Journal of Virology January 15, 2020 | DOI: 10.1128/JVI.02062-19
Joydeep Nag, Reshma Koolaparambil Mukesh, Sreenath Muraleedharan Suma, Umerali Kunnakkadan, Nisha Asok Kumar, John Bernet Johnson
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, however 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 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 also 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.
Chikungunya virus is a vector-borne pathogen of global significance. The morbidity associated with CHIKV infection, neurovirulence and adaptability to Aedes albopictus necessitate 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.