, Leopold et al 2019b, Cordy et al 2019, Lissner et al 2020), but the causes and consequences of many of these metabolic changes remain unknown.…”

“…1a). For each strain, we monitored disease severity, plasma metabolites, plasma cytokines, and circulating immune cells during acute infection (days 5-12 post-infection or days 5-17 for WSB/EiJ mice), when metabolic perturbations in C57BL/6 mice are greatest (Lissner et al 2020).…”

“…To better determine how specifically plasma arginine depletion indicates liver damage, we applied sparse partial least squares discriminant analysis (sPLS-DA) to identify the best metabolic markers for high ALT in our data and in a second dataset (Lissner et al 2020). sPLS-DA is a supervised learning method that selects variables that best differentiate samples based on user-assigned groups, and is well-suited to sparse and heterogeneous multi-omics data (Le Cao et al 2011, Rohart et al 2017, Fletcher et al 2018.…”

CRY-dependent plasticity of tetrad presynaptic sites in the visual system of Drosophila at the morning peak of activity and sleep

“…The tetrad synapses transmit photic and visual information using histamine as a neurotransmitter 7 , however, the inner photoreceptors (R8) which terminate in the medulla, also use acetylcholine as a neurotransmitter 8 . Another type of plastic synapses, feedback synapses, are formed between L2 and photoreceptor terminals 9 , and they seem to modulate the activity of photoreceptors during the rest time and increase their sensitivity during low light intensity at night 10 , 11 .…”