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Mol Biochem Parasitol
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Filarial nematodes cause long-term infections in hundreds of millions of people. A significant proportion of those affected develop a number of debilitating health problems but, remarkably, such infections are often unnoticed for many years. It is well known that parasitic worms modulate, yet do not completely inhibit, host immunological pathways, promoting their survival by limiting effective immune mechanisms. Such immunoregulation largely depends on molecules released by the worms, termed excretory-secretory products (ES). One of these products is the molecule ES-62, which is actively secreted by the rodent filarial nematode Acanthocheilonema viteae. ES-62 has been shown to exert anti-inflammatory actions thorough its phosphorylcholine (PC)-containing moiety on a variety of cells of the immune system, affecting intracellular signalling pathways associated with antigen receptor- and TLR-dependent responses. We summarise here how ES-62 modulates key signal transduction elements and how such immunomodulation confers protection to mice subjected to certain experimental models of inflammatory disease. Finally, we discuss recent results showing that it is possible to synthetise small molecule analogues (SMAs) that mimic the anti-inflammatory properties of ES-62, opening an exciting new drug development field in translational medicine.
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Immunology,
2005]
Secretion of immunomodulatory molecules is a key strategy employed by pathogens to enable their survival in host organisms. For example, arthropod-transmitted filarial nematodes, which achieve longevity within the infected host by suppressing and modulating the host immune response, produce excretory-secretory (ES) products that have been demonstrated to possess immunomodulatory properties. In this review we discuss the immunomodulatory effects of the phosphorylcholine-containing filarial nematode-secreted glycoprotein ES-62 and describe the intracellular signal transduction pathways it targets to achieve these effects.
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Curr Protein Pept Sci,
2003]
ES-62 is a major secreted glycoprotein of the rodent filarial nematode Acanthocheilonema viteae and homologue of molecules found in filarial nematodes which parasitise humans. The molecule consists of a tetramer of apparently identical monomers of ~62 kDa which we have shown by sedimentation equilibrium analytical ultracentrifugation to strongly associate. ES-62 is one of several filarial nematode proteins to contain the unusual post-translational modification of phosphorylcholine (PC) addition. Specifically, we have found that PC is attached to one of three distinct N-type glycans we have characterised on the molecule. The amino acid sequence of ES-62 shows 37-39% identity with a family of 6 other proteins, some of which have been predicted to be amino- or carboxy-peptidases. We have also found that ES-62 is able to interact with a number of cells of the immune system, specifically B- and T-lymphocytes, macrophages and dendritic cells. Lymphocytes exposed to ES-62 in vitro or in vivo are less able to proliferate in response to ligation via the antigen receptor. Peritoneal macrophages pre-exposed to the molecule are less able to produce the cytokines IL-12, IL-6 and TNF-alpha following subsequent incubation with the classical stimulators IFNgamma and LPS. Dendritic cells allowed to mature in the presence of ES-62 acquire a phenotype, which allows them to induce anti-inflammatory "TH2-type" responses. With respect to immunomodulation, the PC moiety of the parasite molecule appears to be predominantly responsible for the effects on lymphocyte proliferation at least and we have also found that its removal converts the murine IgG antibody response to ES-62 from solely IgG1 to mixed IgG1/IgG2a. ES-62 appears to interact with cells of the immune system in a PC-dependent manner and, at least in part, via a molecule of ~82 kDa. Studies of the interaction in lymphocytes show that it is associated with activation of certain signal transduction molecules including a number of protein tyrosine kinases and mitogen activated protein kinases (MAPkinases). Although such activation is insufficient to induce proliferation, it serves to almost completely desensitise the cells to antigen-receptor ligation-induced activation of the phosphoinositide 3-kinase (PI-3-kinase) and Ras/MAPkinase pathways, events critical for lymphocyte proliferation. Such desensitisation reflects ES-62-primed recruitment of a number of negative regulators of these pathways, such as the phosphatases SHP-1 and Pac-1.
