Properdin binds to late apoptotic and necrotic cells independently of C3b and regulates alternative pathway complement activation. Complement factor P is a ligand for the natural killer cell-activating receptor NKp Sci Immunol. Intracellular complement activation sustains T cell homeostasis and mediates effector differentiation.
Mol Immunol. A C3 H20 recycling pathway is a component of the intracellular complement system. J Clin Investig. On the functional overlap between complement and anti-microbial peptides. Pulmonary alveolar type II epithelial cells synthesize and secrete proteins of the classical and alternative complement pathways.
The endothelium is an extrahepatic site of synthesis of the seventh component of the complement system. Clin Exp Immunol. Characteristics and biological variations of M-Ficolin, a pattern recognition molecule, in plasma.
Production of complement components by cells of the immune system. Selective expression of clusterin SGP-2 and complement C1qB and C4 during responses to neurotoxins in vivo and in vitro. Chronic low level complement activation within the eye is controlled by intraocular complement regulatory proteins. Investig Ophthalmol Vis Sci. Differential expression of complement regulatory proteins decay-accelerating factor CD55 , membrane cofactor protein CD46 and CD59 during human spermatogenesis.
J Leukoc Biol. Murine CD93 C1qRp contributes to the removal of apoptotic cells in vivo but is not required for C1q-mediated enhancement of phagocytosis.
CD93 is rapidly shed from the surface of human myeloid cells and the soluble form is detected in human plasma. Activation of human neutrophils by C3a and C5A. C3a and C5a are chemotaxins for human mast cells and act through distinct receptors via a pertussis toxin-sensitive signal transduction pathway. C3a and C5a stimulate chemotaxis of human mast cells.
The human C3a receptor is expressed on neutrophils and monocytes, but not on B or T lymphocytes. Expression of a functional anaphylatoxin C3a receptor by astrocytes. J Neurochem. Activated human T lymphocytes express a functional C3a receptor. Local production and activation of complement up-regulates the allostimulatory function of dendritic cells through C3a-C3aR interaction.
The Anaphylatoxin C3a receptor expression on human M2 macrophages is down-regulated by stimulating the histamine H4 receptor and the IL-4 receptor. Differential expression of complement receptors on human basophils and mast cells.
Human T cells express the C5a receptor and are chemoattracted to C5a. Up-regulation of C5a receptor expression and function on human monocyte derived dendritic cells by prostaglandin E2. The C1q and collectin binding site within C1 q receptor cell surface calreticulin. Role of surfactant proteins A, D, and C1q in the clearance of apoptotic cells in vivo and in vitro : calreticulin and CD91 as a common collectin receptor complex.
Direct interaction between CD91 and C1q. FEBS J. Expression of Complement receptors 1 and 2 on follicular dendritic cells is necessary for the generation of a strong antigen-specific IgG response. Tumor-promoting phorbol esters stimulate C3b and C3b' receptor-mediated phagocytosis in cultured human monocytes.
Complement receptor expression on neutrophils at an inflammatory site, the Pseudomonas-infected lung in cystic fibrosis. Comp Inflamm. Pascual M, Schifferli JA. The binding of immune complexes by the erythrocyte complement receptor 1 CR1. Role of complement receptor 1 CR1; CD35 on epithelial cells: a model for understanding complement-mediated damage in the kidney. Identification of the membrane receptor for the complement fragment C3d by means of a monoclonal antibody.
Structural Immunology of Complement Receptors 3 and 4. Complement receptor 3 ligation of dendritic cells suppresses their stimulatory capacity. CR3 is the dominant phagocytotic complement receptor on human dendritic cells. CRIg: a macrophage complement receptor required for phagocytosis of circulating pathogens. The multiligand-binding protein gC1qR, Putative C1q receptor, is a mitochondrial protein.
C1q-mediated chemotaxis by human neutrophils: involvement of gClqR and G-protein signalling mechanisms. Biochem J. Chemotaxis of human monocyte-derived dendritic cells to complement component C1q is mediated by the receptors gC1qR and cC1qR. Analysis of the interaction between globular head modules of human C1q and its candidate receptor gC1qR.
C5L2, a nonsignaling C5A binding protein. Membrane cofactor protein of complement is present on human fibroblast, epithelial, and endothelial cells. Membrane cofactor protein CD46 protects cells from complement- mediated attack by an intrinsic mechanism. Soluble forms of membrane cofactor protein CD46, MCP are present in plasma, tears, and seminal fluid in normal subjects. Nat Immunol. Complement 1 inhibitor is a regulator of the alternative complement pathway. Human factor H and C4b-binding protein serve as factor I-cofactors both encompassing inactivation of C3b and C4b.
