Sialic acid is a critical fetal defense against maternal complement attack.
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ABSTRACT:
SUBMITTER: Abeln M
PROVIDER: S-EPMC6307973 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:It is essential for early human life that mucosal immunological responses to developing embryos are tightly regulated. An imbalance of the complement system is a common feature of pregnancy complications. We hereby present the first full analysis of the expression and deposition of complement molecules in human pre-implantation embryos. Thus, far, immunological imbalance has been considered in stages of pregnancy following implantation. We here show that complement activation against developing human embryos takes place already at the pre-implantation stage. Using confocal microscopy, we observed deposition of activation products on healthy developing embryos, which highlights the need for strict complement regulation. We show that embryos express complement membrane inhibitors and bind soluble regulators. These findings show that mucosal complement targets human embryos, and indicate potential adverse pregnancy outcomes, if regulation of activation fails. In addition, single-cell RNA sequencing revealed cellular expression of complement activators. This shows that the embryonic cells themselves have the capacity to express and activate C3 and C5. The specific local embryonic expression of complement components, regulators, and deposition of activation products on the surface of embryos suggests that complement has immunoregulatory functions and furthermore may impact cellular homeostasis and differentiation at the earliest stages of life.
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Project description:The complement system is a part of the innate immune system in the fluid phase and efficiently eliminates pathogens. However, its activation requires tight regulation on the host cell surface in order not to compromise cellular viability. Previously, we showed that loss of placental cell surface sialylation in mice in vivo leads to a maternal complement attack at the fetal-maternal interface, ultimately resulting in loss of pregnancy. To gain insight into the regulatory function of sialylation in complement activation, we here generated trophoblast stem cells (TSC) devoid of sialylation, which also revealed complement sensitivity and cell death in vitro. Glycolipid-analysis by multiplexed capillary gel electrophoresis coupled to laser-induced fluorescence detection (xCGE-LIF) allowed us to identify the monosialoganglioside GM1a as a key element of cell surface complement regulation. Exogenously administered GM1a integrated into the plasma membrane of trophoblasts, substantially increased binding of complement factor H (FH) and was sufficient to protect the cells from complement attack and cell death. GM1a treatment also rescued human endothelial cells and erythrocytes from complement attack in a concentration dependent manner. Furthermore, GM1a significantly reduced complement mediated hemolysis of erythrocytes from a patient with Paroxysmal nocturnal hemoglobinuria (PNH). This study demonstrates the complement regulatory potential of exogenously administered gangliosides and paves the way for sialoglycotherapeutics as a novel substance class for membrane-targeted complement regulators.
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Project description:Parasitoid wasps are a fierce predator of Drosophila larvae. Female Leptopilina boulardi (LB) wasps use a sharp ovipositor to inject eggs into the bodies of Drosophila melanogaster larvae. The wasp then eats the Drosophila larva alive from the inside, and an adult wasp ecloses from the Drosophila pupal case instead of a fly. However, the Drosophila larvae are not defenseless as they may resist the attack of the wasps through somatosensory-triggered behavioral responses. Here we describe the full range of behaviors performed by the larval prey in immediate response to attacks by the wasps. Our results suggest that Drosophila larvae primarily sense the wasps using their mechanosensory systems. The range of behavioral responses included both "gentle touch" like responses as well as nociceptive responses. We found that the precise larval response depended on both the somatotopic location of the attack, and whether or not the larval cuticle was successfully penetrated during the course of the attack. Interestingly, nociceptive responses are more likely to be triggered by attacks in which the cuticle had been successfully penetrated by the wasp. Finally, we found that the class IV neurons, which are necessary for mechanical nociception, were also necessary for a nociceptive response to wasp attacks. Thus, the class IV neurons allow for a nociceptive behavioral response to a naturally occurring predator of Drosophila.