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Orphanet J Rare Dis,
2020]
BACKGROUND: Pathogenic variations in the gene encoding the skeletal muscle ryanodine receptor (RyR1) are associated with malignant hyperthermia (MH) susceptibility, a life-threatening hypermetabolic condition and RYR1-related myopathies (RYR1-RM), a spectrum of rare neuromuscular disorders. In RYR1-RM, intracellular calcium dysregulation, post-translational modifications, and decreased protein expression lead to a heterogenous clinical presentation including proximal muscle weakness, contractures, scoliosis, respiratory insufficiency, and ophthalmoplegia. Preclinical model systems of RYR1-RM and MH have been developed to better understand underlying pathomechanisms and test potential therapeutics. METHODS: We conducted a comprehensive scoping review of scientific literature pertaining to RYR1-RM and MH preclinical model systems in accordance with the PRISMA Scoping Reviews Checklist and the framework proposed by Arksey and O'Malley. Two major electronic databases (PubMed and EMBASE) were searched without language restriction for articles and abstracts published between January 1, 1990 and July 3, 2019. RESULTS: Our search yielded 5049 publications from which 262 were included in this review. A majority of variants tested in RYR1 preclinical models were localized to established MH/central core disease (MH/CCD) hot spots. A total of 250 unique RYR1 variations were reported in human/rodent/porcine models with 95% being missense substitutions. The most frequently reported RYR1 variant was R614C/R615C (human/porcine total n=39), followed by Y523S/Y524S (rabbit/mouse total n=30), I4898T/I4897T/I4895T (human/rabbit/mouse total n=20), and R163C/R165C (human/mouse total n=18). The dyspedic mouse was utilized by 47% of publications in the rodent category and its RyR1-null (1B5) myotubes were transfected in 23% of publications in the cellular model category. In studies of transfected HEK-293 cells, 57% of RYR1 variations affected the RyR1 channel and activation core domain. A total of 15 RYR1 mutant mouse strains were identified of which ten were heterozygous, three were compound heterozygous, and a further two were knockout. Porcine, avian, zebrafish, C. elegans, canine, equine, and drosophila model systems were also reported. CONCLUSIONS: Over the past 30years, there were 262 publications on MH and RYR1-RM preclinical model systems featuring more than 200 unique RYR1 variations tested in a broad range of species. Findings from these studies have set the foundation for therapeutic development for MH and RYR1-RM.
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Wiley Interdiscip Rev Dev Biol,
2016]
The Wnt/-catenin pathway plays key roles during animal development. In several species, -catenin is used in a reiterative manner to regulate cell fate diversification between daughter cells following division. This binary cell fate specification mechanism has been observed in animals that belong to very diverse phyla: the nematode Caenorhabditis elegans, the annelid Platynereis, and the ascidian Ciona. It may also play a role in the regulation of several stem cell lineages in vertebrates. While the molecular mechanism behind this binary cell fate switch is not fully understood, it appears that both secreted Wnt ligands and asymmetric cortical factors contribute to the generation of the difference in nuclear -catenin levels between daughter cells. -Catenin then cooperates with lineage specific transcription factors to induce the expression of novel sets of transcription factors at each round of divisions, thereby diversifying cell fate. For further resources related to this article, please visit the WIREs website.
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Wiley Interdiscip Rev Dev Biol,
2014]
UNLABELLED: Synapse formation is the quintessential process by which neurons form specific connections with their targets to enable the development of functional circuits. Over the past few decades, intense research efforts have identified thousands of proteins that localize to the pre- and postsynaptic compartments. Genetic dissection has provided important insights into the nexus of the molecular and cellular network, and has greatly advanced our knowledge about how synapses form and function physiologically. Moreover, recent studies have highlighted the complex regulation of synapse formation with the identification of novel mechanisms involving cell interactions from non-neuronal sources. In this review, we cover the conserved pathways required for synaptogenesis and place specific focus on new themes of synapse modulation arising from studies in Caenorhabditis elegans. For further resources related to this article, please visit the WIREs website. CONFLICT OF INTEREST: The authors have declared no conflicts of interest for this article.