Regulation of complement activation by C-reactive protein: targeting of the inhibitory activity of C4b-binding protein. Arthr Res Ther. C8 binding protein bears I antigenic determinants. Ann Hematol. Inactivation of C3a and C5a octapeptides by carboxypeptidase R and carboxypeptidase N. Identification of the complement decay-accelerating factor DAF on epithelium and glandular cells and in body fluids. Decay-accelerating factor must bind both components of the complement alternative pathway C3 convertase to mediate efficient decay.
Decay-accelerating factor regulates T-cell immunity in the context of inflammation by influencing costimulatory molecule expression on antigen-presenting cells. Human protectin CD59 , an 18,, MW complement lysis restricting factor, inhibits C5b-8 catalysed insertion of C9 into lipid bilayers. CD59 functions as a signal-transducing molecule for human T cell activation. Alternative roles for CD Cell Immunol.
Clusterin, the human apolipoprotein and complement inhibitor, binds to complement C7, C8 beta, and the b domain of C9. Complement factor H: using atomic resolution structure to illuminate disease mechanisms.
Adv Exp Med Biol. Insights into the effects of complement factor H on the assembly and decay of the alternative pathway C3 proconvertase and C3 convertase. Kishore U, Sim RB. Factor H as a regulator of the classical pathway activation. Role of human factor I and C3b receptor in the cleavage of surface-bound C3bi molecules. J Biochem. Hourcade DE. The role of properdin in the assembly of the alternative pathway C3 convertases of complement.
Complement inhibition by human vitronectin involves non-heparin binding domains. Complement and bacterial infections: from molecular mechanisms to therapeutic applications.
Activation of the complement system by Cryptococcus neoformans leads to binding of iC3b to the yeast. Infect Immun. Human C1-inhibitor suppresses malaria parasite invasion and cytoadhesion via binding to parasite glycosylphosphatidylinositol and host cell receptors.
A human serum mannose-binding protein inhibits in vitro infection by the human immunodeficiency virus. Virus complement evasion strategies. Complement and viral pathogenesis.
Viral-derived complement inhibitors: current status and potential role in immunomodulation. Exp Biol Med. Complement evasion strategies of viruses: an overview. Front Microbiol. Natural antibody and complement mediate neutralization of influenza virus in the absence of prior immunity. J Virol. Complement lysis activity in autologous plasma is associated with lower viral loads during the acute phase of HIV-1 Infection. PLoS Med. Complement-dependent lysis of influenza A virus-infected cells by broadly cross-reactive human monoclonal antibodies.
The role of anaphylatoxins C3a and C5a in regulating innate and adaptive immune responses. Inflamm Aller Drug Targets. C5a receptor-deficient dendritic cells promote induction of Treg and Th Lectin-dependent enhancement of ebola virus infection via soluble and transmembrane C-type lectin receptors.
High-dose mannose-binding lectin therapy for Ebola virus infection. Interaction of mannose-binding lectin with HIV type 1 is sufficient for virus opsonization but not neutralization.
Complement opsonization of HIV-1 enhances the uptake by dendritic cells and involves the endocytic lectin and integrin receptor families. Complement opsonization promotes herpes simplex virus 2 infection of human dendritic cells. Mannose-binding lectin in severe acute respiratory syndrome coronavirus infection. A single asparagine-linked glycosylation site of the severe acute respiratory syndrome coronavirus spike glycoprotein facilitates inhibition by mannose-binding lectin through multiple mechanisms.
The SARS coronavirus spike glycoprotein is selectively recognized by lung surfactant protein D and activates macrophages. Association between mannose-binding lectin gene polymorphisms and susceptibility to severe acute respiratory syndrome coronavirus infection. Tissue Antigens. Direct complement restriction of flavivirus infection requires glycan recognition by mannose-binding lectin. Cell Host Microbe. Differential mechanisms of complement-mediated neutralization of the closely related paramyxoviruses simian virus 5 and mumps virus.
Gupta P, Tripathy AS. Alternative pathway of complement activation has a beneficial role against Chandipura virus infection. Med Microbiol Immunol. Complement-mediated neutralization of a potent neurotropic human pathogen, Chandipura virus, is dependent on C1q. Intracellular complement — the complosome — in immune cell regulation. Complement C4 prevents viral infection through capsid inactivation.
Antagonism of the complement component C4 by flavivirus nonstructural protein NS1. Binding of Flavivirus nonstructural protein NS1 to C4b binding protein modulates complement activation. West Nile virus nonstructural protein NS1 inhibits complement activation by binding the regulatory protein factor H. Inhibition of the membrane attack complex by Dengue Virus NS1 through interaction with vitronectin and terminal complement proteins.
