scholarly journals A Novel Factor I Activity in Nipah Virus Inhibits Human Complement Pathways through Cleavage of C3b

2014 ◽  
Vol 89 (2) ◽  
pp. 989-998 ◽  
Author(s):  
John B. Johnson ◽  
Viktoriya Borisevich ◽  
Barry Rockx ◽  
Griffith D. Parks
Keyword(s):  
Protease Activity ◽  
Nipah Virus ◽  
Factor H ◽  
Human Complement ◽  
Emerging Viruses ◽  
Highly Pathogenic ◽  
Enveloped Virus ◽  
Factor I ◽  
Complement Pathways

ABSTRACTComplement is an innate immune system that most animal viruses must face during natural infections. Given that replication and dissemination of the highly pathogenic Nipah virus (NiV) include exposure to environments rich in complement factors, we tested thein vitrosensitivity of NiV to complement-mediated neutralization. Here we show that NiV was completely resistant toin vitroneutralization by normal human serum (NHS). Treatment of purified NiV with NHS activated complement pathways, but there was very little C3 deposition on virus particles. Inin vitroreconstitution experiments, NiV particles provided time- and dose-dependent factor I-like protease activity capable of cleaving C3b into inactive C3b (iC3b). NiV-dependent inactivation of C3b only occurred with the cofactors factor H and soluble CR1 but not with CD46. Purified NiV particles did not support C4b cleavage. Electron microscopy of purified NiV particles showed immunogold labeling with anti-factor I antibodies. Our results suggest a novel mechanism by which NiV evades the human complement system through a unique factor I-like activity.IMPORTANCEViruses have evolved mechanisms to limit complement-mediated neutralization, some of which involve hijacking cellular proteins involved in control of inappropriate complement activation. Here we report a previously unknown mechanism whereby NiV provides a novel protease activity capable ofin vitrocleavage and inactivation of C3b, a key component of the complement cascade. These data help to explain how an enveloped virus such as NiV can infect and disseminate through body fluids that are rich in complement activity. Disruption of the ability of NiV to recruit complement inhibitors could form the basis for the development of effective therapies and safer vaccines to combat these highly pathogenic emerging viruses.

Deficiency of Human Complement Factor I Associated with Lowered Factor H

2000 ◽  
Vol 96 (2) ◽  
pp. 162-167 ◽  
Author(s):  
G.M. Naked ◽  
M.P.C. Florido ◽  
P. Ferreira de Paula ◽  
A.M. Vinet ◽  
J.S. Inostroza ◽  
...  
Keyword(s):  
Factor H ◽  
Complement Factor ◽  
Human Complement ◽  
Factor I ◽  
Complement Factor I

scholarly journals Heparan Sulfate-Dependent Enhancement of Henipavirus Infection

mBio ◽  
2015 ◽  
Vol 6 (2) ◽  
Author(s):  
Cyrille Mathieu ◽  
Kévin P. Dhondt ◽  
Marie Châlons ◽  
Stéphane Mély ◽  
Hervé Raoul ◽  
...  
Keyword(s):  
Heparan Sulfate ◽  
Anticoagulant Activity ◽  
Antiviral Treatment ◽  
Mammalian Species ◽  
Nipah Virus ◽  
Hendra Virus ◽  
Host Cells ◽  
Emerging Infections ◽  
Highly Pathogenic

