Porcine reproductive and respiratory syndrome virus nucleocapsid protein modulates interferon-β production by inhibiting IRF3 activation in immortalized porcine alveolar macrophages

Abstract

Porcine reproductive and respiratory syndrome virus (PRRSV) infection appears to elicit a weak innate immune response suppressing type 1 interferon (IFN) production. Recent studies have revealed that several nonstructural proteins encoded by the PRRSV genome independently antagonize the type 1 IFN system. The present study sought to identify the structural proteins that possess the immune evasion properties in immortalized porcine alveolar macrophages (PAM). Each structural protein gene was stably expressed in a porcine monocyte-derived macrophage cell line, PAM-pCD163, and tested for its potential to inhibit IFN-β induction. We then focused on the nucleocapsid (N) protein, which has a strong inhibitory effect on dsRNA-induced IFN-β production. Upon dsRNA stimulation, IFN-β production was shown to decrease proportionally with increasing levels of N expression. Furthermore, the PRRSV N protein was found to down-regulate IFN-dependent gene production by dsRNA. Taken together, these results indicate the ability of N to modulate the dsRNA-mediated IFN induction pathways. In addition, the N protein significantly interfered with dsRNA-induced phosphorylation and nuclear translocation of IRF3. Our data suggest that the PRRSV N protein is a responsible component, independent of other nonstructural elements, for evading the IFN response by antagonizing IRF3 activation.

The N-N non-covalent domain of the nucleocapsid protein of type 2 porcine reproductive and respiratory syndrome virus enhances induction of IL-10 expression

“…**Significant difference (P,0.01) between groups. The PRRSV N protein conveys immunomodulatory properties Sagong & Lee, 2011). In order to explore the relationships between the functional domains of the N protein and IL-10 expression, both truncants and mutants were constructed and transfected into cells, and IL-10 promoter activity was assessed.…”

HSV-2 Immediate-Early Protein US1 Inhibits IFN-β Production by Suppressing Association of IRF-3 with IFN-β Promoter

“…For example, viruses can bind directly to IRF-3 (17,18) or interact with CBP/p300 coactivator (19)(20)(21) to impair the type I IFN production. In general, some viruses cause the degradation of activated IRF-3 (22,23), whereas most viruses suppress the production of type I IFNs through inhibition of IRF-3 activation, including phosphorylation, dimerization, and nuclear translocation (24)(25)(26)(27)(28)(29)(30). Only a few viruses have been shown to interfere with the binding of activated IRF-3 to IFN-b promoter, resulting in the suppression of type I IFNs (31,32).…”

Immune Evasion Strategies of Pathogens in Macrophages: the Potential for Limiting Pathogen Transmission

“…PRRSV, the causation of PRRS characterized by the serious reproductive failure in pregnant sows and severe respiratory distress in piglets and growing pigs, can inhibit type I IFN expression, especially IFN-α and IFN-β (Sagong and Lee, 2011). Nonstructural protein 1 (NSP1) of PRRSV might be responsible for the inhibition through blocking of IRF3 nuclear translocation (Beura et al, 2010;Sagong and Lee, 2011).…”

“…PRRSV, the causation of PRRS characterized by the serious reproductive failure in pregnant sows and severe respiratory distress in piglets and growing pigs, can inhibit type I IFN expression, especially IFN-α and IFN-β (Sagong and Lee, 2011). Nonstructural protein 1 (NSP1) of PRRSV might be responsible for the inhibition through blocking of IRF3 nuclear translocation (Beura et al, 2010;Sagong and Lee, 2011). Additionally, vesicular stomatitis virus (VSV) infection induces the expression of miR-146a in macrophages, and then miR-146a can function as a negative-feedback regulator of the RLR pathway by targeting TRAF6 (Hou et al, 2009).…”

“…A typical example of such interaction is Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) that causes serious reproduction and respiratory problems in sows. PRRSV can inhibit the innate immune response by suppressing type I IFN expression (Sagong and Lee, 2011). Mycobacteria avium subsp.…”