Complement Proteins as Soluble Pattern Recognition Receptors for Pathogenic Viruses

The complement system represents a crucial part of innate immunity. It contains a diverse range of soluble activators, membrane-bound receptors, and regulators. Its principal function is to eliminate pathogens via activation of three distinct pathways: classical, alternative, and lectin. In the case of viruses, the complement activation results in effector functions such as virion opsonisation by complement components, phagocytosis induction, virolysis by the membrane attack complex, and promotion of immune responses through anaphylatoxins and chemotactic factors. Recent studies have shown that the addition of individual complement components can neutralise viruses without requiring the activation of the complement cascade. While the complement-mediated effector functions can neutralise a diverse range of viruses, numerous viruses have evolved mechanisms to subvert complement recognition/activation by encoding several proteins that inhibit the complement system, contributing to viral survival and pathogenesis. This review focuses on these complement-dependent and -independent interactions of complement components (especially C1q, C4b-binding protein, properdin, factor H, Mannose-binding lectin, and Ficolins) with several viruses and their consequences.

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Systems Biology Modeling of the Complement System Under Immune Susceptible Pathogens

Frontiers in Physics ◽

10.3389/fphy.2021.603704 ◽

2021 ◽

Vol 9 ◽

Author(s):

Nehemiah T. Zewde ◽

Rohaine V. Hsu ◽

Dimitrios Morikis ◽

Giulia Palermo

Keyword(s):

Complement System ◽

Membrane Attack Complex ◽

Factor H ◽

Immunoglobulin M ◽

The Body ◽

Complement Components ◽

Invasive Pathogens ◽

Time Profiles ◽

Related Proteins ◽

The Complement System

The complement system is assembled from a network of proteins that function to bring about the first line of defense of the body against invading pathogens. However, complement deficiencies or invasive pathogens can hijack complement to subsequently increase susceptibility of the body to infections. Moreover, invasive pathogens are increasingly becoming resistant to the currently available therapies. Hence, it is important to gain insights into the highly dynamic interaction between complement and invading microbes in the frontlines of immunity. Here, we developed a mathematical model of the complement system composed of 670 ordinary differential equations with 328 kinetic parameters, which describes all three complement pathways (alternative, classical, and lectin) and includes description of mannose-binding lectin, collectins, ficolins, factor H-related proteins, immunoglobulin M, and pentraxins. Additionally, we incorporate two pathogens: (type 1) complement susceptible pathogen and (type 2) Neisseria meningitidis located in either nasopharynx or bloodstream. In both cases, we generate time profiles of the pathogen surface occupied by complement components and the membrane attack complex (MAC). Our model shows both pathogen types in bloodstream are saturated by complement proteins, whereas MACs occupy <<1.0% of the pathogen surface. Conversely, the MAC production in nasopharynx occupies about 1.5–10% of the total N. meningitidis surface, thus making nasal MAC levels at least about eight orders of magnitude higher. Altogether, we predict complement-imbalance, favoring overactivation, is associated with nasopharynx homeostasis. Conversely, orientating toward complement-balance may cause disruption to the nasopharynx homeostasis. Thus, for sporadic meningococcal disease, our model predicts rising nasal levels of complement regulators as early infection biomarkers.

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Solution structures of complement components by X-ray and neutron scattering and analytical ultracentrifugation

Biochemical Society Transactions ◽

10.1042/bst0300996 ◽

2002 ◽

Vol 30 (6) ◽

pp. 996-1001 ◽

Cited By ~ 34

Author(s):

S. J. Perkins ◽

H. E. Gilbert ◽

M. Aslam ◽

J. Hannan ◽

V. M. Holers ◽

...