ABSTRACTNipah virus and Hendra virus are emerging, highly pathogenic, zoonotic paramyxoviruses that belong to the genusHenipavirus. They infect humans as well as numerous mammalian species. Both viruses use ephrin-B2 and -B3 as cell entry receptors, and following initial entry into an organism, they are capable of rapid spread throughout the host. We have previously reported that Nipah virus can use another attachment receptor, different from its entry receptors, to bind to nonpermissive circulating leukocytes, thereby promoting viral dissemination within the host. Here, this attachment molecule was identified as heparan sulfate for both Nipah virus and Hendra virus. Cells devoid of heparan sulfate were not able to mediate henipavirustrans-infection and showed reduced permissivity to infection. Virus pseudotyped with Nipah virus glycoproteins bound heparan sulfate and heparin but no other glycosaminoglycans in a surface plasmon resonance assay. Furthermore, heparin was able to inhibit the interaction of the viruses with the heparan sulfate and to block cell-mediatedtrans-infection of henipaviruses. Moreover, heparin was shown to bind to ephrin-B3 and to restrain infection of permissive cellsin vitro. Consequently, treatment with heparin devoid of anticoagulant activity improved the survival of Nipah virus-infected hamsters. Altogether, these results reveal heparan sulfate as a new attachment receptor for henipaviruses and as a potential therapeutic target for the development of novel approaches against these highly lethal infections.IMPORTANCETheHenipavirusgenus includes two closely related, highly pathogenic paramyxoviruses, Nipah virus and Hendra virus, which cause elevated morbidity and mortality in animals and humans. Pathogenesis of both Nipah virus and Hendra virus infection is poorly understood, and efficient antiviral treatment is still missing. Here, we identified heparan sulfate as a novel attachment receptor used by both viruses to bind host cells. We demonstrate that heparin was able to inhibit the interaction of the viruses with heparan sulfate and to block cell-mediatedtrans-infection of henipaviruses. Moreover, heparin also bound to the viral entry receptor and thereby restricted infection of permissive cellsin vitro. Consequently, heparin treatment improved survival of Nipah virus-infected hamsters. These results uncover an important role of heparan sulfate in henipavirus infection and open novel perspectives for the development of heparan sulfate-targeting therapeutic approaches for these emerging infections.

scholarly journals The Borrelia hermsii Factor H Binding Protein FhbA Is Not Required for Infectivity in Mice or for Resistance to Human ComplementIn Vitro

2014 ◽  
Vol 82 (8) ◽  
pp. 3324-3332 ◽  
Author(s):  
Lindy M. Fine ◽  
Daniel P. Miller ◽  
Katherine L. Mallory ◽  
Brittney K. Tegels ◽  
Christopher G. Earnhart ◽  
...  
Keyword(s):  
Genetic Manipulation ◽  
Binding Protein ◽  
Factor H ◽  
Negative Regulator ◽  
Human Complement ◽  
Relapsing Fever ◽  
Borrelia Hermsii ◽  
Content Type

ABSTRACTThe primary causative agent of tick-borne relapsing fever in North America isBorrelia hermsii. It has been hypothesized thatB. hermsiievades complement-mediated destruction by binding factor H (FH), a host-derived negative regulator of complement.In vitro,B. hermsiiproduces a single FH binding protein designated FhbA (FH binding protein A). The properties and ligand binding activity of FhbA suggest that it plays multiple roles in pathogenesis. It binds plasminogen and has been identified as a significant target of a B1b B cell-mediated IgM response in mice. FhbA has also been explored as a potential diagnostic antigen forB. hermsiiinfection in humans. The ability to test the hypothesis that FhbA is a critical virulence factorin vivohas been hampered by the lack of well-developed systems for the genetic manipulation of the relapsing fever spirochetes. In this report, we have successfully generated aB. hermsiifhbAdeletion mutant (theB. hermsiiYORΔfhbAstrain) through allelic exchange mutagenesis. Deletion offhbAabolished FH binding by the YORΔfhbAstrain and eliminated cleavage of C3b on the cell surface. However, the YORΔfhbAstrain remained infectious in mice and retained resistance to killingin vitroby human complement. Collectively, these results indicate thatB. hermsiiemploys an FhbA/FH-independent mechanism of complement evasion that allows for resistance to killing by human complement and persistence in mice.

scholarly journals Inhibition of Nipah Virus by Defective Interfering Particles

2020 ◽  
Vol 221 (Supplement_4) ◽  
pp. S460-S470 ◽  
Author(s):  
Stephen R Welch ◽  
Natasha L Tilston ◽  
Michael K Lo ◽  
Shannon L M Whitmer ◽  
Jessica R Harmon ◽  
...  
Keyword(s):  
Rna Virus ◽  
Nipah Virus ◽  
Vero Cells ◽  
Viral Population ◽  
Alternative Source ◽  
Highly Pathogenic ◽  
Defective Interfering Particles ◽  
Viral Genomes ◽  
Antiviral Control

