Next Article in Journal
SARS-CoV-2 Inactivation in Aerosol by Means of Radiated Microwaves
Next Article in Special Issue
Recent Progress in Studies of Porcine Reproductive and Respiratory Syndrome Virus 1 in China
Previous Article in Journal
A Systematic Review on Cardiometabolic Risks and Perinatal Outcomes among Pregnant Women Living with HIV in the Era of Antiretroviral Therapy
Previous Article in Special Issue
Molnupiravir Inhibits Porcine Epidemic Diarrhea Virus Infection In Vitro
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Viruses
Volume 15
Issue 7
10.3390/v15071442
viruses-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Progress in PRRSV Infection and Adaptive Immune Response Mechanisms

by
Huanchang Cai
1,†,
Hewei Zhang
2,3,†,
Huai Cheng
1,
Min Liu
1,
Shubo Wen
4,* and
Jingqiang Ren
1,3,*
1
Wenzhou Key Laboratory for Virology and Immunology, Institute of Virology, Wenzhou University, Wenzhou 325035, China
2
College of Food and Drugs, Luoyang Polytechnic, Luoyang 471099, China
3
Animal Diseases and Public Health Engineering Research Center of Henan Province, Luoyang 471000, China
4
Preventive Veterinary Laboratory, College of Animal Science and Technology, Inner Mongolia Minzu University, Tongliao 028000, China
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Viruses 2023, 15(7), 1442; https://doi.org/10.3390/v15071442
Submission received: 2 June 2023 / Revised: 21 June 2023 / Accepted: 25 June 2023 / Published: 27 June 2023
(This article belongs to the Special Issue Porcine Viruses 2023)
Browse Figures
Versions Notes

Abstract

:
Since its discovery, Porcine reproductive and respiratory syndrome (PRRS) has had a huge impact on the farming industry. The virus that causes PRRS is Porcine Reproductive and Respiratory Syndrome Virus (PRRSV), and because of its genetic diversity and the complexity of the immune response, the eradication of PRRS has been a challenge. To provide scientific references for PRRSV control and vaccine development, this study describes the processes of PRRSV-induced infection and escape, as well as the host adaptive immune response to PRRSV. It also discusses the relationship between PRRSV and the adaptive immune response.

1. Introduction

Porcine reproductive and respiratory syndrome (PRRS), which initially appeared in the United States and Europe in the late 1980s, is a highly infectious disease with high contact and fatality rates. Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) was identified as the causative agent of PRRS through epidemiological analysis and Koch hypothesis studies of initial isolates from both locations [1,2]. A single-stranded, positive-stranded, non-segmented RNA virus with a capsid, PRRSV is a member of the genus Arterivirus and the family Arteriviridae of the order Nidovirales [3]. The interior nucleocapsid of the virus is around 25–30 nm in diameter with icosahedral symmetry, and the majority of the viral particles are spherical or oval, with a smooth appearance under the electron microscope [4]. According to genome sequencing results, PRRSV can be classified into PRRSV-I (European type, prototype strain Lelystad virus) and PRRSV-II (North American type, prototype strain VR-2332 virus) [5,6]. PRRSV-II is predominantly endemic in China, showing diverse pathogenicity, genetic variability, and periodic occurrence of severe disease phenotypes. However, in recent years, PRRSV-I has spread throughout central, northern, southern, eastern, northeastern, and southwestern China, with at least 22 provinces reporting high PRRSV-I prevalence. Epidemiological studies are now being conducted, and PRRSV-I strain surveillance is being increased [7,8,9].
Pigs are typically infected by PRRSV in their monocyte–macrophage system. Pulmonary alveolar macrophages (PAMs) and dendritic cells (DCs) are major members of the mononuclear phagocyte system that deliver antigens to T cells and release cytokines that regulate inflammation and the immunological responses that are crucial for the activation of adaptive immune responses [10,11]. PRRSV-infected hosts exhibit typical immunological characteristics, including persistent viremia, strong suppression of innate cytokines, delayed appearance of neutralizing antibodies, induction of non-neutralizing antibodies, and dysfunction of the natural killer (NK) cell population [12]. We reviewed the connection between PRRSV and the adaptive immune response and summarized PRRSV infection mechanisms, the host’s adaptive immune response to PRRSV, and PRRSV tactics to evade cellular and humoral immunity. For the convenience of readers, the following is a list of professional terms and abbreviations used in this article.