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Trends in Genetics,
1999]
Transgenic technology is currently applied to several animal species of agricultural or medical importance, such as fish, cattle, mosquitos and parasitic worms. However, the repertoire of genetic tools used for molecular analyses of mice and Drosophila is not always applicable to other species. For example, while retroviral enhancer-trap experiments in mice can be based on embryonic stem (ES) cell technology, this is not currently an option with other animals. Similarly, the germline transformation of Drosophila depends on the use of the P-element transposon, which does not jump in other genera. This article analyses the main characteristics of Tc1/mariner transposable elements, examines some of the factors that have contributed to their evolutionary success, and describes their potential, as well as their limitations, for transgenesis and insertional mutagenesis in diverse animals.
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Parasit Vectors,
2017]
Macrocyclic lactones (MLs), specifically the avermectins and milbemycins, are known for their effectiveness against a broad spectrum of disease-causing nematodes and arthropods in humans and animals. In most nematodes, drugs in this class induce paralysis, resulting in starvation, impaired ability to remain associated with their anatomical environment, and death of all life stages. Initially, this was also thought to be the ML mode of action against filarial nematodes, but researchers have not been able to validate these characteristic effects of immobilization/starvation of MLs in vitro, even at higher doses than are possible in vivo. Relatively recently, ML receptor sites exclusively located proximate to the excretory-secretory (ES) apparatus were identified in Brugia malayi microfilaria and an ML-induced suppression of secretory protein release by B. malayi microfilariae was demonstrated in vitro. It is hypothesized here that suppression of these ES proteins prevents the filarial worm from interfering with the host's complement cascade, reducing the ability of the parasite to evade the immune system. Live microfilariae and/or larvae, thus exposed, are attacked and presented to the host's innate immune mechanisms and are ultimately killed by the immune response, not the ML drug. These live, exposed filarial worms stimulate development of innate, cellular and humoral immune responses that when properly stimulated, are capable of clearing all larvae or microfilariae present in the host, regardless of their individual sensitivity to MLs. Additional research in this area can be expected to improve our understanding of the relationships among filarial worms, MLs, and the host immune system, which likely would have implications in filarial disease management in humans and animals.
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Wiley Interdiscip Rev Dev Biol,
2017]
Molecular oscillators are well known for their roles in temporal control of some biological processes like cell proliferation, but molecular mechanisms that provide temporal control of differentiation and postdifferentiation events in cells are less understood. In the nervous system, establishment of neuronal connectivity during development and decline in neuronal plasticity during aging are regulated with temporal precision, but the timing mechanisms are largely unknown. Caenorhabditis elegans has been a preferred model for aging research and recently emerges as a new model for the study of developmental and postdevelopmental plasticity in neurons. In this review we discuss the emerging mechanisms in timing of developmental lineage progression, axon growth and pathfinding, synapse formation, and reorganization, and neuronal plasticity in development and aging. We also provide a current view on the conserved core axon regeneration molecules with the intention to point out potential regulatory points of temporal controls. We highlight recent progress in understanding timing mechanisms that regulate decline in regenerative capacity, including progressive changes of intrinsic timers and co-opting the aging pathway molecules. For further resources related to this article, please visit the WIREs website.
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Wiley Interdiscip Rev Dev Biol,
2015]
UNLABELLED: Glia constitute a major, understudied population of cells in the nervous system. Currently, it is appreciated that these cells exhibit vast morphological, functional, and molecular diversity, but our understanding of glial biology is limited. Some key unanswered questions include how glial diversity is generated during development and what functions distinct glial subtypes serve in the mature nervous system. The nematode Caenorhabditis elegans contains a defined set of glia, which have clear morphological and molecular differences, and thus provides a simplified model for understanding glial diversity. In addition, recent experiments suggest that the molecular mechanisms underlying the generation of glial diversity in C. elegans are conserved with those in mammals. In this review, we summarize the surprising diversity of glial subtypes present in this simple organism, and highlight current thinking about what roles they perform in the nervous system. We emphasize how genetic approaches may be used to identify the mechanistic origins of glial diversity, which is key to understanding how glia function in health and disease. For further resources related to this article, please visit the WIREs website. CONFLICT OF INTEREST: The authors have declared no conflicts of interest for this article.