Vascular leakage in severe dengue virus infections: a potential role for the nonstructural viral protein NS1 and complement. A novel factor I activity in Nipah Virus inhibits human complement pathways through cleavage of C3b.
A factor I-like activity associated with chikungunya virus contributes to its resistance to the human complement system. Human immunodeficiency virus type 1 incorporates both glycosyl phosphatidylinositol-anchored CD55 and CD59 and integral membrane CD46 at levels that protect from complement-mediated destruction.
The paramyxoviruses simian virus 5 and mumps virus recruit host cell CD46 to evade complement-mediated neutralization. Complement-mediated enhancement of HIV-1 infection in peripheral blood mononuclear cells. Scand J Infect Dis. The good and evil of complement activation in HIV-1 infection. Cell Mol Immunol. Anti-HIV-1 antibodies trigger non-lytic complement deposition on infected cells. EMBO Rep. Mechanism of complement inactivation by glycoprotein C of herpes simplex virus.
Barnum SR. C4a: an anaphylatoxin in name only. Chemotactic responses of human peripheral blood monocytes to the complement-derived peptides C5a and C5a des Arg. C3a is a chemotaxin for human eosinophils but not for neutrophils. C3a stimulation of neutrophils is secondary to eosinophil activation. Spiller et al. Experimental verification of this premise by them indeed showed that complement regulators CD46 and CD55 are up-regulated on the infected cells and are responsible for averting complement activation on these cells [ Figure 2F b ].
Viruses seem to have not only been involved in up-regulation of complement regulators, but also in down-regulation of complement components essential for complement activation. One such example is HCV. Banerjee et al. Poxviruses are large brick-shaped nm by nm enveloped viruses that contain linear double-stranded DNA genomes mostly — kbp forming a covalently closed hairpin loop at the terminus Buller and Palumbo, The poxvirus family is divided into two subfamilies — Chordopoxvirinae poxviruses that infect vertebrates and Entomopoxvirinae poxviruses that infect insects.
The two most important members of Chordopoxvirinae are variola virus that causes smallpox, and VACV that was used to control smallpox. Both these viruses have been shown to efficiently evade the complement system. Complement evasion in poxviruses was first identified in VACV. It was shown that one of the two major secretory protein of VACV is a structural homolog of the RCA proteins Kotwal and Moss, and possesses complement regulatory activity Kotwal et al.
Later, it was also shown to support the inactivation of C3b and C4b with the help of factor I termed cofactor activity Sahu et al. The importance of this protein was further enhanced by Isaacs et al. VCP was also shown to interact with heparan sulfate proteoglycans and A56 viral protein which impart surface binding property to the protein Smith et al.
Variola is a human-specific virus, which encodes an ortholog of VCP. Rosengard et al. The protein was found to be fold more potent in inactivating C3b and 6-fold more potent in inactivating C4b Rosengard et al. In vitro studies demonstrated that it possesses cofactor activity for C3b and C4b, but lacks decay-accelerating activity Liszewski et al.
Together the results suggested that though the difference in virulence in these two strains is not due to MOPICE, the protein does play a moderate role in pathogenesis Hudson et al. Apart from the above-mentioned poxviruses, functional complement regulator was also found in cowpox virus [named IMP Miller et al.
Another immune evasion strategy used by VACV is by acquiring host complement regulators into its envelope. Of these virions, only EEV is resistant to complement-mediated neutralization in the absence of specific antibodies. Vanderplasschen et al. The relative role of each of these regulators in protection against complement nonetheless is not yet clear. Like poxviruses, herpesviruses are also large — nm enveloped DNA viruses with linear double-stranded genomes of about — kbp Liu and Zhou, Remarkably, a large part of their genomes encodes for genes that are involved in host control.
They are classified into three subfamilies — Alphaherpesvirinae, Betaherpesvirinae , and Gammaherpesvirinae — and all the subfamilies are known to subvert the complement system. The members of Alphaherpesvirinae encode gC that target complement.
It is clear that deletion of gC-1 and gC-2 from the respective viruses result in their effective neutralization by complement Friedman et al. Data obtained up until now suggest that interaction of gC-1 and gC-2 with C3b helps them evade the complement system. Further, it has been shown that interaction of gC-1 with C3b blocks its interaction with properdin and C5 Harris et al. Of note, the domain that blocks properdin and C5 interaction with C3b is absent in gC-2 suggesting that its mechanism of complement subversion is different than that of gC-1 Kostavasili et al.
These results were also corroborated by in vivo infection studies Lubinski et al. These results also prompted the formulation of a trivalent subunit antigen vaccine for genital herpes which contains gC-2 and gE-2 apart from gD-2 that is essential for viral entry Awasthi et al.
Viruses belonging to this family have been shown to protect themselves from host complement by acquiring complement regulators from the host cells as well as by up-regulating the expression of complement regulators on the infected cells.