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Project description:Complement is a central effector system within the immune system and is implicated in a range of inflammatory disorders. CD59 is a key regulator of complement membrane attack complex (MAC) assembly. The atherogenic role of terminal complement has long been suspected but is still unclear. Here, we demonstrate that among mice deficient in apolipoprotein (Apo)E, the additional loss of murine CD59 (mCd59ab(-/-)/ApoE(-/-)) accelerated advanced atherosclerosis featuring occlusive coronary atherosclerosis, vulnerable plaque, and premature death and that these effect could be attenuated by overexpression of human CD59 in the endothelium. Complement inhibition using a neutralizing anti-mouse C5 antibody attenuated atherosclerosis in mCd59ab(-/-)/ApoE(-/-) mice. Furthermore, MAC mediated endothelial damage and promoted foam cell formation. These combined results highlight the atherogenic role of MAC and the atheroprotective role of CD59 and suggest that inhibition of MAC formation may provide a therapeutic approach for the treatment of atherosclerosis.
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Project description:Although nontypeable Haemophilus influenzae (NTHi) is a human-specific nasopharyngeal commensal bacterium, it also causes upper respiratory tract infections in children and lower respiratory tract infections in the elderly, resulting in frequent antibiotic use. The transition from symbiotic colonizing bacterium to opportunistic pathogen is not completely understood. Incorporation of sialic acids into lipooligosaccharides is thought to play an important role in bacterial virulence. It has been known for more than 25?years that sialic acids increase resistance to complement-mediated killing; however, the mechanism of action has not been elucidated thus far. Here, we provide evidence that growth of NTHi in the presence of sialic acids Neu5Ac and Neu5Gc decreases complement-mediated killing through abrogating the classical pathway of complement activation by preventing mainly IgM antibody binding to the bacterial surface. Therefore, strategies that interfere with uptake or incorporation of sialic acids into the lipooligosaccharide, such as novel antibiotics and vaccines, might be worth exploring to prevent or treat NTHi infections.
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Project description:Pathogenic microbes can devastate populations of marine plants and animals. Yet, many sessile organisms such as seaweeds and sponges suffer remarkably low levels of microbial infection, despite lacking cell-based immune systems. Antimicrobial defenses of marine organisms are largely uncharacterized, although from a small number of studies it appears that chemical defenses may improve host resistance. In this study, we asked whether the common seaweed Lobophora variegata is chemically defended against potentially deleterious microorganisms. Using bioassay-guided fractionation, we isolated and characterized a 22-membered cyclic lactone, lobophorolide (1), of presumed polyketide origin, with sub-microM activity against pathogenic and saprophytic marine fungi. Deterrent concentrations of 1 were found in 46 of 51 samples collected from 10 locations in the Bahamas over a 4-year period. Lobophorolide (1) is structurally unprecedented, yet parts of the molecule are related to tolytoxin, the scytophycins, and the swinholides, macrolides previously isolated from terrestrial cyanobacteria and from marine sponges and gastropods. Until now, compounds of this structural class have not been associated with marine macrophytes. Our findings suggest that seaweeds use targeted antimicrobial chemical defense strategies and that secondary metabolites important in the ecological interactions between marine macroorganisms and microorganisms could be a promising source of novel bioactive compounds.
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Project description:A diverse set of prophage-mediated mechanisms protecting bacterial hosts from infection has been recently uncovered within cluster N mycobacteriophages isolated on the host, Mycobacterium smegmatis mc2155. In that context, we unveil a novel defense mechanism in cluster N prophage Butters. By using bioinformatics analyses, phage plating efficiency experiments, microscopy, and immunoprecipitation assays, we show that Butters genes located in the central region of the genome play a key role in the defense against heterotypic viral attack. Our study suggests that a two-component system, articulated by interactions between protein products of genes 30 and 31, confers defense against heterotypic phage infection by PurpleHaze (cluster A/subcluster A3) or Alma (cluster A/subcluster A9) but is insufficient to confer defense against attack by the heterotypic phage Island3 (cluster I/subcluster I1). Therefore, based on heterotypic phage plating efficiencies on the Butters lysogen, additional prophage genes required for defense are implicated and further show specificity of prophage-encoded defense systems.IMPORTANCE Many sequenced bacterial genomes, including those of pathogenic bacteria, contain prophages. Some prophages encode defense systems that protect their bacterial host against heterotypic viral attack. Understanding the mechanisms undergirding these defense systems is crucial to appreciate the scope of bacterial immunity against viral infections and will be critical for better implementation of phage therapy that would require evasion of these defenses. Furthermore, such knowledge of prophage-encoded defense mechanisms may be useful for developing novel genetic tools for engineering phage-resistant bacteria of industrial importance.