2. Mechanism of PRRSV Infection

The only natural hosts for PRRSV are pigs. As soon as the PRRSV glycoprotein binds to the sialic acid adhesins on porcine macrophages, clathrin-dependent endocytosis is triggered, allowing the virus to enter the cell and initiate transcription, assembly, and release. The body will respond with an immunological reaction when the virus proliferates and releases into the internal environment. However, PRRSV’s immunological escape strategy causes tissue lesions and inflammation, which have a significant negative impact on pigs of all ages. For sows in late gestation, it causes reproductive failure, which is characterized by premature stillbirths, partially autolyzed fetuses, and mummified fetuses. Infected weak newborn piglets will not survive to weaning. Moreover, PRRSV causes respiratory disease in young and growing pigs, resulting in secondary bacterial and viral infections, slow growth, and, in severe cases, death [13].

2.1. PRRSV Infection and Receptor Proteins

PRRSV infection has strict cell and tissue tropism [14], and in addition to PAMs, PRRSV can proliferate in many cell types, such as porcine testicular spermatogenic cells and respiratory epithelial cells, a property associated with specific receptor proteins during PRRSV infection. The main receptors identified so far include the cysteine-rich scavenger receptor (CD163), sialoadhesin (Sn or CD169), heparin sulfate (HS), vimentin, cluster of differentiation 151 (CD151), non-muscle myosin heavy chain 9 (MYH9), heat shock protein member 8 (HSPA8), T-cell immunoglobulin and mucin structural domain (TIM), and dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN or CD209) [15,16].
PRRSV primarily enters cells by receptor-mediated endocytosis, and a key step in this process is the binding of several structural and non-structural proteins to the receptor. To boost viral particle adherence and internalization, the glycoprotein 5 (GP5)/membrane protein (M) heterodimer interacts with HS and the N-terminal structural domains of sialoadhesin, which is facilitated by GP4 binding to HSPA8 [17]. In addition to playing the role of a chaperone, HSPA8 also drives clathrin-mediated endocytosis (CME) and decouples lattice proteins from the vesicle membrane [18]. MYH9 serves as a crucial cofactor in this process, connecting with the CD163 scavenger receptor cysteine-rich (SRCR)1-4 structural domain through its C-terminus to facilitate the internalization of PRRSV [19,20]. CD163 interacts with GP2a/GP3/GP4 to allow host cell penetration through low pH-dependent CME [16,21,22]. PRRSV’s cytoplasmic trafficking and replication are aided by the binding of waveform proteins to other cytoskeleton proteins [23,24]. In addition, PRRSV was found to use viral apoptosis mimicry to invade host cells as an alternative route of infection, in which the virus mimics apoptosis by acquiring phosphatidylserine (PS) on the host surface and exposing it to its own vesicle membrane. It uses this viral apoptosis mimicry as a phagocytic signal to enter cells through TIM induction and macropinocytosis involving CD163 [25]. The specific process is shown in Figure 1.
However, there may be some differences in the utilization of receptor molecules by PRRSV-I and PRRSV-II. CD163 is one of the important receptor molecules for PRRSV entry into host cells, and the deletion of the Marc145 CD163 SRCR5 structural domain caused the American type PRRSV virus to lose its infectivity to Marc145 cells [26]. CD163 knockout pigs with complete deletion of the CD163 gene were not susceptible to either European or American PRRSV, and gene-edited pigs maintained susceptibility to American PRRSV but not to European strains after partial deletion of the CD163 region (SRCR domain 5 deletion) or replacement of CD163 SRCR domain 5 with human CD163 SRCR domain 8 [27,28], possibly because Lys-58 replacing Glu-58 reduces PRRSV-I infectivity [29].
It can be deduced that PRRSV-I is species-specific for the CD163 receptor given issues of insensitivity to Marc145 cells during the isolation of the PRRSV-I virus and the difficulty of culturing. The issue of the European type PRRSV’s insensitivity to Marc145 during production or in the clinic might be resolved if the PAM cell-derived CD163 (PAM-CD163) molecule is persistently produced in Marc145 cells, which are epithelial cells generated from monkey kidneys. These newly created cell lines are acceptable for European and American type PRRSV culture, as demonstrated by the stable expression of the PAM-CD163 molecule in CRL-2843 cells [30].
The best option for PRRSV-I passaging cultures might be a cell line expressing two or more PRRSV receptor molecules, because some virus strains, such as some NADC30-like and NADC34-like strains of PRRSV-II, are not sensitive to Marc145 cells, while others can adapt to successive passages in the same type of cell. Studies have shown that PRRSV-I is more susceptible to CD163+ Sn+ cells [31], and that PK15 cells can maintain larger infection titers of PRRSV-I via stable expression of the sialic acid binding Ig, such as lectin 1 (Siglec1) and CD163 receptors [32].

