Studies on phospholipid turnover argue against sloughing of tegumental membranes in adult Schistosoma mansoni

Parasitology ◽  
1999 ◽  
Vol 119 (3) ◽  
pp. 287-294 ◽  
Author(s):  
J. F. H. M. BROUWERS ◽  
P. J. SKELLY ◽  
L. M. G. VAN GOLDE ◽  
A. G. M. TIELENS
Keyword(s):  
Fatty Acid ◽  
Immune System ◽  
Schistosoma Mansoni ◽  
Immune Evasion ◽  
Crucial Role ◽  
Host Immune System ◽  
Pulse Labelling ◽  
High Turnover ◽  
Membrane Complex

The tegumental membrane complex of Schistosoma mansoni is the site of interaction between the parasite and the host. The tegument is involved in uptake of many nutrients, but also plays a crucial role in the evasion of the actions of the host immune system. Essential for the success of this evasion is maintaining the integrity of the tegumental membranes. The rate of turnover of phospholipids was investigated by pulse-labelling worms cultured in vitro, followed by additional incubation in the presence of unlabelled substrates. Tegumental membranes were isolated, characterized using antibodies against specific tegumental proteins, and analysed. It was demonstrated that the most prominent fatty acid found in tegumental phospholipids, palmitate, incorporated rapidly into the phospholipid fraction during a 30 min pulse labelling. In a subsequent 20 h chase with unlabelled substrates, the incorporated radioactivity was lost again from the tegumental membrane complex. This high turnover of palmitate was found to be limited to phosphatidylcholine (PC) only. The turnover was due to deacylation/reacylation, and not to the sloughing of membranes as is the case in schistosomula. It is speculated that this rapid turnover of PC in the tegument of adult schistosomes plays a new and important role in the immune evasion by the parasite.

scholarly journals Rescuing the Host Immune System by Targeting the Immune Evasion Complex ORF8-IRF3 in SARS-CoV-2 Infection with Natural Products Using Molecular Modeling Approaches

2021 ◽  
Vol 19 (1) ◽  
pp. 112
Author(s):  
Aqel Albutti
Keyword(s):  
Immune System ◽  
Immune Evasion ◽  
Simulation Analysis ◽  
Dynamic Properties ◽  
Natural Compounds ◽  
Host Immune System ◽  
Structural Dynamic ◽  
Novel Drugs

The perennial emergence of SARS-CoV-2 and its new variants causing upper respiratory complexities since December 2019 has aggravated the pandemic situation around the world. SARS-CoV-2 encodes several proteins among which ORF8 is a novel factor that is unique to SARS-CoV-2 only and is reported to help the virus in disease severity and immune evasion. ORF8-IRF3 complex induces endoplasmic reticulum stress, thus helps in the evasion of immune response. Consequently, targeting the ORF8-IRF3 complex is considered as a prime target for the discovery of novel drugs against SARS-CoV-2. In this regard, computational methods are of great interest to fast track the identification and development of novel drugs. Virtual screening of South African Natural Compounds Database (SANCDB), followed by docking and molecular dynamics (MD) simulation analysis, were performed to determine novel natural compounds. Computational molecular search and rescoring of the SANCDB database followed by induced-fit docking (IFD) protocol identified Quercetin 3-O-(6″-galloyl)-beta-D-galactopyranoside (SANC00850), Tribuloside (SANC01050), and Rutin (SANC00867) are the best scoring compounds. Structural-dynamic properties assessment revealed that these three compounds have stable dynamics, compactness, and a higher number of hydrogen bonds. For validation, we used MM/GBSA, in silico bioactivity estimation and dissociation constant (KD) approaches, which revealed that these compounds are the more potent inhibitors of the ORF8-IRF3 complex and would rescue the host immune system potentially. These compounds need further in vitro and in vivo validations to be used as therapeutics against SARS-CoV-2 to rescue the host immune system during COVID-19 infection.

scholarly journals Schistosomes alter expression of immunomodulatory gene products following in vivo praziquantel exposure

