Immune oxysterols: Role in mycobacterial infection and inflammation

Abstract

Infection remains an important cause of morbidity and mortality. Natural defenses to infection are mediated by intrinsic/innate and adaptive immune responses. While our understanding is considerable it is incomplete and emerging areas of research such as those related to the immune-metabolic axis are only beginning to be appreciated. There is increasing evidence showing a connection between immune signalling and the regulation of sterol and fatty acid metabolism. In particular, metabolic intermediates of cholesterol biosynthesis and its oxidized metabolites (oxysterols) have been shown to regulate adaptive immunity and inflammation and for innate immune signalling to regulate the dynamics of cholesterol synthesis and homeostasis. The side-chain oxidized oxysterols, 25-hydroxycholesterol (25HC) and vitamin D metabolites (vitamin D and vitamin D), are now known to impart physiologically profound effects on immune responses. Macrophages play a frontline role in this process connecting immunity, infection and lipid biology, and collaterally are a central target for infection by a wide range of pathogens including viruses and bacteria, especially intracellular bacteria such as mycobacteria. Clinical manifestations of disease severity in the infected host are likely to pay tribute to perturbations of the metabolic-immune phenomena found in lymphocytes and myeloid cells. Historically and consistent with this notion, vitamin D based oxysterols have had a long association with promoting clinical improvements to patients infected with Mycobacterium tuberculosis. Hence understanding the role of early metabolic mediators of inflammatory responses to infection in particular oxysterols, will aid in the development of urgently needed host directed therapeutic and diagnostic design innovation to combat adverse infection outcomes and antibiotic resistance.

Nutrient sensing, signal transduction and immune responses

“…There are multiple branches off the cholesterol biosynthesis pathway that generate intermediates that are important for steroid hormone production, protein prenylation and also have direct effector and regulatory roles in the immune response [124]. Cholesterol can also be oxidized into various oxysterol molecules, such as 25HC, that are important in the control of various aspects of the immune cell function.…”

Interferon Control of the Sterol Metabolic Network: Bidirectional Molecular Circuitry-Mediating Host Protection

“…In the context of bacterial infection, Listeriolysin O, the major virulence factor of the intracellular bacteria L. monocytogenes , is a cholesterol-dependent cytolysin (CDC) responsible for a wide array of functions including disruption of the internalization vacuole (54). Further, M. tuberculosis has cholesterol uptake machinery, an enzyme system capable of catabolizing sterols for growth and potentially utilizes sterols as a carbon and energy source (55, 63). …”

“English Disease”: Historical Notes on Rickets, the Bone–Lung Link and Child Neglect Issues

“…In the last two decades, an intense investigation around Vitamin D and its metabolism has been recorded identifying its important roles in cell signaling during both the adaptive and innate immune response to bacterial and viral infections [30,31,32,83,84,85,86,87,88,89,90]; for example, cholecalciferol in the management of tuberculosis (TB) [14,91,92]. In addition to the conventional T, B, and natural killer (NK) cells, there is a group of recently recognized innate lymphoid cells (ILCs) involved in mediating the host defense [93].…”

“…About 43% of 200 Iranian children admitted to the hospital with radiographically proven rickets had classic signs of bronchopneumonia [116], about half of 250 Kuwaiti children with rickets had pneumonia or bronchopneumonia [117], and even four out of five of Egyptian children with rickets showed acute respiratory infections at some point during hospitalization [118]. As mentioned earlier, this association between rickets and pneumonia may be explained by the effects of 1,25(OH) 2 D 3 on the immune system, because calcitriol stimulates phagocyte-dependent and antibody-dependent macrophage cytotoxicity modulating simultaneously T and B cell function [30,31,32,83,84,85,86,87,88,89,90]. …”

“…More recently, the link between Vitamin D deficiency and impaired immunity, inflammatory response and dysregulated cancer pathways has been emphasized [27,28,29]. In fact, immune system cellular components possess Vitamin D receptors (VDRs) that can bind the active form of Vitamin D (calcitriol, 1,25-dihydroxyVitamin D, 1,25(OH) 2 D) [30,31,32,33]. The storage form of Vitamin D, which is 25-hydroxyvitamin D, or 25(OH)D, can be converted by activated T and B cells to 1,25(OH) 2 D in human cells in vitro [34].…”