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Project description:Strategies to limit complement deposition on Streptococcus pneumoniae are established as virulence features for invasive disease, but their role in respiratory tract infection requires further analysis. We evaluated complement C3 protein deposition on discordant S. pneumoniae isolates of the same serotype (6A) and their capacity to cause nasopharyngeal (NP) colonization and experimental otitis media (EOM) in an animal model. We compared C3 binding to five 6A isolates from asymptomatic NP carriers with five 6A strains that caused invasive disease, and we observed less C3 ( approximately 10-fold less fluorescence) binding to invasive isolates. We selected two high-level C3-binding carriage and two low-level C3-binding invasive 6A isolates for further study. In the EOM model, 11/12 (92%) ears challenged with a low-level C3-binding 6A strain became infected. Only 2/8 (25%) ears challenged with the discordant high-level C3-binding 6A isolate developed disease (P = 0.005). Results with the second discordant 6A isolate pair were comparable. Cobra venom factor (CoVF) treatment, which depletes C3 and consumes complement, restored virulence of the high-level C3-binding strain; 8/8 (100%) ears in CoVF-treated animals developed EOM compared to only 25% of ears in naïve animals (P = 0.007). These studies demonstrate the critical role for complement evasion in pneumococcal EOM. Colonization with carriage isolates that bound high levels of C3 caused EOM in fewer animals compared to low-level C3-binding invasive strains. Thus, limiting C3 deposition on the surface of S. pneumoniae correlates with increased incidence of EOM following NP colonization and barotrauma in the animal model.
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Project description:Plasmodium falciparum is a highly lethal malaria parasite of humans. A major portion of its life cycle is dedicated to invading and multiplying inside erythrocytes. The molecular mechanisms of erythrocyte invasion are incompletely understood. P. falciparum depends heavily on sialic acid present on glycophorins to invade erythrocytes. However, a significant proportion of laboratory and field isolates are also able to invade erythrocytes in a sialic acid-independent manner. The identity of the erythrocyte sialic acid-independent receptor has been a mystery for decades. We report here that the complement receptor 1 (CR1) is a sialic acid-independent receptor for the invasion of erythrocytes by P. falciparum. We show that soluble CR1 (sCR1) as well as polyclonal and monoclonal antibodies against CR1 inhibit sialic acid-independent invasion in a variety of laboratory strains and wild isolates, and that merozoites interact directly with CR1 on the erythrocyte surface and with sCR1-coated microspheres. Also, the invasion of neuraminidase-treated erythrocytes correlates with the level of CR1 expression. Finally, both sialic acid-independent and dependent strains invade CR1 transgenic mouse erythrocytes preferentially over wild-type erythrocytes but invasion by the latter is more sensitive to neuraminidase. These results suggest that both sialic acid-dependent and independent strains interact with CR1 in the normal red cell during the invasion process. However, only sialic acid-independent strains can do so without the presence of glycophorin sialic acid. Our results close a longstanding and important gap in the understanding of the mechanism of erythrocyte invasion by P. falciparum that will eventually make possible the development of an effective blood stage vaccine.
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Project description:Preeclampsia (PE) is a pregnancy specific hypertensive disorder. If untreated PE leads to life threatening condition, eclampsia. Systemic complement activation levels are increased during pregnancy compared to non-pregnant women of childbearing age. In PE, systemic complement levels are further increased, and higher complement deposition has been observed on placentas. We hypothesize that combinations of common SNPs in maternal and fetal complement genes constitute pregnancy specific complotypes and predispose women to PE. In this study, we sequenced two maternal (factor H and C3) and one fetal (CD46) complement genes and identified a total of 9 common SNPs. Minor allele frequencies of two fetal CD46 SNPs were significantly higher in PE. Further, complotypes consisting of fetal CD46 variants and maternal CFH/C3 variants were highly prevalent in PE patients compared to normotensive pregnancies. Placental complement deposition and maternal alternative pathway 50 (AP50) values were higher in PE pregnancies. Irrespective of disease status, two CD46 variants were associated with reduced placental CD46 expression and one CFH variant was associated with increased maternal AP50 values.
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