2.2. Persistent Infection

Persistent infection is an important feature of Arterivirus, as demonstrated in lactate dehydrogenase elevated virus (LDV) and equine arteritis virus (EAV) infections. Even if the infected pigs are asymptomatic or only exhibit minor symptoms, PRRSV can linger in the body for months or even longer and still cause infection in susceptible pigs when it is regularly, repeatedly, or intermittently discharged into the environment [33]. Acute infection, persistent infection, and disappearance are the three main stages of PRRSV infection. Susceptible pigs are not reinfected when placed in a herd containing infected pigs that were confined for more than 200 days [34,35]. PRRSV can be treated in large, infected herds through confinement management, and it can finally be removed by the immune system of pigs. However, it was hypothesized that PRRSV causes a “lifelong” infection in pigs because of their usual 250-day feeding cycle [13]. Consequently, one of the main causes of the difficulty of PRRSV elimination is prolonged infection.
When pigs become infected, the nascent virus must be assembled, released from the cell, and moved to one or more susceptible cells to continue infecting cells. Intercellular transfer of the virus is subject to multiple inhibitors and effects, including blockage by the immune system, an in vivo environment not conducive to virus survival, and necrosis and apoptosis of infected cells, all of which lead to a progressive reduction in the success of intercellular transfer and eventual elimination of PRRSV [36]. However, it was found that PRRSV was rescued from apoptosis and necrosis by transporting infectious viral RNA, certain replicative enzymes, and certain structural proteins to neighboring cells via intercellular tunneling nanotubes (TNTs), which might be an alternative route for PRRSV transmission between cells [37,38].
The current PRRSV vaccine can only reduce the viral load or duration of infection to treat viremia and slow down clinical lesions after PRRSV infection because of an impaired innate immune response, a weak adaptive immune response, and PRRSV escape mechanisms [39,40,41]. The vaccine cannot completely prevent viral infection, eliminate viremia, produce broad strain protection, or block viral transmission in vivo or in vitro. Additionally, EVA, LDV, and Simian hemorrhagic fever virus (SHFV), which are also arteritis viruses, are selected for lower virulence and immunogenicity during the persistent infection phase, in contrast to stable and highly virulent mutations during the acute infection phase of the virus, which will cause the virus to evolve and generate multiple immune escape mechanisms [42].

3. PRRSV and the Adaptive Immune Response

3.1. Cellular Immunity

3.1.1. Cellular Immune Response of the Host

Despite having an impact on the thymus and bone marrow, PRRSV infection does not significantly impair lymphocyte differentiation or maturation or cause severe lymphocyte failure or ablation, indicating that the host’s adaptive immune response is not compromised [43,44]. The adaptive immune response includes T cell-mediated cellular immunity (CMI) and humoral immunity (HI), with specific antibody production by effector B cells. Inflammatory responses, dendritic cells, monocytes, and neutrophil marker gene expression levels were shown to be elevated by PRRSV infection using gene set enrichment analysis, while T cells, B cells, and NK cell-related gene markers were downregulated [45].
T cells are essential to the development and control of antigen-specific immune responses, including the induction and activation of B cells, the selection of cytokines and cytotoxic effector functions in the antigen-presenting environment, and the regulation of the immune response [46]. In contrast, B cells are not only crucial to the immune response, but also to immune system maintenance, and they have the capacity to produce cytokines. The activation and growth of particular CD4+ cells induced by B and T cells are crucial aspects of the immune response.
According to a recent study, CD69 strongly stimulates CD4+ T cells in the lymph and CD8+ T cells in the spleen at 14 days after PRRSV infection [47]. Th1 cells, cytotoxic T lymphocytes (CTLs), T-cell receptor-γδT (TCR-γδT) cells, and regulatory T cells (Tregs) show higher polarization in the cellular immune response [48]. Among them, the CTL response is highest in the lungs’ infected regions and in bronchoalveolar lavage [49]. Moreover, CTLs can also improve the placental barrier to PRRSV-1 infection [50]. Helper T cells (Th) are the main responders during viremia and are linked to viremia remission, whereas γδT cells are the main responders following viremia and are essential for the anti-PRRSV response in the lymphatic system [49].

