Complement-Mediated Neutralization of a Potent Neurotropic Human Pathogen, Chandipura Virus, Is Dependent on C1q

Kunnakkadan, Umerali; Nag, Joydeep; Kumar, Nitesh; Mukesh, Reshma Koolaparambil; Suma, Sreenath Muraleedharan; Johnson, John B.

doi:10.1128/jvi.00994-19

Cited by 12 publications

(11 citation statements)

References 37 publications

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“…To further substantiate the resistance of CHIKV to NHS, a comparative analysis was carried out between CHIKV and Chandipura virus (CHPV). We had earlier observed that the neurotrophic rhabdovirus CHPV, known to cause encephalitis in humans, is readily neutralized by human complement (46). A marked reduction in the number of plaques was seen in the case of CHPV compared to CHIKV upon treatment with NHS at all serum dilutions tested (Fig.…”

Section: Resultsmentioning

confidence: 71%

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

Nag

Mukesh

Suma

et al. 2020

J Virol

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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.

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Section: Resultsmentioning

confidence: 71%

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

Nag

Mukesh

Suma

et al. 2020

J Virol

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“…For Chandipura virus (CHPV), the alternative pathway and factors C3, C5, and factor B were required for complement-mediated virus neutralization in absence of C8 or antibodies ( 158 ). A different study utilized antibodies to observe classical pathway activation and reported that C1q, C3, and C4 were essential components for neutralization, but this was independent of factor B and C8 ( 159 ). The discrepancy of the importance of Factor B for CHPV neutralization could depend on the presence of antibodies and the classical pathway.…”

Section: Antiviral Activity Of the Complement Systemmentioning

confidence: 99%

Viral Evasion of the Complement System and Its Importance for Vaccines and Therapeutics

et al. 2020

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The complement system is a key component of innate immunity which readily responds to invading microorganisms. Activation of the complement system typically occurs via three main pathways and can induce various antimicrobial effects, including: neutralization of pathogens, regulation of inflammatory responses, promotion of chemotaxis, and enhancement of the adaptive immune response. These can be vital host responses to protect against acute, chronic, and recurrent viral infections. Consequently, many viruses (including dengue virus, West Nile virus and Nipah virus) have evolved mechanisms for evasion or dysregulation of the complement system to enhance viral infectivity and even exacerbate disease symptoms. The complement system has multifaceted roles in both innate and adaptive immunity, with both intracellular and extracellular functions, that can be relevant to all stages of viral infection. A better understanding of this virus-host interplay and its contribution to pathogenesis has previously led to: the identification of genetic factors which influence viral infection and disease outcome, the development of novel antivirals, and the production of safer, more effective vaccines. This review will discuss the antiviral effects of the complement system against numerous viruses, the mechanisms employed by these viruses to then evade or manipulate this system, and how these interactions have informed vaccine/therapeutic development. Where relevant, conflicting findings and current research gaps are highlighted to aid future developments in virology and immunology, with potential applications to the current COVID-19 pandemic.

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“…These initial interactions set the stage for sequential progress of the complement cascade promoting virus neutralization. Yet again, marked variations exist even among closely related viruses with regard to the mechanism of neutralization ( Table 1 ) ( 27 , 60 , 61 ). Although it may be anticipated that surface glycoproteins could contribute to these differences, in-depth investigations into these interactions are required to better understand their role.…”

Section: Discussionmentioning

confidence: 99%

“…Chandipura virus (CHPV), another vesiculovirus and a potent human pathogen, has also been shown to activate the CP, which involved the direct binding of C1q to the virus. This virus was highly sensitive to complement and was neutralized effectively by complement-dependent virus aggregation ( 61 ). Although VSV and CHPV belong to the same genus with a single glycoprotein (G) in the virus envelope, marked differences were observed in the mechanism of neutralization.…”

Section: Complement Activation and Its Effects On Rna Virusesmentioning

confidence: 99%

In the Crosshairs: RNA Viruses OR Complement?

et al. 2020

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Complement, a part of the innate arm of the immune system, is integral to the frontline defense of the host against innumerable pathogens, which includes RNA viruses. Among the major groups of viruses, RNA viruses contribute significantly to the global mortality and morbidity index associated with viral infection. Despite multiple routes of entry adopted by these viruses, facing complement is inevitable. The initial interaction with complement and the nature of this interaction play an important role in determining host resistance versus susceptibility to the viral infection. Many RNA viruses are potent activators of complement, often resulting in virus neutralization. Yet, another facet of virus-induced activation is the exacerbation in pathogenesis contributing to the overall morbidity. The severity in disease and death associated with RNA virus infections shows a tip in the scale favoring viruses. Growing evidence suggest that like their DNA counterparts, RNA viruses have co-evolved to master ingenious strategies to remarkably restrict complement. Modulation of host genes involved in antiviral responses contributed prominently to the adoption of unique strategies to keep complement at bay, which included either down regulation of activation components (C3, C4) or up regulation of complement regulatory proteins. All this hints at a possible “hijacking” of the cross-talk mechanism of the host immune system. Enveloped RNA viruses have a selective advantage of not only modulating the host responses but also recruiting membrane-associated regulators of complement activation (RCAs). This review aims to highlight the significant progress in the understanding of RNA virus–complement interactions.

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Complement-Mediated Neutralization of a Potent Neurotropic Human Pathogen, Chandipura Virus, Is Dependent on C1q

Cited by 12 publications

References 37 publications

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

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

Viral Evasion of the Complement System and Its Importance for Vaccines and Therapeutics

In the Crosshairs: RNA Viruses OR Complement?

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