Keyword(s):

Neutron Scattering ◽

Complement System ◽

Analytical Ultracentrifugation ◽

Factor H ◽

Protein Domain ◽

Complement Receptor ◽

Complement Components ◽

X Ray ◽

Solution Studies ◽

The Complement System

The short consensus/complement repeat (SCR) domain (also known as the complement control protein domain) is the most abundant domain type in the complement system. Crystal and NMR structures for proteins that contain single and multiple SCR domains have now been published. These contain inter-SCR linkers of between three and eight residues, and the structures show much variability in inter-SCR orientations. X-ray and neutron scattering, combined with analytical ultracentrifugation and constrained modelling based on known subunit structures will yield a medium-resolution structure for the protein of interest. The fewer parameters that are associated with the structure of interest, the more defined the structure of interest becomes. These solution studies have been applied to several SCR-containing proteins in the complement system, most notably Factor H with 20 SCR domains, a complement receptor type 2 fragment with two SCR domains, and rat complement receptor-related protein (Crry) which contains five SCR domains. The results show great conformational variability in the inter-SCR orientation, and these will be reviewed. Even though the rotational orientation cannot be modelled, it is nonetheless possible to measure the degree of extension of the multi-SCR proteins and, from this, to obtain functionally useful results.

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INTERACTIONS OF THE COMPLEMENT SYSTEM WITH ENDOTOXIC LIPOPOLYSACCHARIDE

Journal of Experimental Medicine ◽

10.1084/jem.128.2.259 ◽

1968 ◽

Vol 128 (2) ◽

pp. 259-275 ◽

Cited By ~ 120

Author(s):

R. Snyderman ◽

H. Gewurz ◽

S. E. Mergenhagen

Keyword(s):

Molecular Weight ◽

Complement System ◽

Sucrose Density Gradient ◽

Chemotactic Factor ◽

Low Molecular Weight ◽

Complement Components ◽

Heat Stable ◽

Chemotactic Factors ◽

System Activation ◽

The Complement System

Endotoxic lipopolysaccharide has recently been shown to fix large amounts of the complement components related to the biologic activities mediated by that system. The present study sought to determine whether the generation of chemotactic factor by endotoxin in serum was dependent upon complement system activation. Preheating serum, incubating at 0°C, or incubating in the presence of EDTA, all prevented chemotactic factor generation as well as complement fixation by endotoxin. "Endotoxoids" deficient in complement-firing activity were also deficient in chemotactic factor generation. Chemotactic factor could not be generated by endotoxin in sera of mice congenitally deficient in the C'S component of complement, while chemotactic factor was generated by endotoxin in the sera of coisogenic mice with normal complement levels for that species. The chemotactic factor induced by endotoxin was heat stable and nondialyzable. Molecular sieve chromatography and sucrose density gradient ultracentrifugation demonstrated that the chemotactic factor was a relatively low molecular weight product (15,000–30,000) and as such different from previously scribed C' system-derived chemotactic factors. These experiments demonstrate that generation of chemotactic factor by endotoxin in serum is dependent upon C' system activation involving at least C'5. Furthermore, the relatively low molecular weight of this factor suggests that it might be derived from activation of a single complement component rather than from complexing of multiple complement components.

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Preliminary genomic survey and sequence analysis of the complement system in non-eutherian mammals

Australian Mammalogy ◽

10.1071/am15036 ◽

2016 ◽

Vol 38 (1) ◽

pp. 80 ◽

Cited By ~ 4

Author(s):

Oselyne T. W. Ong ◽

Lauren J. Young ◽

Julie M. Old

Keyword(s):

Complement System ◽

Membrane Attack Complex ◽

Tammar Wallaby ◽

Monodelphis Domestica ◽

Tasmanian Devil ◽

Complement Components ◽

Phascolarctos Cinereus ◽

Ornithorhynchus Anatinus ◽

Platypus Genome ◽

The Complement System

The complement system is a major mediator of the vertebrate immune system, which functions in both innate and specific immune responses. It comprises more than 30 proteins working to remove foreign cells by way of anaphylatoxins, opsonins or the membrane attack complex. Over the last few years, whole genome sequences of non-eutherian mammals (marsupials and a monotreme), the gray short-tailed opossum (Monodelphis domestica), tammar wallaby (Macropus eugenii), Tasmanian devil (Sarcophilus harrisii), koala (Phascolarctos cinereus) and platypus (Ornithorhynchus anatinus), have become publicly available. Using these sequences, we have identified an array of complement components in non-eutherians using online search tools and algorithms. Of 57 complement and complement-related genes investigated, we identified 46 in the gray short-tailed opossum genome, 27 in the tammar wallaby genome, 44 in the Tasmanian devil genome, 47 in the koala genome and 40 in the platypus genome. The results of this study confirm the presence of key complement components in the immune repertoire of non-eutherian mammals and provide a platform for future studies on immune protection in young marsupials.