3.1.2. Mechanism of PRRSV in Anti-Cellular Immunity

Through a variety of methods, PRRSV infection can impair healthy thymic function and control immunological responses, lowering or modifying T cell development, delaying and weakening adaptive immune responses, and disrupting cytokine responses [43]. After PRRSV infection of PAMs, it is thought that NK cells in the innate system might also exert adaptive immune response capabilities, dramatically reducing virus vulnerability to NK cell toxicity [51,52].
Previous studies used interferon gamma (IFN-γ) enzyme-linked immunosorbent spot assays (ELISPOT) and immunostaining to detect the cellular response during the infection phase. The results were compared to the local distribution and abundance of PRRSV in the infected tissues, and the infected site’s T cell phenotype was identified. It was discovered that there was a local CMI reaction in both acute and chronic infections, and that γδT cells considerably decreased, particularly in the lungs and lymph nodes. PRRSV impairs T cell identification of infected macrophages, compromising CMI and extending PRRSV infection [53]. In addition, Treg cells are induced to multiply and produce a significant amount of the inhibitory cytokine interleukin 10 (IL-10) in the lungs of infected pigs under any infection state, and interleukin-1 receptor antagonist (IL-1Ra) is involved in immunosuppression, affecting the induced Treg cells in conjunction with IL-10 [54,55]. Furthermore, immunological negative regulatory factors and immune checkpoint molecules (including programmed cell death 1 ligand 1 (PD-L1), PD-L2, IL-10, and transforming growth factor beta 2 (TGFB2)) are elevated as a result of PRRSV infection in a virus-dependent manner [56]. The host’s adaptive immune response is negatively regulated by this overexpression, which also impacts T cell growth, maturation, and selection [57]. One example is the imbalance between co-stimulatory and co-inhibitory immunological checkpoint markers in relation to lung lesions following PRRSV-1 infection [58].

3.1.3. Cellular Immunity and Vaccine Development

Early research suggested that viral matrix peptides might be important for cellular immunity, and several PRRSV proteins, including M, nucleocapsid (N), GP3, GP4, GP5, nonstructural protein (NSP)2, NSP5, and NSP9, have been found to contain T-cell epitopes [59,60]. Meanwhile, researchers have discovered a variety of pertinent peptides, such as those from GP3 and NSP9, by developing T cell-based vaccines using CTL epitopes [61,62,63,64]. They have further identified PRRSV-interacting epitopes from a class 1 major histocompatibility complex (MHC-1) perspective, and they have noted that NSPs are a major source of MHC-I presenting peptides and that the identified epitopes trigger IFN-γ responses in vitro [65].
Currently, researchers are evaluating cellular immune responses or using key factors in the cellular immune response to design novel vaccines that enhance the immune response, as summarized in Table 1.
In conclusion, while PRRSV infection impairs cellular immunity, the immune response’s cellular epitopes can be enhanced through vaccination by combining modified live viruses (MLVs) with an array of vaccine delivery methods. However, the discovery of effective strategies to suppress the escape mechanisms of PRRSV against cellular immunity would be facilitated by further identification of T and B cell epitopes and in-depth research into the processes of PRRSV evasion against NK cells.

3.2. Humoral Immunity

Weak neutralizing antibody responses, delayed responses, and the development of significant numbers of non-neutralizing antibodies are the main ways by which PRRSV impacts host humoral immunity [72]. It takes 7–9 days for PRRSV to stimulate the body to produce antibodies; however, these antibodies are not protective and even aggravate the infection, while neutralizing antibodies (Nabs) are not present until 28 days post-infection (dpi) [46].

