[Source: Journal of Virology, full page: (LINK). Abstract, edited.]
Complement mediated neutralization of a potent neurotropic human pathogen, Chandipura virus, is dependent on C1q.
Umerali Kunnakkadan, Joydeep Nag, Nisha Asok Kumar, Reshma Koolaparambil Mukesh, Sreenath Muraleedharan Suma, John Bernet Johnson
Among the innate immune sentinels, the complement system is a formidable first line of defense against pathogens including viruses. Chandipura virus (CHPV), a neurotropic vesiculovirus of the family Rhabdoviridae is a deadly human pathogen known to cause fatal encephalitis especially among children. The nature of interaction and the effect of human complement on CHPV are unknown. Here, we report that CHPV is a potent activator of complement and thus is highly sensitive to complement proteins in normal human serum (NHS). Utilizing a panel of specific complement component depleted/reconstituted human serum we have demonstrated that CHPV neutralization is C3, C4 and C1q dependent and independent of factor B suggesting the importance of the classical pathway in limiting CHPV. Employing a range of biochemical approaches we could show a) direct association of C1q to CHPV b) deposition of complement proteins C3b, C4b and C1q on CHPV and c) virus aggregation. Depletion of C8, an important component of the pore forming complex of complement had no effect on CHPV further supporting the finding that aggregation and not virolysis is the mechanism of virus neutralization. With no approved vaccines or treatment modalities in place against CHPV, insights into such interactions can be exploited to develop potent vaccines or therapeutics targeting CHPV.
Chandipura virus is a clinically important human pathogen of the Indian subcontinent. The rapidity in death associated with CHPV infection in addition to the absence of an effective vaccine or therapeutics results in poor clinical prognosis. The biology of the virus and its interaction with the host immune system including the complement system is understudied. Our investigation reveals the susceptibility of CHPV to fluid phase complement and also dissects the pathway involved and the mechanism of virus neutralization. Direct binding of C1q, an important upstream component of the classical pathway of complement to CHPV and the strong dependency on C1q for virus neutralization highlights the significance of identifying such interactions to better understand CHPV pathogenesis and devise strategies to target this deadly pathogen.
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Keywords: Rhabdovirus; Vesciculavirus; Chandipura virus; Viral pathogenesis.