Search

To determine if adrenocortical gene expression is associated with clinical outcomes or response to corticosteroid treatment in septic shock. A pre-specified nested cohort study of a randomised controlled trial of hydrocortisone compared to placebo in septic shock. Blood was collected for RNAseq analysis prior to treatment with hydrocortisone or placebo. The expression of adrenocortical candidate genes related to pituitary releasing hormones, mineralocorticoid and glucocorticoid receptors, intracellular glucocorticoid metabolism and transport proteins was measured. From May 2014 to April 2017, 671 patients were enrolled in the nested cohort study, from which 494 samples were available for analysis. We found no evidence of an association between candidate gene expression levels and either 90-day mortality, 28-day mortality or time to shock reversal. We observed evidence of a significant interaction between expression and treatment group for time to shock reversal in two genes; GLCCI1 (HR 3.81, 95%CI 0.57–25.47 vs. HR 0.64, 95%CI 0.13–3.07 for hydrocortisone and placebo respectively, p for interaction 0.008) and BHSD1 (HR 0.55, 95%CI 0.28–1.09 vs. HR 1.32 95%CI 0.67–2.60, p for interaction 0.01). In patients with septic shock, there is no association between adrenocortical candidate gene expression and mortality. Patients with higher expression of GLCCI1 who received hydrocortisone achieved shock resolution faster than those receiving placebo; conversely, patients who had higher expression of BHSD1 who received hydrocortisone achieved shock resolution slower than those who received placebo. Variation in gene expression may be a mechanism for heterogeneity of treatment response to corticosteroids in septic shock.

It is well-established that aberrant WNT expression and signaling is associated with developmental defects, malignant transformation and carcinogenesis. More recently, WNT ligands have emerged as integral components of host responses to infection but their functions in the context of immune responses are incompletely understood. Roles in the modulation of inflammatory cytokine production, host cell intrinsic innate defense mechanisms, as well as the bridging of innate and adaptive immunity have been described. To what degree WNT responses are defined by the nature of the invading pathogen or are specific for subsets of host cells is currently not well-understood. Here we provide an overview of WNT responses during infection with phylogenetically diverse pathogens and highlight functions of WNT ligands in the host defense against infection. Detailed understanding of how the WNT network orchestrates immune cell functions will not only improve our understanding of the fundamental principles underlying complex immune response, but also help identify therapeutic opportunities or potential risks associated with the pharmacological targeting of the WNT network, as currently pursued for novel therapeutics in cancer and bone disorders.