2020 ◽  
Author(s):  
Paul McCusker ◽  
Claudia M. Rohr ◽  
John D. Chan
Keyword(s):  
Immune System ◽  
Immune Evasion ◽  
Host Immune System ◽  
Gene Products ◽  
Response To Chemotherapy ◽  
Kunitz Type ◽  
Insight Into ◽  
Immunomodulatory Gene

AbstractControl of the neglected tropical disease schistosomiasis relies almost entirely on praziquantel (PZQ) monotherapy. How PZQ clears parasite infections remains poorly understood. Many studies have examined the effects of PZQ on worms cultured in vitro, observing outcomes such as muscle contraction. However, conditions worms are exposed to in vivo may vary considerably from in vitro experiments given the short half-life of PZQ and the importance of host immune system engagement for drug efficacy in animal models. Here, we investigated the effects of in vivo PZQ exposure on Schistosoma mansoni. Measurement of pro-apoptotic caspase activation revealed that worm death occurs only after parasites shift from the mesenteric vasculature to the liver, peaking 24 hours after drug treatment. This indicates that PZQ is not directly schistocidal, since the drug’s half-life is ∼2 hours, and focuses attention on parasite interactions with the host immune system following the shift of worms to the liver. RNA-Seq of worms harvested from mouse livers following sub-lethal PZQ treatment revealed drug-evoked changes in the expression of putative immunomodulatory and anticoagulant gene products. Several of these gene products localized to the schistosome esophagus and may be secreted into the host circulation. These include several Kunitz-type protease inhibitors, which are also found in the secretomes of other blood feeding animals. These transcriptional changes may reflect mechanisms of parasite immune-evasion in response to chemotherapy, given the role of complement-mediated attack and the host innate / humoral immune response in parasite elimination. One of these isoforms, SmKI-1, has been shown to exhibit immunomodulatory and anti-coagulant properties. These data provide insight into the effect of in vivo PZQ exposure on S. mansoni, and the transcriptional response of parasites to the stress of chemotherapy.Author SummaryThe disease schistosomiasis is caused by parasitic worms that live within the circulatory system. While this disease infects over 200 million people worldwide, treatment relies almost entirely on one drug, praziquantel, whose mechanism is poorly understood. In this study, we analyzed the effects of praziquantel treatment on the gene expression of parasites harvested from mice treated with praziquantel chemotherapy. Despite the rapid action of the drug on worms in vitro, we found that key outcomes in vivo (measurement of cell death and changes in gene expression) occurred relatively late (12+ hours after drug administration). We found that worms increased the expression of immunomodulatory gene products in response to praziquantel, including a Kunitz-type protease inhibitor that localized to the worm esophagus and may be secreted to the external host environment. These are an intriguing class of proteins, because they display anti-coagulant and immunomodulatory properties. Up-regulation of these gene products may reflect a parasite mechanism of immune-evasion in response to chemotherapy. This research provides insight into the mechanism of praziquantel by observing the effect of this drug on worms within the context of the host immune system.

scholarly journals Schistosoma mansoni alter transcription of immunomodulatory gene products following in vivo praziquantel exposure

2021 ◽  
Vol 15 (3) ◽  
pp. e0009200
Author(s):  
Paul McCusker ◽  
Claudia M. Rohr ◽  
John D. Chan
Keyword(s):  
Immune System ◽  
Schistosoma Mansoni ◽  
Half Life ◽  
Drug Efficacy ◽  
Blood Feeding ◽  
Host Immune System ◽  
Gene Products ◽  
Response To Chemotherapy

