The viral innate immune antagonism and an alternative vaccine design for PRRS virus

Abstract

Porcine reproductive and respiratory syndrome (PRRS) remains one of the most economically significant diseases in the swine industry worldwide. The current vaccines are less satisfactory to confer protections from heterologous infections and long-term persistence, and the need for better vaccines are urgent. The immunological hallmarks in PRRSV-infected pigs include the unusually poor production of type I interferons (IFNs-α/β) and the aberrant and delayed adaptive immune responses, indicating that PRRSV has the ability to suppress both innate and adaptive immune responses in the host. Type I IFNs are the potent antiviral cytokines and recent studies reveal their pleiotropic functions in the priming of expansion and maturation of adaptive immunity. Thus, IFN antagonism-negative PRRSV is hypothesized to be attenuated and to build effective and broad- spectrum innate and adaptive immune responses in pigs. Such vaccines are promising alternatives to traditional vaccines for PRRSV.

Fig. 1

Pleiotropic roles of type I IFNs for regulation of adaptive immunity. Type I IFNs stimulate dendritic cells (DC), CD4+ T cells, CD8+ T cells, B cells, and NK cells (indicated in solid arrow lines). Type I IFNs also promote the cross-talk of DCs with NK cells and CD4+ T cells. The inter-connection of CD4+ T cells with CD8+ T cells and plasma B cells help the development of adaptive immunity (indicated in dotted arrow lines). Vertical arrows indicate positive regulation (↑) or negative regulation (↓) of cellular functions by type I IFNs. Numbers in parenthesis indicate relevant references. ‘(h)’ associated with references in the figure legend denotes the information derived for humans and ‘(m)’ denotes the information derived from murine models. (1) Ito et al., 2001 (h), (2) Montoya et al., 2002 (m), (3) Le Bon et al., 2003 (h), (4) Spadaro et al., 2012 (h), (5) Parlato et al., 2001 (h), (6) Rouzaut et al., 2010 (m), (7) Gautier et al., 2005 (h, m), (8) Cousens et al., 1997 (m), (9) Dauer et al., 2003 (m), (10) Lucas et al., 2007 (m), (11) Havenar-Daughton et al., 2006 (m), (12) Le Bon et al., 2006b (m), (13) Brinkmann et al., 1993 (m), (14) Le Bon et al., 2006a (m), (15) Pinto et al., 2011 (m), (16) Urban et al., 2016 (m), (17) Marshall et al., 2010 (m), (18) Jennings et al., 2014 (m), (19) Kolumam et al., 2005 (m), (20) Ramos et al., 2009 (m), (21) Thompson et al., 2006 (m), (22) Crouse et al., 2014 (m), (23) Xu et al., 2014 (m), (24) Curtsinger et al., 2005 (m), (25) Keppler et al., 2012 (m), (26) Chang et al., 2007 (m), (27) Coro et al., 2006 (m), (28) Rau et al., 2009 (m), (29) Heer et al., 2007 (m), (30) Bach et al., 2007 (m), (31) Fink et al., 2006 (m), (32) Purtha et al., 2008 (m), (33) Martinez et al., 2008 (m), (34) Lucas et al., 2007 (m), (35) Hu et al., 2014 (h), (36) Hwang et al., 2012 (m), (37) Madera et al., 2016(h).

Fig. 2

Functional motifs and domains identified in the nsp1α, nsp1β, nsp2, nsp4, nsp11, and N proteins of PRRSV. Amino acids are presented in single letters. Numbers indicate amino acid positions. ZF1, zinc finger domain of C8-C10-C25-C28; ZF2, zinc-finger domain of C70-C76-H146-M180; PLP1α, papain-like protease domain of C76-H146; PLP1β, papain-like protease domain of C90-H159; HV, hyper-variable region; TM, transmembrane domain; Cr, cysteine-rich domain; NLS, nuclear localization signal; NoLS, nucleolar localization signal; NendoU, nidovirus-specific endoribonuclease; C23 of N, residue for homodimerization; Vertical arrows indicate the cleavage sites specific for PLP1α of nsp1α, PLP1β of nsp1b, PLP2 of nsp2, and serine protease (SP) of nsp4.

Fig. 3

Coding strategy of the PRRSV genome and type I IFN viral antagonists encoded by PRRSV. Viral IFN antagonists are indicated in magenta for nsp1α, red for nsp1b, light green for nsp2, yellow for nsp11, and purple for N. Vertical arrows indicate the specific cleavage sites for polyprotein processing. Colors match with respective proteinases and cleavage sites. IFN antagonistic functions are illustrated for individual viral proteins. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)