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Complement Components, C3 and C4, and the Metabolic Syndrome

Current Diabetes Reviews ◽

10.2174/1573399814666180417122030 ◽

2018 ◽

Vol 15 (1) ◽

pp. 44-48 ◽

Cited By ~ 14

Author(s):

Melanie Copenhaver ◽

Chack-Yung Yu ◽

Robert P. Hoffman

Keyword(s):

Metabolic Syndrome ◽

Significant Role ◽

Complement System ◽

Gene Copy ◽

Future Research ◽

Obese Adults ◽

Complement Components ◽

Cardiometabolic Diseases ◽

The Metabolic Syndrome ◽

The Complement System

Introduction: Increased systemic inflammation plays a significant role in the development of adult cardiometabolic diseases such as insulin resistance, dyslipidemia, atherosclerosis, and hypertension. The complement system is a part of the innate immune system and plays a key role in the regulation of inflammation. Of particular importance is the activation of complement components C3 and C4. C3 is produced primarily by the liver but is also produced in adipocytes, macrophages and endothelial cells, all of which are present in adipose tissues. Dietary fat and chylomicrons stimulate C3 production. Adipocytes in addition to producing C3 also have receptors for activated C3 and other complement components and thus also respond to as well as produce a target for complement. C3adesArg, also known as acylation stimulation factor, increases adipocyte triglyceride synthesis and release. These physiological effects play a significant role in the development of metabolic syndrome. Epidemiologically, obese adults and non-obese adults with cardiometabolic disease who are not obese have been shown to have increased complement levels. C4 levels also correlate with body mass index. Genetically, specific C3 polymorphisms have been shown to predict future cardiovascular events and. D decreased C4 long gene copy number is associated with increased longevity. Conclusion: Future research is clearly needed to clarify the role of complement in the development of cardiovascular disease and mechanisms for its action. The complement system may provide a new area for intervention in the prevention of cardiometabolic diseases.

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Simple Method To Distinguish between Primary and Secondary C3 Deficiencies

Clinical and Diagnostic Laboratory Immunology ◽

10.1128/cdli.10.2.216-220.2003 ◽

2003 ◽

Vol 10 (2) ◽

pp. 216-220

Author(s):

Marlene Pereira de Carvalho Florido ◽

Patrícia Ferreira de Paula ◽

Lourdes Isaac

Keyword(s):

Human Serum ◽

Complement System ◽

Factor H ◽

Normal Human Serum ◽

Alternative Complement Pathway ◽

Complement Pathway ◽

Factor B ◽

Alternative Complement ◽

Normal Human ◽

The Complement System

ABSTRACT Due to the increasing numbers of reported clinical cases of complement deficiency in medical centers, clinicians are now more aware of the role of the complement system in the protection against infections caused by microorganisms. Therefore, clinical laboratories are now prepared to perform a number of diagnostic tests of the complement system other than the standard 50% hemolytic component assay. Deficiencies of alternative complement pathway proteins are related to severe and recurrent infections; and the application of easy, reliable, and low-cost methods for their detection and distinction are always welcome, notably in developing countries. When activation of the alternative complement pathway is evaluated in hemolytic agarose plates, some but not all human sera cross-react to form a late linear lysis. Since the formation of this linear lysis is dependent on C3 and factor B, it is possible to use late linear lysis to routinely screen for the presence of deficiencies of alternative human complement pathway proteins such as factor B. Furthermore, since linear lysis is observed between normal human serum and primary C3-deficient serum but not between normal human serum and secondary C3-deficient serum caused by the lack of factor H or factor I, this assay may also be used to discriminate between primary and secondary C3 deficiencies.