In addition, these viruses have also been demonstrated to utilize CD46 as a cellular receptor. Further, treatment of the virions with antibodies against the acquired regulators showed a reduction in the infectious titer when incubated with complement indicating that the acquired regulators help to protect the virus from complement Spear et al.
Though these viruses have a broad tropism for different human cell types, only a restricted number of non-human primate species show susceptibility to HHV Thus, efforts were directed at identifying a receptor that is ubiquitous, yet have significant species differences.
Identification of CD46 domains crucial for interacting with the virions revealed that only CCP domains 2 and 3 are essential for the interaction Greenstone et al. Initial attempts to ascertain the viral glycoprotein that interacts with CD46 resulted in the identification of glycoprotein H gH as the ligand. More recently, it has been demonstrated that apart from the heterotetramer complex, gB is also essential for the membrane fusion by HHV-6 Tanaka et al.
Among the components of the heterotetramer, gQ1 and gQ2 seem to play a critical role in binding to CD46 Jasirwan et al. Gammaherpesviruses have been shown to encode homologs of the human RCA and CD59 that help them elude the complement system.
Moreover, they also utilize CRs for cellular entry, which are widely expressed on the host cells. Initial characterization of this protein showed that it has the ability to inhibit complement activation Fodor et al. Besides, the domain requirement of this protein for complement inactivation was essentially similar to that of the poxviral RCA proteins Singh et al.
Expression of HVSCD59 on the surface of different cells was shown to protect these cells from the complement-mediated damage Rother et al. Importantly, it is expressed on the infected cells as well as on the virion envelope Spiller et al.
In-depth mapping of its functional domains and mutational analysis revealed that it functions in a manner similar to that of the human RCA proteins Mullick et al. Electrostatic modeling and mutagenesis studies indicated that the positive electrostatic potential in domains 1 and 4, and in the linkers between domains 1—2 and 2—3, influence the complement regulatory activities of Kaposica Pyaram et al.
More recently, efforts were made to understand the molecular mechanism behind its cofactor activity. This model also seems to be true for the human RCA proteins Gautam et al. Murine gammaherpesvirus 68 also encodes a four CCP domain homolog of RCA that exist in both soluble and membrane-bound forms Kapadia et al.
The protein was also examined for its role during the infection which suggested that it is vital for viral pathogenesis Kapadia et al. Both have been shown to display the complement regulatory functions Okroj et al. Unlike the above-mentioned viruses, EBV targets the complement system for its entry into B cells. We now know that it targets CR-1 Ogembo et al.
These results were also corroborated by the X-ray structure of the gp Szakonyi et al. Adenoviruses are medium sized 90— nm non-enveloped DNA viruses that contain a linear double-stranded genome of 26—48 kbp Wold and Horwitz, ; Arnberg, They are classified into five genera of which human AdV of the genus Mastadenovirus have been widely studied and divided into seven species A to G which contain more than 50 serotypes.
Certain serotypes of human AdV have been shown to target CD46 for their cellular entry. It was also shown that the fiber knob protein of these viruses helps them to interact with the extracellular domain of CD Moreover, the investigations also revealed that expression of CD46 on the non-permissive cells renders them susceptible to viral attachment and infection Segerman et al.
Efforts to decipher the mechanism of molecular recognition between CD46 and fiber knob revealed that this interaction requires contact between two N-terminal CCP domains of CD46 with two fiber knob monomers Persson et al. Consequently, a study in particular with AdV, also looked at the utilization of various CD46 isoforms for infection by this serotype.
One of the NS proteins, NS1, has been shown to function as a complement regulator. Non-structural protein 1 is a 48 kDa glycoprotein of the flaviviruses which is required for effective viral replication Mackenzie et al. Remarkably, the protein has the capability to subvert all the three major activation pathways of complement.
It is synthesized as a soluble monomer that dimerizes upon post-translational modification in the endoplasmic reticulum. After its secretion from the infected cells, it forms large oligomers, e. However, later it became clear that NS1-mediated activation of complement was due to the formation of NS1-antibody immune complexes Avirutnan et al.
We now know that NS1 directly binds and recruits factor H Chung et al. Interestingly, NS1 has also been shown to directly interact with C9 and inhibit its polymerization Conde et al.
Further, the soluble hexameric NS1 is also known to interact with C4 and pro-C1s forming a trimolecular complex C4-NS1-C1s which promotes the cleavage of C4 to C4b consuming the molecule in solution Avirutnan et al.
Thus, multiple interactions of NS1 with the complement components and regulators seem to enhance its effectiveness as a complement regulator. Hepaciviruses members of the family Flaviviridae contain single-stranded positive-sense RNA genome of about 9.
