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Plasmodium parasites contain various virulence factors that modulate the host immune response. Malarial pigment, or hemozoin (Hz), is an undegradable crystalline product of the hemoglobin degradation pathway in the parasite and possesses immunomodulatory properties. An association has been found between Hz accumulation and severe malaria, suggesting that the effects of Hz on the host immune response may contribute to the development of malarial complications. Although the immunomodulatory roles of Hz have been widely investigated, many conflicting data exist, likely due to the variability between experimental set-ups and technical limitations of Hz generation and isolation methods. Here, we critically assess the potential immunomodulatory effects of Hz, its role in malarial complications, and its potential effects after parasite clearance., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

During malaria, the hypothalamic-pituitary-adrenal (HPA) axis is activated and glucocorticoid (GC) levels are increased, but their essential roles have been largely overlooked. GCs are decisive for systemic regulation of vital processes such as immune responses, vascular function, and metabolism, which are crucial in malaria. Here, we introduce GCs in general, followed by their versatile roles for disease tolerance in malaria. A complementary comparison is provided with their role in sepsis. Finally, potential translational implications are considered. The failed clinical trials of dexamethasone against cerebral malaria in the past have diminished the interest in GCs in malaria. However, the issue of relative corticosteroid insufficiency has barely been explored in malaria patients, but may hold promise for a better understanding and treatment of specific malaria complications., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Astemizole is a H 1 -antagonist endowed with antimalarial activity, but has hERG liabilities. Systematic structural modifications of astemizole led to the discovery of analogues that display very potent activity as inhibitors of the growth of the Plasmodium parasite, but show a decreased hERG inhibition, when compared to astemizole. These compounds can be used as starting point for the development of a new class of antimalarials., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Chemokines, binding their various G protein-coupled receptors, lead the way for leukocytes in health and inflammation. Yet chemokine receptor expression is not limited to leukocytes. Accordingly, chemokines are remarkably pleiotropic molecules involved in a range of physiological as well as pathological processes. For example, the CXCR3 chemokine receptor is expressed on activated T lymphocytes, dendritic cells and natural killer cells, but also fibroblasts and smooth muscle, epithelial and endothelial cells. In men, these cells express either CXCR3A, its splice variant CXCR3B or a balanced combination of both. The CXCR3 ligands, activating both receptor variants, include CXCL4, CXCL4L1, CXCL9, CXCL10 and CXCL11. Upon CXCR3A activation these ELR-negative CXC chemokines mediate chemotactic and proliferative responses, for example in leukocytes. In contrast, CXCR3B induces anti-proliferative and anti-migratory effects, as exemplified by angiostatic effects on endothelial cells. Taken together, the unusual and versatile characteristics of CXCR3 and its ligands form the basis for their pertinent involvement in a myriad of diseases. In this review, we discuss the presence and function of all CXCR3 ligands in various malignant, angiogenic, infectious, inflammatory and other disorders. By extension, we have also elaborated on the potential therapeutic applicability of CXCR3 ligand administration or blockade, as well as their additional value as predictive or prognostic biomarkers. This review illustrates the multifunctional, intriguing character of the various CXCR3-binding chemokines., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

The Malaria Immunology Database (MalarImDB, www.malarimdb.org) is a novel literature-based database of host mediators in blood-stage malaria. We designed this open-access online tool because intensive malaria research has resulted in a dazzling complexity of host mediators with pathogenic or protective functions. MalarImDB allows comparisons between expression levels in humans, expression levels in murine models, and functional data from experimental treatments in mice. The database is equipped with multiple search engines to retrieve information from many published studies. The search output is visualized schematically in tables, thereby revealing similarities and disparities. Thus, the primary aim of this database is to present a clear overview of the currently available data about malaria and to simplify literature searches., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Malaria-associated acute respiratory distress syndrome (MA-ARDS) is an increasingly reported, often lethal, and incompletely understood complication of malaria. We discuss and compare the pathogenesis of MA-ARDS in patients and in different murine models, including recent models without cerebral involvement, and summarize the roles of different leukocyte subclasses, adhesion molecules, cytokines, and chemokines. In patients as well as in mice, severe edema and impaired gas exchange are associated with abundant inflammatory infiltrates consisting of mainly mononuclear cells and parasite sequestration, and the pathogenesis appears different from cerebral malaria (CM). Experimental anti-inflammatory interventions are successful in mice and remain to be validated in patients., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Unlike polyribonucleotides, such as poly(I:C), chlorite-oxidized oxyamylose (COAM) has been poorly characterized as a polyanionic antiviral. COAM possesses a controversial interferon (IFN)-inducing capacity and its mechanism of action has not been elucidated. In this study, COAM was biochemically characterized and fractionated according to molecular mass. In comparison with a strong IFN induction and upregulation of the helicase RIG-I and MDA-5 mRNAs by poly(I:C), COAM did not enhance IFN-alpha or -beta and IFN-inducible RNA helicases in mouse fibroblastoid cells. Instead, COAM inhibited virus entry by blocking the attachment to the cells. These results suggest that COAM can alter the outcome of infection, not by IFN induction and in turn modifying the cellular antiviral state, but through inhibition of virus entry into cells.

Gram-negative sepsis, bacterial meningitis and endotoxin shock are life-threatening disorders, associated with the rapid release of neutrophil enzymes. Neutrophil collagenase/matrix metalloproteinase-8 (MMP-8) and gelatinase B/matrix metalloproteinase-9 (MMP-9) are contained in granules, are quickly exocytosed upon granulocyte activation and efficiently cleave intact and denatured collagens, respectively. Genetic ablation of gelatinase B protects against endotoxin-induced mortality. Therefore, we designed and synthesized a peptidomimetic gelatinase B inhibitor Regasepin1, and compared the selectivity for the collagenases MMP-1, MMP-8 and MMP-13. Regasepin1 was found to inhibit, almost to the same degree, the neutrophil enzymes MMP-8 and MMP-9 and the monocytic tumor necrosis factor-alpha (TNF-alpha) converting enzyme (TACE/ADAM-17) in vitro. With the use of mass spectrometry analysis, the plasma half-life of inhibitor levels was determined after an intraperitoneal bolus injection in mice. Plasma peak levels of the inhibitor were reached at 50 min after intraperitoneal injection and the subsequent half-life in the circulation exceeded 40 min. Regasepin1 protected mice against lethal endotoxinemia by intraperitoneal and intravenous injection routes. This proves the principle that early neutrophil MMP inhibition followed by TACE blockade may become a treatment strategy of gram-negative sepsis, endotoxinemia and other life-threatening inflammatory reactions.

Matrix metalloproteinases form a proteinase family with at least 20 members, which are involved in several pathological conditions and which fulfill a large number of physiological functions. Gelatinase A/MMP-2 is a constitutively produced homeostatic enzyme, whereas gelatinase B/MMP-9 is upregulated in acute and chronic inflammations and forms a target for the development of therapeutic inhibitors. We have used a recently developed assay with fluorescent gelatin to analyze gelatinase inhibitors. A peptidomimetic, based on the consensus sequence of the cleavage sites in type II collagen, and various derivatives of a neutralizing antibody were compared as gelatinase inhibitors. A single-chain variable fragment (scFv) derived from the gelatinase B-selective monoclonal antibody REGA-3G12 was tagged with oligohistidine and was also compared with the untagged scFv. Both scFv derivatives inhibited gelatinase B but the peptidomimetic was inefficient. As an extra control and serendipitously it was found that polyhistidine is an inhibitor of gelatinases, presumably by altering the active site by chelation of the catalytic Zn2+.