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MOLECULAR GENETIC CHARACTERISTICS OF COMPONENTS OF THE COMPLEMENT SYSTEM IN SEVERE ACNE

PEDIATRIA Journal named after G N SPERANSKY ◽

10.24110/0031-403x-2021-100-2-40-48 ◽

2021 ◽

Vol 100 (2) ◽

pp. 40-48

Author(s):

A.G. Rumyantsev ◽

◽

A.G. Rumyantsev ◽

O.M. Demina ◽

◽

...

Keyword(s):

Nucleotide Sequence ◽

Complement System ◽

Molecular Genetic ◽

Factor H ◽

Host Cells ◽

Pathophysiological Mechanism ◽

Genetic Characteristics ◽

Severe Acne ◽

C3 Gene ◽

The Complement System

It has been shown that the inflammatory response in acne develops at the early subclinical stages of the disease, sometimes before the formation of comedones. It is known that an important component of the innate immune system is the complement system, which includes more than 60 components, including 9 basic proteins (C1-C9), a variety of activation products (C3a, C3b, iC3b, C3d and C3dg), regulatory and inhibitory molecules [factor H, fH-like protein 1 (FHL1), CR1 (CD35), C4b-binding protein (C4BP), C1inh and vitronectin], proteases and secreted enzymes (factor B, factor D, C3bBb and C4bC2b), as well as receptors for effector molecules [C3aR, C5aR, C5L2 and C1q receptor (C1qR)]. The compliment is the central part of innate immunity, which is the first line of protection against alien and altered host cells. The objectives of this study were to determine and analyze the variants of the nucleotide sequence of the genes of the complement system C1QA, C1S, C2, C3, C5, C6, C7, C8A, C8B, C8G, C9 in patients with severe acne. Materials and methods of research: To achieve the target a prospective open non-randomized one-center study was carried out in 2017–2020. Under our supervision in the clinical setting at the Department of Skin Diseases and Cosmetology of the Pirogov Russian National Research Medical University, there were 50 patients in the main group and 20 participants in the comparison group (70 people in total) (42/60% men and 28/40% women) aged 15 to 46 years (median – 22,1 years). Molecular genetic diagnostics was performed in all 70 patients of the main and control groups by the method of high-throughput DNA sequencing – next-generation sequencing (NGS). Results: when analyzing the nucleotide sequence variants of the complement system genes identified in our study, it is shown that the severe form of acne probably has an association (4 SNPs of the C8A gene, 1 SNPs of the C8B gene, 2 SNPs of the C1S gene, 3 SNPs of the C3 gene, 2 SNPs of the C9 gene, 1 SNPs of the C7 gene, 1 SNPs of the C6 gene, 1 SNPs of the C2 gene, 2 SNPs of the C5 gene, 2 SNPs of the C8G gene), 13 SNPs of the complement system genes in introns (1 SNPs of the C8A gene, 1 SNPs of the C8B gene, 2 SNPs of the C1S gene, 1 SNPs of the C3 gene, 1 SNPs of the C7 gene, 2 SNPs of the C6 gene, 4 SNPs of the C5 gene, 1 SNPs of C8G gene), 6 SNPs of the complement system genes (2 SNPs of the C8B gene: one SNPs each in the 3'UTR and 5'UTR zones; 3 SNPs of the C3 gene in the 5'UTR zone, 1 SNPs of the C7 gene in the 3'UTR zone). Two mutations of the frame shift of the C2 gene (frameshift deletion) and the C9 gene (rs748464075, frameshift insertion) seem to have a protective effect in the development of acne. Conclusion: the obtained variants of the nucleotide sequence of the genes of the complement system C1QA, C1S, C2, C3, C5, C6, C7, C8A, C8B, C8G, C9, apparently, are associated with the formation of severe acne and cause an imbalance of the components of the complement system. It can cause a defect in chemotactic and phagocytic reactions, and as a result a disturbance of the regulation of the inflammatory reaction with chronization of the skin process occures. Thus, results of studies carried out, revealed – for the first time – polymorphic loci of genes of components of the complement system, the imbalance of which is the pathophysiological mechanism of acne.

