Activating Fc Gamma Receptors and Viral Receptors Are Required for Antibody-Dependent Enhancement of Porcine Reproductive and Respiratory Syndrome Virus Infection

SIMPLE SUMMARY: Porcine reproductive and respiratory syndrome virus (PRRSV)-specific sub- or non-neutralizing antibodies promote the adhesion and internalization of the virion into host cells. This phenomenon is known as antibody-dependent enhancement (ADE) of PRRSV infection. It has long been accepted that Fc gamma receptors (FcγRs) are responsible for mediating ADE of virus infection. However, few researchers pay attention to the role of the virus receptors in the ADE of virus infection. In this study, we showed that activating FcγRs (FcγRI and FcγRIII) were responsible for mediating PRRSV-ADE infection. Simultaneously, we showed that the viral receptors (sialoadhesin and CD163) were involved in FcγR-mediated PRRSV-ADE infection. The extracellular domains 1-6 of sialoadhesin and the scavenger receptor cysteine-rich 5 domain of CD163 might play central roles in PRRSV-ADE infection. In conclusion, our studies indicated that activating FcγRs and virus receptors were required for PRRSV-ADE infection. Our findings should allow a more precise understanding of the structural basis for the mechanism of PRRSV-ADE infection, which would provide references for screening targets of novel PRRS vaccines or antiviral drugs against the PRRSV. ABSTRACT: Antibody-dependent enhancement (ADE) is an event in preexisting sub-, or non-neutralizing antibodies increasing the viral replication in its target cells. ADE is one crucial factor that intensifies porcine reproductive and respiratory syndrome virus (PRRSV) infection and results in PRRSV-persistent infection. Nevertheless, the exact mechanisms of PRRSV-ADE infection are poorly understood. In the current research, the results of the ADE assay showed that porcine immunoglobulin G (IgG) specific for the PRRSV significantly enhanced PRRSV proliferation in porcine alveolar macrophages (PAMs), suggesting that the ADE activity of PRRSV infection existed in pig anti-PRRSV IgG. The results of the RNA interference assay showed that knockdown of the Fc gamma receptor I (FcγRI) or FcγRIII gene significantly suppressed the ADE activity of PRRSV infection in PAMs, suggesting that FcγRI and FcγRIII were responsible for mediating PRRSV-ADE infection. In addition, the results of the antibody blocking assay showed that specific blocking of the Sn1, 2, 3, 4, 5, or 6 extracellular domain of the sialoadhesin (Sn) protein or selective blockade of the scavenger receptor cysteine-rich (SRCR) 5 domain of the CD163 molecule significantly repressed the ADE activity of PRRSV infection in PAMs, suggesting that Sn and CD163 were involved in FcγR-mediated PRRSV-ADE infection. The Sn1–6 domains of porcine Sn protein and the SRCR 5 domain of porcine CD163 molecule might play central roles in the ADE of PRRSV infection. In summary, our studies indicated that activating FcγRs (FcγRI and FcγRIII) and viral receptors (Sn and CD163) were required for ADE of PRRSV infection. Our findings provided a new insight into PRRSV infection that could be enhanced by FcγRs and PRRSV receptors-mediated PRRSV-antibody immune complexes (ICs), which would deepen our understanding of the mechanisms of PRRSV-persistent infection via the ADE pathway.