Abstract The error-prone nature of RNA-dependent RNA polymerases drives the diversity of RNA virus populations. Arising within this diversity is a subset of defective viral genomes that retain replication competency, termed defective interfering (DI) genomes. These defects are caused by aberrant viral polymerase reinitiation on the same viral RNA template (deletion DI species) or the nascent RNA strand (copyback DI species). DI genomes have previously been shown to alter the dynamics of a viral population by interfering with normal virus replication and/or by stimulating the innate immune response. In this study, we investigated the ability of artificially produced DI genomes to inhibit Nipah virus (NiV), a highly pathogenic biosafety level 4 paramyxovirus. High multiplicity of infection passaging of both NiV clinical isolates and recombinant NiV in Vero cells generated an extensive DI population from which individual DIs were identified using next-generation sequencing techniques. Assays were established to generate and purify both naturally occurring and in silico-designed DIs as fully encapsidated, infectious virus-like particles termed defective interfering particles (DIPs). We demonstrate that several of these NiV DIP candidates reduced NiV titers by up to 4 logs in vitro. These data represent a proof-of-principle that a therapeutic application of DIPs to combat NiV infections may be an alternative source of antiviral control for this disease.

scholarly journals A Factor I-Like Activity Associated with Chikungunya Virus Contributes to Its Resistance to the Human Complement System

2020 ◽  
Vol 94 (7) ◽  
Author(s):  
Joydeep Nag ◽  
Reshma Koolaparambil Mukesh ◽  
Sreenath Muraleedharan Suma ◽  
Umerali Kunnakkadan ◽  
Nisha Asok Kumar ◽  
...  
Keyword(s):  
Disease Severity ◽  
Complement System ◽  
Chikungunya Virus ◽  
Factor H ◽  
Host Immune System ◽  
Dependent Manner ◽  
Human Complement ◽  
Chikv Infection ◽  
Factor I ◽  
The Complement System

ABSTRACT Chikungunya virus (CHIKV) is an emerging pathogen capable of causing explosive outbreaks. Prior studies showed that exacerbation in arthritogenic alphavirus-induced pathogenesis is attributed to its interaction with multiple immune components, including the complement system. Viremia concomitant to CHIKV infection makes exposure of the virus to complement unavoidable, yet very little is known about CHIKV-complement interactions. Here, we show that CHIKV activated serum complement to modest levels in a concentration- and time-dependent manner, but the virus effectively resisted complement-mediated neutralization. Heat-inactivated serum from seropositive donors could actively neutralize CHIKV due to the presence of potent anti-CHIKV antibodies. Deposition of key complement components C3 and C4 did not alter the resistance of CHIKV to complement. Further, we identified a factor I-like activity in CHIKV that limited complement by inactivating C3b into inactive C3b (iC3b), the complement component known to significantly contribute to disease severity in vivo, but this activity had no effect on C4b. Inactivation of C3b by CHIKV was largely dependent on the concentration of the soluble host cofactor factor H and the virus concentration. A factor I function-blocking antibody had only a negligible effect on the factor I-like activity associated with CHIKV, suggesting that this activity is independent of host factor I and could be of viral origin. Thus, our findings suggest a complement modulatory action of CHIKV which not only helps the virus to evade human complement but may also have implications in alphavirus-induced arthritogenic symptoms. IMPORTANCE Chikungunya virus is a vector-borne pathogen of global significance. The morbidity associated with chikungunya virus (CHIKV) infection, neurovirulence and adaptability to Aedes albopictus, necessitates a deeper understanding of the interaction of CHIKV with the host immune system. Here, we demonstrate that CHIKV is resistant to neutralization by one of the potent barriers of the innate immune arm, the complement system. Chikungunya virus showed marked resistance to complement despite activation and deposition of complement proteins. Interestingly the C3 component associated with the virion was found to be inactive C3b (iC3b), a key factor implicated in the pathogenesis and disease severity in the mouse model of Ross River virus infection. CHIKV also had an associated unique factor I-like activity that mediated the inactivation of C3b into iC3b. We have unraveled a smart strategy adopted by CHIKV to limit complement which has serious implications in viral dissemination, pathogenesis, and disease.

scholarly journals Breakdown of C3 after complement activation. Identification of a new fragment C3g, using monoclonal antibodies.