Among these viruses, HCV is the major human pathogen that causes hepatitis, hepatocellular carcinoma and lymphoma Sanyal et al. Studies performed to understand the complement evasion mechanisms of HCV suggest that the virus utilizes three distinct strategies to escape the complement-mediated attack.
The second strategy involves incorporation of host complement regulators onto its envelope. The virus as well as the core protein was also shown to up-regulate the expression of CD55 onto the hepatocytes Mazumdar et al. The third strategy that HCV employs is regulation of complement synthesis. The virus effectively inhibits the expression of C2 Kim et al. Retroviruses are spherical nm in diameter , enveloped, single-stranded, positive strand RNA viruses with a DNA intermediate.
The virus contains two identical copies of genomic RNA of 7—10 kb Coffin, The family Retroviridae is divided into subfamily Orthoretrovirinae and Spumaretrovirinae. HIV-1, which falls under the genus Lentivirus of Orthoretrovirinae subfamily, has been well-studied for its interaction with complement. It maintains an intricate balance of complement activation and regulation to achieve maximum infection without undergoing lysis Stoiber et al. During HIV infection, a significant number of free virions can be found in the plasma of infected person suggesting these virions must be resistant to complement-mediated virolysis Ho et al.
Saifuddin et al. Examination of the role of individual complement regulators in virion protection from complement revealed that each of the regulators plays a protective role Saifuddin et al.
Since the expression levels of CD55, CD46, and CD59 vary among different cell types, the sensitivity or resistance of HIV to complement depends on the type of host cell from which the virions are derived Saifuddin et al. Factor H is another complement regulator which is abundantly present in the body fluids.
HIV has also been demonstrated to recruit factor H on its surface via interaction with gp41 and gp Pinter et al. An illustration of this premise was performed using an in vitro experiment wherein HIV virions were shown to be lysed in a complement-dependent fashion when treated with factor H-deficient sera and anti-HIV antibody Stoiber et al. Human immunodeficiency virus is well-known to employ complement for its benefit.
The first observation was made by Robinson et al. Afterward, multiple studies including experimental infection in rhesus macaques Macaca mulatta with SIV presented data supporting this thesis [reviewed in detail in Stoiber et al.
The complement opsonized virions bound to CD35 on erythrocytes are also liable for spread to antigen-presenting cells bearing CR-2, -3, and -4 Hess et al. Specifically, it was hypothesized that CD35 on erythrocytes can support the cleavage of C3b attached to HIV with the help of factor I, the cleaved C3b iC3b or C3dg has less affinity for CD35 and hence will be transferred to antigen-presenting cells decorated with receptors for inactivated C3b.
It is likely that these viruses carrying B cells disseminate infection systemically. In addition to B cells, follicular dendritic cells also trap HIV which is maintained in the germinal centers Joling et al.
The echoviruses, coxsackieviruses, and enteroviruses belonging to the genera enterovirus have been shown to employ CD55 as a cellular receptor or as a binding protein for attachment. The first observation that echoviruses namely echo-6, -7, , , , and use CD55 as a receptor for attachment and infection was made by Bergelson et al.
The evidence provided include: i loss of the capacity to bind to echo-7 by HeLa cells after treatment with phosphatidylinositol-specific phospholipase C, which removes GPI-anchored proteins from the cell surface, ii binding of echo-7 to CHO cells transfected with CD55, iii prevention of echovirus infection in HeLa cells by anti-CD55 antibody. Experimentations sought to determine CD55 domains critical for the echo-7 binding established the requirement of CCPs Clarkson et al.
Contrary to echoviruses, in coxsackieviruses B1, B3, B5, and A21 in particular, it was found that CD55 supports the binding of these viruses to the cell surface, but does not facilitate entry and lytic infection Shafren et al.
Dissection of human specificity of coxsackievirus B3 depicted that S in the CCP2 domain of human CD55 is critical for imparting the specificity Pan et al. Apart from the above viruses, enterovirus 70 has also been documented to use CD55 as a facilitator for virus entry Karnauchow et al.
The family is composed of two genera — Mamastrovirus and Avastrovirus. The HAstV belong to genus Mamastrovirus and are responsible for causing viral diarrhea in young children Madeley and Cosgrove, A series of studies conducted by Krishna and colleagues provided clear evidence that the coat protein of HAstVs is capable of inhibiting the CP and LP of complement Sharp et al.
Human astroviruses are classified into eight serotypes of which serotype 1 is the most predominant worldwide. Early efforts demonstrated that serotypes 1 as well as 2—4 effectively suppress complement activation Bonaparte et al.