Control of the neglected tropical disease schistosomiasis relies almost entirely on praziquantel (PZQ) monotherapy. How PZQ clears parasite infections remains poorly understood. Many studies have examined the effects of PZQ on worms cultured in vitro, observing outcomes such as muscle contraction. However, conditions worms are exposed to in vivo may vary considerably from in vitro experiments given the short half-life of PZQ and the importance of host immune system engagement for drug efficacy in animal models. Here, we investigated the effects of in vivo PZQ exposure on Schistosoma mansoni. Measurement of pro-apoptotic caspase activation revealed that worm death occurs only after parasites shift from the mesenteric vasculature to the liver, peaking 24 hours after drug treatment. This indicates that PZQ is not directly schistocidal, since PZQ’s half-life is ~2 hours in humans and ~30 minutes in mice, and focuses attention on parasite interactions with the host immune system following the shift of worms to the liver. RNA-Seq of worms harvested from mouse livers following sub-lethal PZQ treatment revealed drug-evoked changes in the expression of putative immunomodulatory and anticoagulant gene products. Several of these gene products localized to the schistosome esophagus and may be secreted into the host circulation. These include several Kunitz-type protease inhibitors, which are also found in the secretomes of other blood feeding animals. These transcriptional changes may reflect mechanisms of parasite immune-evasion in response to chemotherapy, given the role of complement-mediated attack and the host innate/humoral immune response in parasite elimination. One of these isoforms, SmKI-1, has been shown to exhibit immunomodulatory and anti-coagulant properties. These data provide insight into the effect of in vivo PZQ exposure on S. mansoni, and the transcriptional response of parasites to the stress of chemotherapy.

scholarly journals Biofilm formation in the lung contributes to virulence and drug tolerance of Mycobacterium tuberculosis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Poushali Chakraborty ◽  
Sapna Bajeli ◽  
Deepak Kaushal ◽  
Bishan Dass Radotra ◽  
Ashwani Kumar
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Immune System ◽  
Biofilm Formation ◽  
Antimycobacterial Activity ◽  
Drug Tolerance ◽  
Host Immune System ◽  
Tissue Sections ◽  
Slow Growing

AbstractTuberculosis is a chronic disease that displays several features commonly associated with biofilm-associated infections: immune system evasion, antibiotic treatment failures, and recurrence of infection. However, although Mycobacterium tuberculosis (Mtb) can form cellulose-containing biofilms in vitro, it remains unclear whether biofilms are formed during infection in vivo. Here, we demonstrate the formation of Mtb biofilms in animal models of infection and in patients, and that biofilm formation can contribute to drug tolerance. First, we show that cellulose is also a structural component of the extracellular matrix of in vitro biofilms of fast and slow-growing nontuberculous mycobacteria. Then, we use cellulose as a biomarker to detect Mtb biofilms in the lungs of experimentally infected mice and non-human primates, as well as in lung tissue sections obtained from patients with tuberculosis. Mtb strains defective in biofilm formation are attenuated for survival in mice, suggesting that biofilms protect bacilli from the host immune system. Furthermore, the administration of nebulized cellulase enhances the antimycobacterial activity of isoniazid and rifampicin in infected mice, supporting a role for biofilms in phenotypic drug tolerance. Our findings thus indicate that Mtb biofilms are relevant to human tuberculosis.

An appraisal of survival strategies

Parasitology ◽  
1984 ◽  
Vol 88 (4) ◽  
pp. 575-577 ◽  
Author(s):  
N. A. Mitchison
Keyword(s):  
Immune System ◽  
Immune Responses ◽  
Survival Strategies ◽  
Host Immune System ◽  
Cellular Immunology ◽  
Host Immune Responses ◽  
Host Defence System ◽  
Bio Engineering

Only a few years ago parasite immunology looked an unattractive subject better left to the dogged specialists. Parasites and hosts had been playing chess together for a million years, and there seemed little prospect of perturbing matters in favour of the host immune system. All that has changed, for three reasons. Firstly, we have learned how to grow at least some parasites in vitro, and prospects of doing so with others are encouraging. Secondly, progress in cellular immunology has revealed the sort of loopholes in the host defence system which parasites are likely to exploit: we are learning the questions which matter about parasites as antigens. Thirdly, and most importantly, molecular genetics is being brought to bear on parasites: we can now see a real, though long-term, prospect of manufacturing practicable vaccines through bio-engineering, and more immediately it gives us the tools needed to probe the host immune responses in the form of cloned antigens.

scholarly journals Studies of the antibody-dependent killing of schistosomula of Schistosoma mansoni employing haptenic target antigens. I. Evidence that the loss in susceptibility to immune damage undergone by developing schistosomula involves a change unrelated to the masking of parasite antigens by host molecules.

