Role of Hepatic Lipase and Endothelial Lipase in High-Density Lipoprotein—Mediated Reverse Cholesterol Transport

Reverse cholesterol transport (RCT) constitutes a key part of the atheroprotective properties of high-density lipoproteins (HDL). Hepatic lipase (HL) and endothelial lipase (EL) are negative regulators of plasma HDL cholesterol levels. Although overexpression of EL decreases overall macrophage-to-feces RCT, knockout of both HL and EL leaves RCT essentially unaffected. With respect to important individual steps of RCT, current data on the role of EL and HL in cholesterol efflux are not conclusive. Both enzymes increase hepatic selective cholesterol uptake; however, this does not translate into altered biliary cholesterol secretion, which is regarded the final step of RCT. Also, the impact of HL and EL on atherosclerosis is not clear cut; rather it depends on respective experimental conditions and chosen models. More mechanistic insights into the diverse biological properties of these enzymes are therefore required to firmly establish EL and HL as targets for the treatment of atherosclerotic cardiovascular disease

Porcine Sialoadhesin (CD169/Siglec-1) Is an Endocytic Receptor that Allows Targeted Delivery of Toxins and Antigens to Macrophages

Sialoadhesin is exclusively expressed on specific subpopulations of macrophages. Since sialoadhesin-positive macrophages are involved in inflammatory autoimmune diseases, such as multiple sclerosis, and potentially in the generation of immune responses, targeted delivery of drugs, toxins or antigens via sialoadhesin-specific immunoconjugates may prove a useful therapeutic strategy. Originally, sialoadhesin was characterized as a lymphocyte adhesion molecule, though recently its involvement in internalization of sialic acid carrying pathogens was shown, suggesting that sialoadhesin is an endocytic receptor. In this report, we show that porcine sialoadhesin-specific antibodies and F(ab')2 fragments trigger sialoadhesin internalization, both in primary porcine macrophages and in cells expressing recombinant porcine sialoadhesin. Using chemical inhibitors, double immunofluorescence stainings and dominant-negative constructs, porcine sialoadhesin internalization was shown to be clathrin- and Eps15-dependent and to result in targeting to early endosomes but not lysosomes. Besides characterizing the sialoadhesin endocytosis mechanism, two sialoadhesin-specific immunoconjugates were evaluated. We observed that porcine sialoadhesin-specific immunotoxins efficiently kill sialoadhesin-expressing macrophages. Furthermore, porcine sialoadhesin-specific albumin immunoconjugates were shown to be internalized in macrophages and immunization with these immunoconjugates resulted in a rapid and robust induction of albumin-specific antibodies, this compared to immunization with albumin alone. Together, these data expand sialoadhesin functionality and show that it can function as an endocytic receptor, a feature that cannot only be misused by sialic acid carrying pathogens, but that may also be used for specific targeting of toxins or antigens to sialoadhesin-expressing macrophages

A Research Agenda for Helminth Diseases of Humans: Modelling for Control and Elimination

Mathematical modelling of helminth infections has the potential to inform policy and guide research for the control and elimination of human helminthiases. However, this potential, unlike in other parasitic and infectious diseases, has yet to be realised. To place contemporary efforts in a historical context, a summary of the development of mathematical models for helminthiases is presented. These efforts are discussed according to the role that models can play in furthering our understanding of parasite population biology and transmission dynamics, and the effect on such dynamics of control interventions, as well as in enabling estimation of directly unobservable parameters, exploration of transmission breakpoints, and investigation of evolutionary outcomes of control. The Disease Reference Group on Helminth Infections (DRG4), established in 2009 by the Special Programme for Research and Training in Tropical Diseases (TDR), was given the mandate to review helminthiases research and identify research priorities and gaps. A research and development agenda for helminthiasis modelling is proposed based on identified gaps that need to be addressed for models to become useful decision tools that can support research and control operations effectively. This agenda includes the use of models to estimate the impact of large-scale interventions on infection incidence; the design of sampling protocols for the monitoring and evaluation of integrated control programmes; the modelling of co-infections; the investigation of the dynamical relationship between infection and morbidity indicators; the improvement of analytical methods for the quantification of anthelmintic efficacy and resistance; the determination of programme endpoints; the linking of dynamical helminth models with helminth geostatistical mapping; and the investigation of the impact of climate change on human helminthiases. It is concluded that modelling should be embedded in helminth research, and in the planning, evaluation, and surveillance of interventions from the outset. Modellers should be essential members of interdisciplinary teams, propitiating a continuous dialogue with end users and stakeholders to reflect public health needs in the terrain, discuss the scope and limitations of models, and update biological assumptions and model outputs regularly. It is highlighted that to reach these goals, a collaborative framework must be developed for the collation, annotation, and sharing of databases from large-scale anthelmintic control programmes, and that helminth modellers should join efforts to tackle key questions in helminth epidemiology and control through the sharing of such databases, and by using diverse, yet complementary, modelling approaches