Like the viral particles, the CoPt also inhibited the activation of complement, in particular, the CP. Examination of the target protein for the CoPt demonstrated that it interacts with the A-chain of C1q Bonaparte et al. Further investigations to dissect the mechanism of complement inhibition revealed that binding of CoPt to C1q results in inhibition of C1 activation owing to displacement of the protease tetramer C1s—C1r—C1r—C1s Hair et al.
As expected, the protein effectively performed both these functions. Examination of sequence homology of CoPt with other C1q binding proteins showed limited homology with neutrophil defensin-1, which helped identification of a 30 amino acid peptide of the CoPt that inhibited C1 activation Gronemus et al. A smaller yet more potent analog of this peptide was also made which can be developed further for blocking complement-mediated inflammation observed in various clinical conditions Sharp et al.
Togaviruses are simple, spherical shaped 60—70 nm in diameter , enveloped, positive strand single-stranded RNA viruses with a genome of 9. They are divided into two genera namely the Alphavirus and Rubivirus. Among these, the members of the alphaviruses have been shown to interact with complement.
For example, complement activation and complement-mediated damage have been reported during Ross River virus infection Morrison et al.
During the late s and early s when complement was discovered to play an important role during viral infection, Sindbis virus was found to activate the AP Hirsch et al.
By this time, it was also known that membrane sialic acid favors interaction with the AP regulator factor H, which in turn prevents the activation of AP on the cell surface. Consequently, it was examined whether sialic acid acquired by Sindbis virus from the host cell during budding affects its ability to activate the AP.
As anticipated, the ability of the virus to activate AP was inversely related to its sialic acid content Hirsch et al. Moreover, the in vivo clearance rate of the virus with less sialic acid content was higher compared to the virus having more sialic acid content and this was dependent on complement Hirsch et al.
This raised the question — are individuals differentially susceptible to Sindbis virus infection owing to their ability to modify the sialic acid content of the virus? The answer came from the infection experiment performed in outbred Swiss mice. The results demonstrated that tissue sialic acid content of the host influences the ability to resist the infection Hirsch et al.
Thus, these data supported the proposition that host sialic acid content embodies a way of natural resistance to Sindbis virus infection Hirsch et al. The members of the family Orthomyxoviridae are helical to spherical enveloped particles ranging from 80 to nm in size Hale et al.
Influenza viruses have been shown to subvert complement by acquiring CD59 on their envelope Shaw et al. Very recently, recognition of the pandemic influenza A H1N1 virus by the AP, in particular, was shown to be hampered due to the inability of human C3b to recognize the viral surface Rattan et al. About a decade ago, Shaw et al. Thus, it can be envisaged that the acquired CD59 would protect the virus from the MAC-mediated lysis.
However, it should be mentioned here that multiple reports have now established that coating of the INFLV surface with C3b is enough for its neutralization Jayasekera et al. In the case of lymphocytes and perhaps phagocytic cells, this interaction may lead to antibody-dependent cellular cytotoxicity ADCC [51, 58].
The exposed Fc regions may also facilitate attempts at ingestion by monocytes, macrophages, and polymorphonuclear leukocytes. This pathway also functions as an amplification loop for the cleavage of C3 initially triggered by other mechanisms. Both the classical and alternative convertases function to cleave C3 to C3a and C3b.
Similar to C4, cleavage of C3 exposes a reactive thioester bond in C3b that allows for the covalent attachment of C3b to target surfaces. In addition, C3b can bind to either the classical or alternative C3 convertases resulting in a change of the substrate specificity of the convertases from C3 to C5.
These C5 convertases cleave C5 to C5a and C5b. Release of C5b promotes assembly of the C5b—C9 membrane attack complex MAC which can directly lyse pathogens or pathogen-infected cells. The anaphylatoxins C3a and C5a interact with specific receptors to promote chemotaxis and regulate effector functions of cells of both the innate and adaptive immune response.
Schematic of the complement system. Complement is activated by three major pathways. The classical pathway is primarily activated when C1q interacts with IgM and certain IgG isotypes bound to antigen.
Cleavage of C3 exposes a reactive thioester bond in C3b that allows for the covalent attachment of C3b to target surfaces. C3b is further cleaved by factor I fI , a function enhanced by factor H fH , to generate degradation products such as iC3b and C3dg.
C3b and its degradation products interact with cellular receptors to regulate effector functions such as phagocytosis and B cell activation. A variety of soluble and membrane-associated proteins regulate complement activation.
C4BP functions similar to fH in that it promotes dissociation of C4bC2a convertases and acts as a cofactor for fI-mediated cleavage of C4b. These proteins function to destabilize both the classical and alternative complement convertases, act as cofactors for fI-mediated cleavage of C3b and C4b, and prevent assembly of the MAC on cell surfaces.