1980 ◽  
Vol 152 (1) ◽  
pp. 41-53 ◽  
Author(s):  
G Moser ◽  
D L Wassom ◽  
A Sher
Keyword(s):  
Structural Change ◽  
Schistosoma Mansoni ◽  
Immune Evasion ◽  
Gamma Globulin ◽  
Morphological Examination ◽  
Host Molecules ◽  
Minimal Loss ◽  
Effector Mechanisms

A method was developed for coupling a hapten, trinitrophenyl (TNP), to the surface of schistosomula of Schistosoma mansoni which results in a minimal loss in their viability as judged by morphological examination in vitro and survival after injection in vivo. Skin-stage (3-h-old) and lung-stage (5-d-old) schistosomula surface labeled in this manner were then compared for their susceptibility to killing by anti-TNP antibody-dependent effector mechanisms both in vivo and in vitro. TNP skin-stage larvae were readily rejected in mice actively immunized against TNP bovine gamma globulin and were highly susceptible to anti-TNP-dependent killing mediated either by complement or purified human eosinophils in vitro. In contrast, TNP-lung-stage schistosomula, which were shown by microfluorimetry to bind anti-TNP antibody to approximately the same extent as skin-stage schistosomula, were found to be resistant to killing by the same in vivo and in vitro mechanisms. These findings suggest that the insusceptibility of postskin-stage schistosomula to antibody-dependent killing must result at least in part from an intrinsic structural change in the integument of the parasite and cannot be caused solely by the masking of parasite antigens by acquired host molecules, a mechanism of immune evasion previously proposed for schistosomes.

scholarly journals Antitumor and immunomodulatory activity of Inonotus obliquus

2017 ◽  
Vol 63 (2) ◽  
pp. 48-58 ◽  
Author(s):  
Justyna Staniszewska ◽  
Marcin Szymański ◽  
Ewa Ignatowicz
Keyword(s):  
Immune System ◽  
Tumor Cells ◽  
Good Alternative ◽  
Immunomodulatory Activity ◽  
Host Immune System ◽  
Protein Synthesis Inhibition ◽  
Inonotus Obliquus ◽  
Different Types

SummaryThe article presents the antitumor and immunomodulatory activity of compounds and extracts fromInonotus obliquus.Polysaccharides isolated from sclerotium have a direct antitumor effect due to protein synthesis inhibition in tumor cells. Polysaccharides derived from the mycelium function by activating the immune system. Due to the limited toxicity of these substances, both extracts as well as isolated and purified chemicals may be a good alternative to current chemotherapy and play a role in cancer prevention.In vitroexperiments have shown the inhibition of inflammation with the influence of action ofI. obliquusextracts; however,in vivoexperiments on animals implanted with tumor cells of different types have shown the activation of the host immune system. This led to decrease in tumor mass and prolonged survival. The immunomodulatory mechanism of action is complex and it seems that stimulation of macrophages and induction of apoptosis in cancer cells is of great importance.

scholarly journals Post-conversion sialylation of prions in lymphoid tissues

2015 ◽  
Vol 112 (48) ◽  
pp. E6654-E6662 ◽  
Author(s):  
Saurabh Srivastava ◽  
Natallia Makarava ◽  
Elizaveta Katorcha ◽  
Regina Savtchenko ◽  
Reinhard Brossmer ◽  
...  
Keyword(s):  
Immune System ◽  
Sialic Acid ◽  
Mammalian Cells ◽  
Sialic Acids ◽  
Raw 264.7 Cells ◽  
Lymphoid Tissues ◽  
Host Immune System ◽  
Molecular Pattern ◽  
Secondary Lymphoid Organs

