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

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.

Antibody-dependent enhancement of porcine reproductive and respiratory syndrome virus infection downregulates the levels of interferon-gamma/lambdas in porcine alveolar macrophages in vitro

“…The prolonged duration of viremia and the isolation of the virus from the tissues of piglets with low maternal antibodies ulteriorly provide evidence of in vivo PRRSV-ADE activity ( 13 ). In vitro , the enhanced replication of PRRSV in the presence of sub-neutralizing specific antibodies against PRRSV has also been confirmed ( 14 , 15 ). These studies show that ADE is likely to increase the severity of PRRS and the susceptibility to PRRSV in pigs with declining maternal antibodies for PRRSV or with low levels of specific antibodies induced by exposure to wild-type or vaccine virus strains.…”

Mucosal immune responses and protective efficacy elicited by oral administration AMP-ZnONPs-adjuvanted inactivated H9N2 virus in chickens

“…The HI titer can be used to assess the body's immune response to the H9N2 vaccine and provide a preliminary indication of the vaccine's protective effect ( Ali et al, 2017 ). IgG is part of the systemic immune system and is mainly found in body fluids ( Zhang et al, 2022 ). As shown in Figure 2 A, it can be observed that the serum HI antibody titers of the vaccine group and WIV+AMP-ZnONPs group in the 2 to 5 wk after the second immunization were significantly higher than those of the control group and WIV group.…”

Progress in PRRSV Infection and Adaptive Immune Response Mechanisms

“…A virus’s capacity to increase the infectivity of immune cells, such as macrophages, monocytes, and granulocytes, and to promote viral proliferation when specific Nabs are at sub-neutralizing levels or when nonspecific antibodies are present, is termed antibody-dependent enhancement (ADE). Immune cell surface receptors, mainly Fc receptors (Fc Rs), complement receptors (CRs), and β2-microglobulin, mediate the effects of ADE caused by viral infection [ 82 , 83 ].…”

“…The body produces antibodies quickly and for several months early in the infection when the antigenic epitopes of PRRSV structural proteins (e.g., GP5, M, and N) and nonstructural proteins (e.g., NSP1, NSP2, NSP4, and NSP7) are present; however, these antibodies are not connected to Nabs. Pigs produce quite a few of these non-neutralizing antibodies with high titers, which bind to the virus to form antibody complexes that mediate virus entrance into cells with the assistance of Fc Rs (primarily FcRI, FcRIIb, FcRIII, and FcεRI), greatly boosting PRRSV infectivity [ 83 , 84 , 85 , 86 ] ( Figure 2 ). When PRRSV-ADE affects a cell, it significantly increases the expression of mitochondrial respiratory chain complexes, interferes with antiviral protein function, the ubiquitin–proteasome system, and ribosome function, and changes the intrinsic immune function of PAMs by interfering with innate immune signaling and by impairing the transcription of associated transcription factors [ 87 , 88 ].…”