ABSTRACT
Legionella pneumophila is an accidental human bacterial pathogen that infects and replicates within alveolar macrophages causing a severe atypical pneumonia known as Legionnaires' disease. As a prototypical vacuolar pathogen L. pneumophila establishes a unique endoplasmic reticulum (ER)-derived organelle within which bacterial replication takes place. Bacteria-derived proteins are deposited in the host cytosol and in the lumen of the pathogen-occupied vacuole via a type IVb (T4bSS) and a type II (T2SS) secretion system respectively. These secretion system effector proteins manipulate multiple host functions to facilitate intracellular survival of the bacteria. Subversion of host membrane glycerophospholipids (GPLs) by the internalized bacteria via distinct mechanisms feature prominently in trafficking and biogenesis of the Legionella -containing vacuole (LCV). Conventional GPLs composed of a glycerol backbone linked to a polar headgroup and esterified with two fatty acids constitute the bulk of membrane lipids in eukaryotic cells. The acyl chain composition of GPLs dictates phase separation of the lipid bilayer and therefore determines the physiochemical properties of biological membranes - such as membrane disorder, fluidity and permeability. In mammalian cells, fatty acids esterified in membrane GPLs are sourced endogenously from de novo synthesis or via internalization from the exogenous pool of lipids present in serum and other interstitial fluids. Here, we exploited the preferential utilization of exogenous fatty acids for GPL synthesis by macrophages to reprogram the acyl chain composition of host membranes and investigated its impact on LCV homeostasis and L. pneumophila intracellular replication. Using saturated fatty acids as well as cis - and trans - isomers of monounsaturated fatty acids we discovered that under conditions promoting lipid packing and membrane rigidification L. pneumophila intracellular replication was significantly reduced. Palmitoleic acid - a C16:1 monounsaturated fatty acid - that promotes membrane disorder when enriched in GPLs significantly increased bacterial replication within human and murine macrophages but not in axenic growth assays. Lipidome analysis of infected macrophages showed that treatment with exogenous palmitoleic acid resulted in membrane acyl chain reprogramming in a manner that promotes membrane disorder and live-cell imaging revealed that the consequences of increasing membrane disorder impinge on several LCV homeostasis parameters. Collectively, we provide experimental evidence that L. pneumophila replication within its intracellular niche is a function of the lipid bilayer disorder and hydrophobic thickness.
ABSTRACT
Angioedema is a localized swelling of the dermis, subcutaneous tissues, and/or submucosal tissues caused by fluid extravasation into these tissues. Angioedema is associated with certain vasoactive molecules and is typically mediated by histamine or bradykinin. It manifests clinically as facial edema, swelling of the extremities and urogenital area, and potential involvement of the larynx, leading to dyspnea and inspiratory stridor, which can become life-threatening. Histamine-mediated angioedema is associated with urticaria and pruritus and will show classic signs of allergic (type 1 hypersensitivity) reactions. Bradykinin-mediated angioedema is often familial (hereditary angioedema) and is more often associated with gastrointestinal symptoms (abdominal pain, nausea, vomiting, diarrhea), edema of the extremities and trunk, and a lack of urticaria and pruritus. Angiotensin-converting enzyme inhibitors (ACEIs) are a class of medications commonly prescribed for hypertension, heart failure, and diabetic nephropathy. ACEIs are associated with an increased risk of angioedema, which can range from a mild reaction to severe and life-threatening. ACEI-induced angioedema is a bradykinin-mediated reaction that can occur in individuals with a genetic predisposition. Other medications, such as angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs, and certain antibiotics, most notably those in the beta-lactam class, can also cause drug-induced angioedema. The present investigation describes current knowledge of the pathophysiology, epidemiology, clinical manifestations, predisposing factors, and management of drug-induced angioedema.