Sialylated glycans on the surface of mammalian cells act as part of a “self-associated molecular pattern,” helping the immune system to recognize “self” from “altered self” or “nonself.” To escape the host immune system, some bacterial pathogens have evolved biosynthetic pathways for host-like sialic acids, whereas others recruited host sialic acids for decorating their surfaces. Prions lack nucleic acids and are not conventional pathogens. Nevertheless, prions might use a similar strategy for invading and colonizing the lymphoreticular system. Here we show that the sialylation status of the infectious, disease-associated state of the prion protein (PrPSc) changes with colonization of secondary lymphoid organs (SLOs). As a result, spleen-derived PrPSc is more sialylated than brain-derived PrPSc. Enhanced sialylation of PrPSc is recapitulated in vitro by incubating brain-derived PrPSc with primary splenocytes or cultured macrophage RAW 264.7 cells. General inhibitors of sialyltranserases (STs), the enzymes that transfer sialic acid residues onto terminal positions of glycans, suppressed extrasialylation of PrPSc. A fluorescently labeled precursor of sialic acid revealed ST activity associated with RAW macrophages. This study illustrates that, upon colonization of SLOs, the sialylation status of prions changes by host STs. We propose that this mechanism is responsible for camouflaging prions in SLOs and has broad implications.

scholarly journals Sneaking Out for Happy Hour: Yeast-Based Approaches to Explore and Modulate Immune Response and Immune Evasion

Genes ◽  
2019 ◽  
Vol 10 (9) ◽  
pp. 667 ◽  
Author(s):  
Gaëlle Angrand ◽  
Alicia Quillévéré ◽  
Nadège Loaëc ◽  
Chrysoula Daskalogianni ◽  
Anton Granzhan ◽  
...  
Keyword(s):  
Cell Wall ◽  
Immune System ◽  
Immune Evasion ◽  
Budding Yeast ◽  
Pathogenic Fungi ◽  
Surface Proteins ◽  
Host Immune System ◽  
Antigenic Peptides ◽  
Yeast Saccharomyces Cerevisiae ◽  
Barr Virus

Many pathogens (virus, bacteria, fungi, or parasites) have developed a wide variety of mechanisms to evade their host immune system. The budding yeast Saccharomyces cerevisiae has successfully been used to decipher some of these immune evasion strategies. This includes the cis-acting mechanism that limits the expression of the oncogenic Epstein–Barr virus (EBV)-encoded EBNA1 and thus of antigenic peptides derived from this essential but highly antigenic viral protein. Studies based on budding yeast have also revealed the molecular bases of epigenetic switching or recombination underlying the silencing of all except one members of extended families of genes that encode closely related and highly antigenic surface proteins. This mechanism is exploited by several parasites (that include pathogens such as Plasmodium, Trypanosoma, Candida, or Pneumocystis) to alternate their surface antigens, thereby evading the immune system. Yeast can itself be a pathogen, and pathogenic fungi such as Candida albicans, which is phylogenetically very close to S. cerevisiae, have developed stealthiness strategies that include changes in their cell wall composition, or epitope-masking, to control production or exposure of highly antigenic but essential polysaccharides in their cell wall. Finally, due to the high antigenicity of its cell wall, yeast has been opportunistically exploited to create adjuvants and vectors for vaccination.

scholarly journals Viral Modulation of TLRs and Cytokines and the Related Immunotherapies for HPV-Associated Cancers

2018 ◽  
Vol 2018 ◽  
pp. 1-17 ◽  
Author(s):  
Marconi Rego Barros ◽  
Talita Helena Araújo de Oliveira ◽  
Cristiane Moutinho Lagos de Melo ◽  
Aldo Venuti ◽  
Antonio Carlos de Freitas
Keyword(s):  
Immune Response ◽  
Human Papillomavirus ◽  
Immune System ◽  
Immune Evasion ◽  
Innate Immune System ◽  
Innate Immune ◽  
Cell Maturation ◽  
Host Immune System ◽  
Key Factor ◽  
Infected Cells

The modulation of the host innate immune system is a well-established carcinogenesis feature of several tumors, including human papillomavirus- (HPV-) related cancers. This virus is able to interrupt the initial events of the immune response, including the expression of Toll-like receptors (TLRs), cytokines, and inflammation. Both TLRs and cytokines play a central role in HPV recognition, cell maturation and differentiation as well as immune signalling. Therefore, the imbalance of this sensitive control of the immune response is a key factor for developing immunotherapies, which strengthen the host immune system to accomplish an efficient defence against HPV and HPV-infected cells. Based on this, the review is aimed at exposing the HPV immune evasion mechanisms involving TLRs and cytokines and at discussing existing and potential immunotherapeutic TLR- and cytokine-related tools.

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