Metabolic Adaptation Establishes Disease Tolerance to Sepsis

Abstract

SummarySepsis is an often lethal syndrome resulting from maladaptive immune and metabolic responses to infection, compromising host homeostasis. Disease tolerance is a defense strategy against infection that preserves host homeostasis without exerting a direct negative impact on pathogens. Here, we demonstrate that induction of the iron-sequestering ferritin H chain (FTH) in response to polymicrobial infections is critical to establish disease tolerance to sepsis. The protective effect of FTH is exerted via a mechanism that counters iron-driven oxidative inhibition of the liver glucose-6-phosphatase (G6Pase), and in doing so, sustains endogenous glucose production via liver gluconeogenesis. This is required to prevent the development of hypoglycemia that otherwise compromises disease tolerance to sepsis. FTH overexpression or ferritin administration establish disease tolerance therapeutically. In conclusion, disease tolerance to sepsis relies on a crosstalk between adaptive responses controlling iron and glucose metabolism, required to maintain blood glucose within a physiologic range compatible with host survival.

Cooperative Metabolic Adaptations in the Host Can Favor Asymptomatic Infection and Select for Attenuated Virulence in an Enteric Pathogen

“…A recent study has suggested that liver iron sequestration regulates blood glucose levels by inducing ferritin to maintain liver gluconeogenesis during sepsis (Weis et al, 2017). Our study provides an alternative explanation: tissue iron sequestration regulates glycemia by inducing acute IR during infection.…”

Characterization of plasma labile heme in hemolytic conditions

“…Upon oxidation, extracellular Hb can release its noncovalently bound heme b groups [6–9], generating pro-oxidant labile heme [8,14,15] that acts as a alarmin [16], sensed by pattern recognition receptors, such as Toll like receptor 4 [17] or NACHT, LRR and PYD domains-containing protein 3 (NALP3) [18]. This endows labile heme with pro-inflammatory [16–20], vasoactive [21], and cytotoxic [10,22–25] effects, while also regulating metabolism [26] and interfering with coagulation [27]. Presumably, these pathophysiologic effects of labile heme contribute critically to the pathogenesis of hemolytic conditions, such as malaria caused upon infection by the protozoan parasites of the genus Plasmodium [6,28], severe sepsis caused by polymicrobial infections [10] or sickle cell disease caused by mutations in the gene encoding the β chain of Hb [21,29,30].…”

Central metabolic interactions of immune cells and microbes: prospects for defeating infections

“…In another mouse study, injection of LPS or infection with S. Typhimurium caused hypoglycaemia when co-administered with a low dose of insulin [53]. A transient reduction in host blood glucose was also reported in a mouse model of polymicrobial bacterial septic infection [115]. A transient reduction in host blood glucose was also reported in a mouse model of polymicrobial bacterial septic infection [115].…”

“…Infection can impact on insulin clearance [53] and reduce glucose biosynthesis by gluconeogenesis in the liver [115]. These two scenarios are not mutually exclusive.…”

“…b-glucan as well as the BCG vaccine also protect from unrelated infections by enhancing pro-inflammatory responses, suggesting the possibility to stimulate protective mechanisms against infectious diseases and also cancers [121]. Targeting these epigenetic mechanisms directly has emerged as a potential Glucose administration prevents hypoglycaemia (loss of blood glucose) in Candida albicans-infected mice treated with metformin and in polymicrobial infections in the absence of liver gluconeogenesis, thereby promoting mouse survival [44,115]. Targeting these epigenetic mechanisms directly has emerged as a potential Glucose administration prevents hypoglycaemia (loss of blood glucose) in Candida albicans-infected mice treated with metformin and in polymicrobial infections in the absence of liver gluconeogenesis, thereby promoting mouse survival [44,115].…”