1982 ◽  
Vol 156 (1) ◽  
pp. 205-216 ◽  
Author(s):  
P J Lachmann ◽  
M K Pangburn ◽  
R G Oldroyd
Keyword(s):  
Monoclonal Antibodies ◽  
Complement Activation ◽  
Antigenic Determinant ◽  
Fluid Phase ◽  
Factor H ◽  
Alpha Chain ◽  
Factor I ◽  
Activation Products ◽  
Do So

The physiological breakdown of C3 has been studied using monoclonal anti-C3 antibodies, and it has been found that the later stages of this process--the breakdown of C3bi--is more complex than had previously been recognized. C3bi is the reaction product produced from C3b by the action of factor I which, in the presence of factor H, produces a double cleavage in the alpha chain of C3b. It is here reported that, both on cells and in the fluid phase, the breakdown of C3bi in serum gives rise to two products: C3c and the product previously described as alpha 2D, which we now propose to designate C3d,g. Alpha 2D differs from C3d in that it contains an additional fragment of approximately 8,000 mol wt that carries the antigenic determinant for the clone 9 monoclonal anti-C3 antibody. C3g cannot be precipitated by anti-C3 antisera and therefore behaves as a uni- or bideterminant antigen. The cleavage of C3d,g to C3d and C3g does not occur in sterile serum. It is also still uncertain what enzyme cleaves C3bi to C3c and C3d,g in plasma. Plasmin can do so in vitro, but plasminogen-depleted serum can still produce the cleavage. The antigenic determinant recognized by clone 9 in C3 is not exposed in C3 or C3b, but appears as a neoantigen in C3bi (and in C3d,g). Anti-C3g therefore is a potentially useful ligand for detecting complement-activation products. C3g represents a new, highly anionic C3 fragment and seems not to be identical with the C3e fragment described by others.

scholarly journals SARS-CoV-2 Cellular Infection and Therapeutic Opportunities: Lessons Learned from Ebola Virus

Membranes ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 64
Author(s):  
Jordana Muñoz-Basagoiti ◽  
Daniel Perez-Zsolt ◽  
Jorge Carrillo ◽  
Julià Blanco ◽  
Bonaventura Clotet ◽  
...  
Keyword(s):  
Viral Entry ◽  
Ebola Virus ◽  
Lessons Learned ◽  
Productive Infection ◽  
Target Cells ◽  
Emerging Viruses ◽  
Highly Pathogenic ◽  
Life Threatening ◽  
Pathogenic Viruses ◽  
Cellular Machinery

Viruses rely on the cellular machinery to replicate and propagate within newly infected individuals. Thus, viral entry into the host cell sets up the stage for productive infection and disease progression. Different viruses exploit distinct cellular receptors for viral entry; however, numerous viral internalization mechanisms are shared by very diverse viral families. Such is the case of Ebola virus (EBOV), which belongs to the filoviridae family, and the recently emerged coronavirus SARS-CoV-2. These two highly pathogenic viruses can exploit very similar endocytic routes to productively infect target cells. This convergence has sped up the experimental assessment of clinical therapies against SARS-CoV-2 previously found to be effective for EBOV, and facilitated their expedited clinical testing. Here we review how the viral entry processes and subsequent replication and egress strategies of EBOV and SARS-CoV-2 can overlap, and how our previous knowledge on antivirals, antibodies, and vaccines against EBOV has boosted the search for effective countermeasures against the new coronavirus. As preparedness is key to contain forthcoming pandemics, lessons learned over the years by combating life-threatening viruses should help us to quickly deploy effective tools against novel emerging viruses.

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