The complement system is increasingly recognized as a mediator of protection or pathology in a variety of viral infections. Furthermore, the continued identification of novel mechanisms of viral antagonism of complement highlight the important role this system has in viral pathogenesis.
Here, we review recent studies of viral interactions with a variety of components of the complement system and emphasize those findings that describe how these interactions impact the development of virus-induced disease.
Perhaps the best evidence that complement has an important role in the outcome of virus infection is the identification of specific mechanisms evolved by viruses to evade the complement system Fig.
One mechanism employed by viruses is to directly encode proteins that have structural and functional homology to host proteins that function as regulators of complement activation. Examples of viral evasion of the complement system. Virally encoded proteins allow viruses to evade complement-mediated destruction.
Influenza A matrix M1 protein also binds C1q. Viruses, with their corresponding proteins that interfere with the complement cascade in parentheses, are indicated in red.
Some viruses recruit host complement regulatory proteins into their virions. Physiological complement regulatory proteins are shown in green.
Viruses that incorporate these regulatory proteins into their virions are indicated in red. Poxviruses, such as variola virus, vaccinia virus, monkeypox virus, and ectromelia virus, also encode complement regulatory proteins that have structural and functional homology to host encoded regulators of the complement pathway Mullick et al. A VCP-deleted vaccinia virus produced smaller skin lesions in rabbits compared to wild-type vaccinia virus Isaacs et al.
Taken together, these studies and the findings that multiple components of the complement pathway are required for mice to survive ectromelia virus infection discussed below , indicate that complement activation and viral evasion of the complement system are critical determinants of poxvirus pathogenesis. In contrast to herpesviruses and poxviruses, flaviviruses encode a protein that antagonizes the complement system despite the lack of any sequence homology to known regulators of the complement system.
The nonstructural protein 1 NS1 encoded by flaviviruses is a glycosylated protein detected within infected cells, on cell surfaces, and secreted from infected cells Alcon-LePoder et al. NS1 accumulates in the serum of dengue virus-infected individuals and high circulating levels are associated with severe disease Avirutnan et al. These activities enhanced the cleavage of C4 to C4b and resulted in reduced activity of the classical C3 convertase C4b2a and reduced C4b and C3b deposition on cell surfaces Avirutnan et al.
Soluble NS1 has also been reported to bind the complement inhibitory factor clusterin, which normally inhibits the formation of the C5b—C9 membrane attack complex Kurosu et al. Many other viruses employ a similar complement evasion strategy by encoding proteins that bind and inhibit or sequester complement components.
For example, the coat protein of human astrovirus type 1 HAstV-1 suppresses complement activation by binding C1q, functionally displacing the protease tetramer, and thus inhibiting classical pathway activation Bonaparte et al. This was further demonstrated for serotypes 2 and 4 Bonaparte et al. The astrovirus coat protein also bound MBL and inhibited mannan-mediated activation of the lectin pathway Hair et al. As discussed below, C1q enhances the neutralizing and hemagglutination inhibition activity of anti-influenza antibodies.
Experimental evidence suggests that the matrix M1 protein of influenza A virus has evolved to counteract this host response, as M1 prevents complement-mediated neutralization of influenza virus in vitro by binding C1q and blocking the interaction between C1q and IgG Zhang et al. Herpes simplex virus 1 HSV-1 encodes several immune modulators, including glycoprotein C gC , which inhibits activation of the complement cascade by binding C3 and C3 fragments Friedman et al.
These effects are mediated by two distinct domains in gC: one domain blocks properdin and C5 binding to C3b, and the other directly binds C3 and C3 fragments Hung et al.
Studies in animal models have confirmed the importance of gC-mediated complement inhibition in HSV-1 pathogenesis. When inoculated intravaginally into wild-type guinea pigs, but not C3-deficient guinea pigs, a gC-null HSV-1 replicated less efficiently and caused significantly less severe vaginitis compared to wild-type HSV-1 Lubinski et al.
The C3-dependent attenuated phenotype of gC-null HSV-1 was confirmed by inoculating wild-type and C3-deficient mice via skin scratch and evaluating HSVinduced zosteriform disease Lubinski et al. Importantly, the gC mutant viruses were as virulent as wild-type virus in C3-deficient mice, indicating that the gC interactions with the complement system regulate HSV-1 pathogenesis Lubinski et al. Most recently, the knowledge gained from these studies was utilized to improve vaccine efficacy against HSV-1 infection.
Awasthi and colleagues demonstrated that combined immunization with the HSV-1 glycoprotein D gD , a potent immunogen, and gC prevented HSV-1 evasion from complement, due to the development of an anti-gC antibody response, and enhanced the protection provided by gD immunization Awasthi et al.