3.2.1. Delayed Production of Neutralizing Antibodies

Passive transfer of PRRSV Nabs to a sow can prevent gestational reproductive failure and confer immunity to the sow and her offspring. High titers of PRRSV Nabs can protect weaned piglets and reduce viremia and virus transmission, and passive immunization produces neutralizing antibodies for prophylactic protection and homologous protection [73,74]. However, PRRSV infection typically results in a poor and delayed Nab response in pigs. This response is controlled by a variety of parameters, most notably the impact on B cell maturation, non-neutralizing antibody interference, and glycan shielding. Follicular helper T cells (Tfh) signal antibody affinity maturation to B cells and encourage the antiviral effects of IgG2a/c subclasses during infection; however, in the case of PRRSV infection, thymic function is compromised and signal transmission between Tfh and B cells is decreased, delaying the emergence of high-affinity PRRSV Nabs [43,75]. The B-cell antigenic epitopes in the PRRSV structural protein GP5 comprise non-neutralizing epitope A and neutralizing epitope B. At the start of the PRRSV infection, epitope A yields a substantial number of non-neutralizing antibodies while inhibiting the ability of epitope B to trigger the generation of Nabs [76,77]. Furthermore, the extracellular domain of GP5 and the N-glycan of GP3 can prevent the virus from being neutralized by antibodies and reduce the immunogenicity of the neutralizing epitope [78,79,80,81].

3.2.2. Non-Neutralizing Antibodies and ADE

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]. The effects of Fc receptor CD16-mediated ADE boost viral infection, suggesting that it might be possible to make PRRSV infect CD16-expressing cells and spread to more organs [89].
However, the relationship between ADE and PRRSV infection in vivo is debatable. Following attenuated vaccination and PRRSV attack, severe sickness after attack has not been shown in immunized animals, and no elevation of infection has been observed [39,74,90]. The link between ADE and PRRSV could be the main focus when it comes to the reproduction of this immunization phenomenon under conditions of more severe clinical illness in pigs [91].

3.2.3. The Virucidal Effect of Non-Neutralizing Antibodies

Non-neutralizing antibodies are generally used to identify or assess whether an animal has been exposed to, or infected with, the virus. As discussed before, PRRSV infection can induce substantial numbers of active non-neutralizing antibodies. Although many of the structural and nonstructural proteins of PRRSV can cause potent humoral immune reactions, the majority of antibodies are unable to neutralize the virus. Recent research has demonstrated that active non-neutralizing antibodies might have a greater effect on the immune response than previously thought. For example, antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent complement-mediated cytotoxicity (CDC), and antibody-dependent cellular phagocytosis (ADCP) all contribute to virus infection or virus clearance in animals. In the process of viral infection, or in the removal of viruses from animals, CDC and ADCP play crucial roles. Studies on the effects of antibodies on pathogens, such as the Ebola virus (EBOV), HIV, and influenza viruses, are currently being conducted. Examples include porcine lgG subclasses that activate CDC, ADCC, and ADCP to protect against H1N1 infection [92], and non-neutralizing or weakly neutralizing antibodies that can neutralize EBOV via ADCP and ADCC [93].
Innate effector cells, primarily NK cells, identify non-neutralizing antibody–viral protein immune complexes on infected cells via FcRs and release cytotoxic factors (including perforin and granzyme) that kill virally infected cells, thus causing ADCC. Through ADCC, NK cells kill infected cells in HIV invasion-susceptible cells and prevent viral replication [94,95]. In addition, genetic variations of the NK cell receptor, FcRIIIa, impact the particular ADCC response to SARS-CoV-2 [96]. Although no studies utilizing ADCC to suppress PRRSV infection have been reported, it is possible that the immune escape mechanism of PRRSV makes innate effector cells, such as NKs, less sensitive, allowing them to evade the ADCC effect. Additional research should be carried out to observe the ADCC response to PRRSV infection.
Through the activation of the complement cascade response, CDC causes inflammation to lyse-infected cells [97]. The ability of PRSSV-specific non-neutralizing active antibodies to wipe out the virus in alveolar macrophages was validated using PRSSV-infected pig alveolar macrophages [98]; however, the precise mechanism of action remains unknown.
Pathogens can also be eliminated by ADCP in addition to ADCC and CDC. In ADCP, FcRs on the surface of macrophages are activated by antibody-conditioned target cells to cause phagocytosis, which internalizes and destroys viral particles. By causing ADCP to swallow viral particles, recombinant cytomegalovirus viral glycoprotein B (gB) vaccination protected against HCMV infection [99,100]. However, ADCP is not currently involved in PRRSV immunological research, which might be related to PRRSV’s predilection for macrophages.

