Kumar , J. and Yadav , V.N. and Phulera , S. and Kamble , A. and Gautam , A.K. and Panwar , H.S. and Saha , A. (2017) Species specificity of vaccinia virus complement control protein towards bovine classical pathway is governed primarily by direct interaction of its acidic residues with factor I. Journal of Virology .

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Abstract

Poxviruses display species tropism - variola virus is a human-specific virus, while vaccinia virus causes repeated outbreaks in dairy cattle. Consistent with this, variola virus complement regulator SPICE exhibit selectivity in inhibiting the human alternative complement pathway and vaccinia virus complement regulator VCP display selectivity in inhibiting the bovine alternative complement pathway. In the present study, we examined the species-specificity of VCP and SPICE towards the classical pathway (CP). We observed that VCP is ∼43-fold superior in inhibiting bovine CP than SPICE. Further, functional assays revealed that increased inhibitory activity of VCP towards bovine CP is solely due to its enhanced cofactor activity with no effect on decay of bovine CP C3-convertase. To probe the structural basis of this specificity, we utilized single- and multi-amino acid substitution mutants wherein one or more of the 11 variant VCP residues were substituted onto the SPICE template. Examination of these mutants for their ability to inhibit bovine CP revealed that E108, E120 and E144 are majorly responsible for imparting the specificity and contribute to the enhanced cofactor activity of VCP. Binding and functional assays suggested that these residues interact with bovine factor I, but not bovine C4(H2O) (a conformationally similar moiety to C4b). Mapping of these residues onto the modelled structure of bovine C4b-VCP-bovine factor I supported the mutagenesis data. Together, our data help explain why the vaccine strain of vaccinia virus was able to gain a foothold in domesticated animals.IMPORTANCE Vaccinia virus was used for smallpox vaccination. The vaccine-derived virus is now circulating and causing outbreaks in dairy cattle in India and Brazil. The reason for this tropism however is unknown. It is well recognized that the virus is susceptible to neutralization by the classical complement pathway (CP). Because the virus encodes a soluble complement regulator VCP, we examined whether this protein displays selectivity in targeting bovine CP. Our data show that it does exhibit selectivity in inhibiting the bovine CP, and this is primarily determined by its amino acids E108, E120 and E144, which interact with bovine serine protease factor I to inactivate bovine C4b - one of the two subunits of CP C3-convertase. Of note, the variola complement regulator SPICE contains positively charged residues at these positions. Thus, these variant residues in VCP help enhance its potency against the bovine CP and thereby fitness of the virus in cattle.

Item Type:	Article
Subjects:	Infection and Immunity
Depositing User:	Mr. Rameshwar Nema
Date Deposited:	29 Aug 2017 07:19
Last Modified:	29 Aug 2017 07:19
URI:	http://nccs.sciencecentral.in/id/eprint/447

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