Valerie O'Donnell

The role of procoagulant phospholipids on the surface of circulating blood cells in thrombosis and haemostasis.
Protty MB, Jenkins PV, Collins PW, O'Donnell VB

Phospholipids (PLs) are found in all cell types and are required for structural support and cell activation signalling pathways. In resting cells, PLs are asymmetrically distributed throughout the plasma membrane with native procoagulant aminophospholipids (aPLs) being actively maintained in the inner leaflet of the membrane. Upon platelet activation, aPLs rapidly externalize to the outer leaflet and are essential for supporting the coagulation cascade by providing binding sites for factors in the cell-based model. More recent work has uncovered a role for enzymatically oxidized PLs (eoxPLs) in facilitating coagulation, working in concert with native aPLs. Despite this, the role of aPLs and eoxPLs in thrombo-inflammatory conditions, such as arterial and venous thrombosis, has not been fully elucidated. In this review, we describe the biochemical structures, distribution and regulation of aPL externalization and summarize the literature on eoxPL generation in circulating blood cells. We focus on the currently understood role of these lipids in mediating coagulation reactions , and in human thrombotic disease. Finally, we highlight gaps in our understanding in how these lipids vary in health and disease, which may place them as future therapeutic targets for the management of thrombo-inflammatory conditions.

Open biology, 12, 4, Apr 2022

The SARS-CoV2 envelope differs from host cells, exposes pro-coagulant lipids, and is disrupted in vivo by oral rinses.
Saud Z, Tyrrell VJ, Zaragkoulias A, Protty MB, Statkute E, Rubina A, Bentley K, White DA, Rodrigues PDS, Murphy RC, Köfeler H, Griffiths WJ, Alvarez-Jarreta J, Brown RW, Newcombe RG, Heyman J, Pritchard M, Mcleod RW, Arya A, Lynch CA, Owens D, Jenkins PV, Buurma NJ, O'Donnell VB, Thomas DW, Stanton RJ

The lipid envelope of SARS-CoV-2 is an essential component of the virus; however, its molecular composition is undetermined. Addressing this knowledge gap could support the design of anti-viral agents, as well as further our understanding of viral-host protein interactions, infectivity, pathogenicity, and innate immune system clearance. Using lipidomics analyses, we revealed that the virus envelope comprised mainly phospholipids (PL), with little cholesterol or sphingolipids, indicating significant differences from the composition of host membranes. Unlike cellular membranes, procoagulant aminophospholipids were present on the external side of the viral envelope at levels exceeding those on activated platelets. As a result, virions directly promoted blood coagulation. To investigate whether these differences could enable selective targeting of the viral envelope in vivo, we tested whether oral rinses containing lipid-disrupting chemicals could reduce viral infectivity. Products containing PL-disrupting surfactants (such as cetylpyridinium chloride (CPC)) met European virucidal standards in vitro; however, components that altered the critical micelle concentration reduced efficacy, and products containing essential oils, PVP-I, or Chlorhexidine were ineffective. This result was recapitulated in vivo, where a 30-second oral rinse with CPC mouthwash eliminated live virus in the oral cavity of COVID-19 patients for at least one hour, while PVP-Iodine and saline mouthwashes were found ineffective. We conclude the SARS-CoV-2 lipid envelope (i) is distinct from the host plasma membrane, which may enable design of selective anti-viral approaches; (ii) contains exposed PE and PS, which may influence thrombosis, pathogenicity, and inflammation; and (iii) can be selectively targeted in vivo by specific oral rinses.

Journal of lipid research, 1, 1, 15 Apr 2022

Formation, Signaling and Occurrence of Specialized Pro-Resolving Lipid Mediators-What is the Evidence so far?
Schebb NH, Kühn H, Kahnt AS, Rund KM, O'Donnell VB, Flamand N, Peters-Golden M, Jakobsson PJ, Weylandt KH, Rohwer N, Murphy RC, Geisslinger G, FitzGerald GA, Hanson J, Dahlgren C, Alnouri MW, Offermanns S, Steinhilber D

Formation of specialized pro-resolving lipid mediators (SPMs) such as lipoxins or resolvins usually involves arachidonic acid 5-lipoxygenase (5-LO, ALOX5) and different types of arachidonic acid 12- and 15-lipoxygenating paralogues (15-LO1, ALOX15; 15-LO2, ALOX15B; 12-LO, ALOX12). Typically, SPMs are thought to be formed via consecutive steps of oxidation of polyenoic fatty acids such as arachidonic acid, eicosapentaenoic acid or docosahexaenoic acid. One hallmark of SPM formation is that reported levels of these lipid mediators are much lower than typical pro-inflammatory mediators including the monohydroxylated fatty acid derivatives (e.g., 5-HETE), leukotrienes or certain cyclooxygenase-derived prostaglandins. Thus, reliable detection and quantification of these metabolites is challenging. This paper is aimed at critically evaluating i) the proposed biosynthetic pathways of SPM formation, ii) the current knowledge on SPM receptors and their signaling cascades and iii) the analytical methods used to quantify these pro-resolving mediators in the context of their instability and their low concentrations. Based on current literature it can be concluded that i) there is at most, a low biosynthetic capacity for SPMs in human leukocytes. ii) The identity and the signaling of the proposed G-protein-coupled SPM receptors have not been supported by studies in knock-out mice and remain to be validated. iii) In humans, SPM levels were neither related to dietary supplementation with their ω-3 polyunsaturated fatty acid precursors nor were they formed during the resolution phase of an evoked inflammatory response. iv) The reported low SPM levels cannot be reliably quantified by means of the most commonly reported methodology. Overall, these questions regarding formation, signaling and occurrence of SPMs challenge their role as endogenous mediators of the resolution of inflammation.

Frontiers in pharmacology, 13, 1, 2022