Modulation of host cell responses and evasion strategies for porcine reproductive and respiratory syndrome virus

Abstract

The immune surveillance system protects host cells from viral infection, and viruses have evolved to escape this system for efficient proliferation in the host. Host cells produce cytokines and chemokines in response to viral infection, and among such effector molecules, type I interferons are the principal antiviral cytokines and therefore effective targets for viruses to disarm host surveillance. Porcine reproductive and respiratory syndrome virus (PRRSV) expresses proteins that circumvent the IFN response and other cellular processes, and to compensate the small coding capacity of PRRSV, these proteins are multifunctional. To date, at least four viral proteins have been identified and studied as viral antagonists of host defenses: N as a structural protein and three non-structural proteins, Nsp1 (Nsp1α and Nsp1β), Nsp2, and Nsp11. Among these, N and Nsp1 are nuclear-cytoplasmic proteins distributed in both the nucleus and cytoplasm of cells. Nsp1 and Nsp2 are viral proteases while Nsp11 is an endoribonuclease. This review describes the current understanding of the role of these proteins in modulating the host innate immune responses. Blocking against virus-mediated inhibition of the innate response may lead to the future development of effective vaccines. The understanding of viral mechanisms modulating the normal cellular processes will be a key to the design of an effective control strategy for PRRS.

Fig. 1

Production of type I interferon via RIG-I dependent pathway and IFN-mdediated JAK-STAT signalling pathway. For explanation, see the text (adopted from Aaronson and Horvath, 2002, Bowie and Unterholzner, 2008, Sadler and Williams, 2008).

Fig. 3

Nuclear cytoplasmic distribution of N, Nsp1, and Nsp1α subunit of Nsp1. HeLa cells were gene-transfected and stained at 24 h with N-specific monoclonal antibody SDOW17 (top panel), or with anti-FLAG antibody for Nsp1 (middle panel) and Nsp1α proteins (bottom panel). Nuclear distribution is indicated by white or black arrows. The N protein in particular is distributed in the nucleolus (yellow arrows), in addition to the nucleus and cytoplasm.

Fig. 2

Processing of PRRSV Nsp1 protein and primary structure of Nsp1α and Nsp1β subunits of Nsp1. Numbers indicate amino acid positions. ZF1 represents the zinc-finger motif composed of C8–C10–C25–C28 in the N-terminal region, and ZF2 represents the second zinc-finger motif of C70–C76–C146–C180 in the C-terminal region of Nsp1α identified by X-ray cystallography (Sun et al., 2009b). Nsp1 is autocleaved internally at M180-A181 by PCPα to release Nsp1α, and Nsp1β is released from Nsp2 (not shown here) by PCPβ (arrows). PCPα and PCPβ motifs are indicated by black areas. C76 and H46 participate in both PCPα activity and ZF2 formation. Panel (B) represents the authentic structures of the Nsp1α and Nsp1β subunits used in our study (Sun et al., 2009b, Yoo et al., 2009). Panel (C) represents the structure of two subunits based on the previous prediction (den Boon et al., 1995), and panel (D) represents the constructs used in the study by Beura et al. (2010). ZF2 is destroyed in the Nsp1α constructs in (C) and (D) due to the loss of M180.