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Development of a Novel Cytomedical Treatment that can Protect Entrapped Cells from Host Humoral Immunity

Cell Transplantation ◽

10.3727/000000002783985305 ◽

2002 ◽

Vol 11 (8) ◽

pp. 787-797 ◽

Cited By ~ 5

Author(s):

Ryo Suzuki ◽

Yasuo Yoshioka ◽

Etsuko Kitano ◽

Tatsunobu Yoshioka ◽

Hiroaki Oka ◽

...

Keyword(s):

Humoral Immunity ◽

Complement System ◽

Alternative Pathway ◽

Classical Pathway ◽

Dependent Manner ◽

Complement Components ◽

Alternative Pathways ◽

Low Cytotoxicity ◽

The Complement System

Cell therapy is expected to relieve the shortage of donors needed for organ transplantation. When patients are treated with allogeneic or xenogeneic cells, it is necessary to develop a means by which to isolate administered cells from an immune attack by the host. We have developed “cytomedicine, ” which consists of functional cells entrapped in semipermeable polymer, and previously reported that alginate-poly-l-lysine-alginate microcapsules and agarose microbeads could protect the entrapped cells from injury by cellular immunity. However, their ability to isolate from humoral immunity was insufficient. It is well known that the complement system plays an essential role in rejection of transplanted cells by host humoral immunity. Therefore, the goal of the present study was to develop a novel cytomedical device containing a polymer capable of inactivating complement. In the screening of various polymers, polyvinyl sulfate (PVS) exhibited high anticomplement activity and low cytotoxicity. Murine pancreatic β-cell line (MIN6 cell) entrapped in agarose microbeads containing PVS maintained viability and physiological insulin secretion, replying in response to glucose concentration, and resisted rabbit antisera in vitro. PVS inhibited hemolysis of sensitized sheep erythrocytes (EAs) and rabbit erythrocytes by the complement system. This result suggests that PVS inhibits both the classical and alternative complement pathways of the complement system. Next, the manner in which PVS exerts its effects on complement components was examined. PVS was found to inhibit generation of C4a and Ba generation in activation of the classical and alternative pathways, respectively. Moreover, when the EAC1 cells, which were carrying C1 on the EAs, treated with PVS were exposed to C1-deficient serum, hemolysis decreased in a PVS dose-dependent manner. These results suggest that PVS inhibits C1 in the classical pathway and C3 convertase formation in the alternative pathway. Therefore, PVS may be a useful polymer for developing an anticomplement device for cytomedical therapy.

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Inherited complement deficiencies

Philosophical Transactions of the Royal Society of London Series B Biological Sciences ◽

10.1098/rstb.1984.0102 ◽

1984 ◽

Vol 306 (1129) ◽

pp. 419-430 ◽

Cited By ~ 21

Keyword(s):

Immune Complex ◽

Complement System ◽

Lupus Erythematosus ◽

Alternative Pathway ◽

Strong Association ◽

Factor H ◽

Complement Deficiency ◽

Classical Pathway ◽

The Complement System

Isolated genetic deficiencies of individual components of the complement system have been described in man for all the components of the classical pathway and the membrane attack complex as well as for Factor I, Factor H and properdin. It is only for Factor B and Factor D of the alternative pathway that homozygous deficiency states are not so far known. Complement deficiency states provide the most direct way of looking at the role of the complement system in vivo and emphasize the importance of complement in resistance to bacterial infection and in particular to infection with Neisseria . This association is not unexpected since in vitro studies have shown complement to be an efficient enhancer of phagocytosis and inflammation. The particularly frequent occurrence of neisserial infection may be ascribed to the ability of these organisms to survive in phagocytic cells so that the plasma cytolytic activity provided by complement is needed to kill them. On the other hand the strong association between complement deficiencies and immune-complex diseases - especially systemic lupus erythematosus — was unexpected and seems paradoxical in view of the large part played by complement in the pathogenesis of immune complex mediated tissue damage. The paradox can be explained in part by the necessity for an intact complement system in the solubilization and the proper handling of immune complexes. It is also likely that complement deficiency can allow the persistence of low virulence organisms that produce disease solely by an immune complex mechanism. Recently described deficiencies of complement receptors and their effects in vivo are described.

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