4. Conclusions

Porcine reproductive and respiratory syndrome (PRRS) has been a severe veterinary disease of significant economic significance for more than three decades, and it is a highly contagious disease affecting the pig business globally. The current commercial vaccine offers only modest protection for pigs, and specific therapeutic drugs have not yet reached their full potential, making the prevention, control, and eradication of PRRS difficult. The enormous genetic diversity of PRRSV, the induction of persistent infection, the inhibition of the host immune response, and the evasion of innate and adaptive immunity have impeded vaccine development and the development of effective drugs.
Massive replication, shedding, and ongoing transmission of PRRSV in the host are caused by the tardy response of the protective cellular and humoral immunity. Virus removal occurs in the late stages of infection after the production of neutralizing antibodies and cellular immunity to kill virus-infected cells. Therefore, ongoing research on the mechanisms by which PRRSV evades cellular and humoral immunity, the targets of virus–T cell action, the relationship between T cells and the delayed production of neutralizing antibodies, and the protective role of non-neutralizing antibodies could help to clarify these mechanisms and aid in the development of highly protective vaccines.

Author Contributions

J.R., H.C. (Huanchang Cai) and S.W. contributed to the study’s conception, the research design, and manuscript writing. H.Z., J.R., H.C. (Huai Cheng), M.L. and H.C. (Huanchang Cai) performed data curation and analysis. H.Z., S.W. and J.R. supervised this study and contributed to manuscript revision and funding acquisition. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Youth Growth Technology Project of Jilin Provincial Science and Technology Development Program (No. 20210508019RQ) and the Core Technical Public Welfare Project of Luoyang, China (No. 2202034A).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

We thank Yanyan Liang for her assistance with the preparation of this manuscript.

Conflicts of Interest

The authors declare that there is no conflict of interest regarding the publication of this paper.

Abbreviations

The following abbreviations are used in this manuscript:
GPGlycoprotein
GP2aGlycoprotein 2a
GP3Glycoprotein 3
GP4Glycoprotein 4
GP5Glycoprotein 5
MMembrane protein
NNucleocapsid
GP5/M heterodimerGlycoprotein 5/Membrane protein heterodimer
NSPNonstructural protein
NSP2Nonstructural protein 2
NSP5Nonstructural protein 5
NSP9Nonstructural protein 9
PAMsPulmonary alveolar macrophages
CD163Cysteine-rich scavenger receptor
PAM-CD163PAM cell-derived CD163
Sn or CD169Sialoadhesin
CD163+ Sn+ cellsexist CD163 and Sn cells
DCsDendritic cells
NKNatural killer
HSHeparin sulfate
CD151Cluster of differentiation 151
MYH9Non-muscle myosin heavy chain 9
HSPA8Heat shock protein member 8
CMEClathrin-mediated endocytosis
TIMT-cell immunoglobulin mucin structural domain
PSPhosphatidylserine
SRCRScavenger receptor cysteine-rich
DC-SIGN or CD209Dendritic cell-specific intercellular adhesion mole-Cule-3-grabbing non-integrin
Marc145Epithelial cells generated from monkey kidney
NabsNeutralizing antibodies
TfhFollicular helper T cells
ADEAntibody-dependent enhancement
Fc RsImmune cell surface receptors, mainly Fc receptors
CRsComplement receptors
ADCCAntibody-dependent cell-mediated cytotoxicity
CDCAntibody-dependent complement-mediated cytotoxicity
ADCPAntibody-dependent cellular phagocytosis

