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Endogenous glucocorticoids are central players in disease tolerance to malaria

Boek - Dissertatie

Malaria is a global disease caused by infection with Plasmodium parasites and leads yearly to around 216 million cases and 445 000 deaths. It is mostly characterized by a mild febrile disease. In malaria-endemic areas, infected persons acquire semi-immunity, which suppresses parasite replication and prevents severe illness. In non-immune individuals, highly lethal complications can suddenly arise and these include cerebral malaria, severe malarial anemia, placental malaria and malaria-associated acute respiratory distress syndrome (MA-ARDS). In addition, metabolic changes in patients, e.g. lactic acidosis and hypoglycemia, contribute considerably to the severity of disease. Several processes take part in the pathogenesis, such as parasite sequestration and excessive host inflammatory responses. The immune response to malaria needs to be well balanced in order to control the infection without causing severe immunopathology. Tolerance mechanisms enable the host to cope with the consequences of infection without interfering with parasite growth. Endogenous glucocorticoids (GCs), cortisol in humans and corticosterone in rodents, regulate a wide range of physiological processes. They are synthesized upon stimulation of the hypothalamic-pituitary-adrenal (HPA) axis, in particular in conditions of stress. In malaria infections, similar to other types of infection, cortisol levels are increased. However, their importance and precise role have not been defined. In light of the delicate balance in immune and metabolic responses, we hypothesized that endogenous GCs might have an important regulating function during malaria. Therefore, this doctoral research was designed to obtain a better understanding of the role of GCs in malaria. We first studied the effect of the GC metabolising enzyme, 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1). Within cells, this enzyme converts intrinsically inert GCs into their active forms. Knock-out of the 11β-HSD1 gene specifically abolishes this conversion, which results in a decreased negative feedback to the HPA axis. Therefore, the adrenal production of GCs is increased, leading to maintained or even elevated levels of circulating active corticosterone. 11β-HSD1 shapes endogenous GC action and is immunomodulatory. We investigated the role of 11β-HSD1 in two mouse models of malaria. We infected 11β-HSD1-deficient C57BL/6 mice with two strains of murine Plasmodium parasites: P. chabaudi AS (PcAS) and the 'New York' clone of P. berghei NK65 (PbNK65-NY). PcAS-infected C57BL/6 mice are able to clear the parasite and survive the infection despite a transient phase of liver inflammation. 11β-HSD1 deficiency did not affect survival after infection with PcAS parasites, but increased disease severity (i.e. clinical disease score) and parasitemia. IL-4 plasma levels were increased, but anti-malaria antibody production and pathology were unaltered by 11β-HSD1 deficiency. To address differences in preference between the RBC type (normocyte versus reticulocyte) that becomes infected, we also used the reticulocyte-restricted PbNK65-NY parasite, which can cause late-stage hyperparasitemia. 11β-HSD1 deficiency led to a trend towards less hyperparasitemia, paralleled by increased levels of pro-inflammatory interleukin (IL)-6 and tumor necrosis factor (TNF)-α. Overall, 11β-HSD1 is not crucial for survival during experimental malaria, but modulates its progression, depending on the parasite strain. We reasoned that the modest effects of 11β-HSD1 in immune cells might shape the efficiency of parasite clearance. In contrast to 11β-HSD1-deficiency, adrenalectomy abrogates the induction of GCs upon stress. To investigate the consequences of such a drastic lack of GCs on malaria disease, the effects of adrenalectomy were studied in four distinct mouse models of malaria: PbNK65-E in C57BL/6 (MA-ARDS model), PbNK65-E in BALB/c (late hyperparasitemia and anemia), PcAS in C57BL/6 (self-resolving) and PbNK65-NY in C57BL/6 (reticulocyte-restricted). We demonstrated that adrenal hormones confer disease tolerance in malaria, since they protect against early death, without affecting parasitemia. Surprisingly, this was not paralleled by increased inflammatory pathology in the lungs. Also malaria-associated anemia and pathology in the liver and kidneys were not or only mildly affected by adrenal hormones. Instead, circulating levels of cytokines (interferon-γ, IL-6, TNF-α and IL-10) increased. Furthermore, adrenal hormones protected against excessive inflammation in the brain, characterized by the expression of a range of pro-inflammatory cytokines and chemokines and the infiltration of CD4+ T cells and neutrophils. Besides the potent immunomodulatory features, regulation of metabolism by GCs is equally important and metabolic dysregulations are known to complicate malarial disease. Adrenalectomy caused exhaustion of hepatic glycogen and lethal hypoglycemia upon infection. Glucagon levels were controlled by a normal counter-regulatory increase, whereas the transcription of hepatic gluconeogenic enzymes remained unaltered in infected adrenalectomised mice. The marked hypoglycemia could not be prevented or reversed by glucose administration, TNF-α neutralization or administration of clonidine, an α2 adrenergic agonist, which potently inhibits pancreatic insulin release. In contrast, treatment with a synthetic glucocorticoid (dexamethasone) prevented the hypoglycemia, lowered cerebral cytokine expression and significantly increased survival rates. Interestingly, this was not accompanied by the induction of gluconeogenic enzyme expression, suggesting that DEX mainly mediated its protective effect via the inhibition of excessive inflammation. Overall, we conclude that impaired intracellular reactivation of GCs has modest effects on parasite load without influencing the outcome of malaria infection. When the increase of GCs in response to malaria infection is abrogated by adrenalectomy, malaria evolves into a lethal infection, regardless of the pathogen burden. This so-called loss of tolerance is paralleled by excessive systemic and brain inflammation and severe hypoglycemia. These findings may have implications for human malaria disease. The HPA axis is stimulated upon infection, but in patients with severe malaria, the HPA axis has been reported to be hyporesponsive. As suggested by our experimental study in mouse models, such dysregulated HPA response might cause a loss of tolerance and the development of severe hypoglycemia and hyperinflammation. Metabolic complications of malaria are poorly understood. Here, we provide evidence for a possible link between metabolism and inflammation in malaria, and proof the importance of an intact GC response.
Jaar van publicatie:2018
Toegankelijkheid:Open