A number of viruses evade the complement system by recruiting host complement regulatory proteins into their virions Fig. Simian virus 5 SV5 and mumps virus MuV , both paramyxoviruses, can be neutralized in a C3-dependent manner resulting in virion aggregation and virion lysis, respectively Johnson et al. Thus, these viruses have evolved to usurp host complement regulatory proteins to avoid complement-mediated destruction.
Mannose binding lectin MBL is a C-type lectin that plays an important role in innate immunity by binding to carbohydrates on a wide range of pathogens Fujita, Recognition of carbohydrates is mediated via a C-terminal carbohydrate recognition domain. Polymorphisms in the promoter and structural regions of the human MBL2 gene affect MBL oligomer formation and circulating levels of the protein Madsen et al.
Due to these different mutations, humans exhibit a fold variation in circulating MBL levels that occur with varying frequencies in different populations.
Recently, a number of studies have demonstrated that direct interactions between MBL and virus particles can neutralize infection. The finding that the HIV envelope glycoprotein, gp, is modified with high mannose oligosaccharides led researchers to test the potential of HIV and gp to function as ligands for MBL.
The importance of these interactions was demonstrated by experiments showing MBL could inhibit infection of specific target cells by cell culture-derived HIV. Different studies investigating the association between MBL levels and HIV infection have found no association, increased susceptibility among individuals with low MBL levels, and increased susceptibility among individuals with high MBL levels Ji et al. However, this area of research has led to an effort to identify lectins that interact with HIV and inhibit infection as a novel therapeutic approach to prevent HIV infection and disease Alexandre et al.
Similarly, MBL binds efficiently to retroviral particles pseudotyped with Ebola virus or Marburg virus glycoproteins Ji et al. Importantly, all of these studies showed direct MBL-mediated neutralization of virus infection Ip et al.
These findings indicated that MBL opsonization was not sufficient for neutralization, but rather deposition of C3 or C4 onto virions was also required. For WNV, neutralization occurred only with virus produced in insect cells; for DENV, neutralization occurred with insect and mammalian cell-derived virus Fuchs et al. The complement system enhances humoral immunity by a number of different mechanisms. Complement regulates effector functions of both natural and immune antibodies, complement component C3 and its receptors participate in the capture and transport of antigen to the B cell compartments of secondary lymphoid tissue Gonzalez et al.
On B lymphocytes, CR2 forms a complex with other proteins, such as CD19, to activate signal transduction pathways that regulate B cell activation. Coligation of the B cell receptor and CR2, which binds the cleavage products iC3b, C3dg, and C3d covalently attached to antigen, lowers the threshold of B cell activation Bradbury et al.
In fact, linking C3d to a model antigen generated a fusion protein that was — fold more immunogenic Dempsey et al. Numerous studies have established a critical role for the complement system in regulating humoral immunity to virus infection. Below, we highlight recent findings with a particular emphasis on studies that have investigated these pathways in the context of viral pathogenesis.
Natural IgM is polyreactive and it is thought that endogenous antigens drive the generation of natural IgM. IgM, which exists in circulation primarily as a pentamer, has a fold greater binding affinity for C1q compared with IgG, making it a potent activator of the complement system Ehrenstein and Notley, Earlier studies had shown that a natural IgM antibody to a VSV antigen forms an immune complex that activates C1 and initiates complement activation via the classical pathway at the viral surface, thus neutralizing VSV Beebe and Cooper, This neutralization was associated with C3b deposition on the viral envelope that likely interferes with VSV attachment to susceptible cells.
Natural IgM and components of the classical activation pathway have also been shown to neutralize influenza virus Jayasekera et al.
Interestingly, rather than resulting in lysis of virions, these interactions resulted in coating and aggregation of virus particles. Reconstitution prolonged mouse survival following influenza challenge, suggesting that natural IgM and complement also protect the host from influenza infection.
Furthermore, both complement and IgM were required for the development of protective immunity against influenza virus after immunization Fernandez Gonzalez et al. Further analyses revealed that opsonization of ectromelia virus particles with C3b and C4b was the primary mediator of neutralization. Consistent with these findings, ectromelia virus dissemination was more efficient and viral loads in tissues were greater in mice deficient in C3.
In mortality studies, the genetic deficiency in the complement components C3, C4, or fB resulted in a higher mortality rate compared to wild-type mice. In sum, these studies have revealed the important role of natural antibodies and complement in protection from virus infection.
The study of humoral responses to herpesvirus infections has yielded important insights into complement-mediated regulation of B cell function. Interestingly, C3-deficient mice reconstituted with bone marrow from wild-type mice developed normal antibody responses following HSV-1 infection, while wild-type mice reconstituted with bone marrow from C3-deficient mice had significantly diminished IgG responses Verschoor et al.
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