Expression of the pseudorabies virus gB glycoprotein triggers NK cell cytotoxicity and increases binding of the activating NK cell receptor PILRbeta

De Pelsmaeker, Steffi; Dierick, Evelien; Klupp, Barbara GND; Mettenleiter, Thomas C. GND; Cantoni, Claudia; Vitale, Massimo; Favoreel, Herman W.

Natural killer (NK) cells are members of the innate immunity and are key players in the defense against viral infected and malignant cells. NK cells are particularly important in the innate defense against herpesviruses, including alphaherpesviruses. Aggravated and life-threatening alphaherpesvirus-induced disease has been reported in patients with NK cell deficiencies. NK cells are regulated by a diversity of activating and inhibitory cell surface receptors that recognize specific ligands on the plasma membrane of viral infected or malignant target cells. Although alphaherpesviruses have developed several evasion strategies against NK cell-mediated attack, alphaherpesvirus-infected cells are still readily recognized and killed by NK cells. However, the (viral) factors that trigger NK cell activation against alphaherpesvirus-infected cells are largely unknown. In this study, we show that expression of the gB glycoprotein of the alphaherpesvirus pseudorabies virus (PRV) triggers NK cell-mediated cytotoxicity, both in PRV-infected and in gB-transfected cells. In addition, we report that, like their human and murine counterpart, porcine NK cells express the activating receptor paired immunoglobulin-like type 2 receptor β (PILRβ) and show that gB expression triggers increased binding of recombinant porcine PILRβ to the surface of PRV-infected cells and gB-transfected cells. Importance Natural killer (NK) cells display a prominent cytolytic activity against virus-infected cells and are indispensable in the innate antiviral response, particularly against herpesviruses. Despite their importance in the control of alphaherpesvirus infections, relatively little is known about the mechanisms that trigger NK cell cytotoxicity against alphaherpesvirus-infected cells. Here, using the porcine alphaherpesvirus pseudorabies virus (PRV), we report that the conserved alphaherpesvirus glycoprotein gB triggers NK cell-mediated cytotoxicity, both in virus-infected and gB-transfected cells. In addition, we report that gB expression results in increased cell surface binding of porcine paired immunoglobulin-like type 2 receptor β (PILRβ), an activating NK cell receptor. The interaction between PILRβ and viral gB may possibly have consequences that stretch beyond the interaction with NK cells, including virus entry in host cells. The identification of gB as an NK cell-activating viral protein may be of importance in the construction of future vaccines and therapeutics requiring optimized interactions of alphaherpesviruses with NK cells.

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De Pelsmaeker, Steffi / Dierick, Evelien / Klupp, Barbara / et al: Expression of the pseudorabies virus gB glycoprotein triggers NK cell cytotoxicity and increases binding of the activating NK cell receptor PILRbeta. 2019.

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