References

  1. Wensvoort, G.; Terpstra, C.; Pol, J.M.; ter Laak, E.A.; Bloemraad, M.; de Kluyver, E.P.; Kragten, C.; van Buiten, L.; den Besten, A.; Wagenaar, F.; et al. Mystery swine disease in The Netherlands: The isolation of Lelystad virus. Vet. Q. 1991, 13, 121–130. [Google Scholar] [CrossRef]
  2. Collins, J.E.; Benfield, D.A.; Christianson, W.T.; Harris, L.; Hennings, J.C.; Shaw, D.P.; Goyal, S.M.; McCullough, S.; Morrison, R.B.; Joo, H.S.; et al. Isolation of swine infertility and respiratory syndrome virus (isolate ATCC VR-2332) in North America and experimental reproduction of the disease in gnotobiotic pigs. J. Vet. Diagn. Investig. 1992, 4, 117–126. [Google Scholar] [CrossRef]
  3. Ruedas-Torres, I.; Rodríguez-Gómez, I.M.; Sánchez-Carvajal, J.M.; Larenas-Muñoz, F.; Pallarés, F.J.; Carrasco, L.; Gómez-Laguna, J. The jigsaw of PRRSV virulence. Vet. Microbiol. 2021, 260, 109168. [Google Scholar] [CrossRef] [PubMed]
  4. Dokland, T. The structural biology of PRRSV. Virus Res. 2010, 154, 86–97. [Google Scholar] [CrossRef]
  5. Nelson, E.A.; Christopher-Hennings, J.; Drew, T.; Wensvoort, G.; Collins, J.E.; Benfield, D.A. Differentiation of U.S. and European isolates of porcine reproductive and respiratory syndrome virus by monoclonal antibodies. J. Clin. Microbiol. 1993, 31, 3184–3189. [Google Scholar] [CrossRef] [Green Version]
  6. Yu, F.; Yan, Y.; Shi, M.; Liu, H.Z.; Zhang, H.L.; Yang, Y.B.; Huang, X.Y.; Gauger, P.C.; Zhang, J.; Zhang, Y.H.; et al. Phylogenetics, Genomic Recombination, and NSP2 Polymorphic Patterns of Porcine Reproductive and Respiratory Syndrome Virus in China and the United States in 2014–2018. J. Virol. 2020, 94, e01813-19. [Google Scholar] [CrossRef] [PubMed]
  7. Li, C.; Xu, H.; Zhao, J.; Gong, B.; Sun, Q.; Xiang, L.; Li, W.; Guo, Z.; Li, J.; Tang, Y.D.; et al. Epidemiological investigation and genetic evolutionary analysis of PRRSV-1 on a pig farm in China. Front. Microbiol. 2022, 13, 1067173. [Google Scholar] [CrossRef]
  8. Yu, F.; Liu, L.; Tian, X.; Chen, L.; Huang, X.; Sun, Y.; Yan, Y.; Tian, Z.; Cai, X.; Liu, D.; et al. Genomic Analysis of Porcine Reproductive and Respiratory Syndrome Virus 1 Revealed Extensive Recombination and Potential Introduction Events in China. Vet. Sci. 2022, 9, 450. [Google Scholar] [CrossRef] [PubMed]
  9. Zhao, J.; Xu, Z.; Xu, T.; Zhou, Y.; Li, J.; Deng, H.; Li, F.; Xu, L.; Sun, X.; Zhu, L. Molecular Characterization of the Nsp2 and ORF5s of PRRSV Strains in Sichuan China during 2012–2020. Animals 2022, 12, 3309. [Google Scholar] [CrossRef]
  10. Hume, D.A. Macrophages as APC and the dendritic cell myth. J. Immunol. 2008, 181, 5829–5835. [Google Scholar] [CrossRef] [Green Version]
  11. Murtaugh, M.P.; Genzow, M. Immunological solutions for treatment and prevention of porcine reproductive and respiratory syndrome (PRRS). Vaccine 2011, 29, 8192–8204. [Google Scholar] [CrossRef] [PubMed]
  12. Du, T.; Nan, Y.; Xiao, S.; Zhao, Q.; Zhou, E.M. Antiviral Strategies against PRRSV Infection. Trends Microbiol. 2017, 25, 968–979. [Google Scholar] [CrossRef] [PubMed]
  13. Lunney, J.K.; Fang, Y.; Ladinig, A.; Chen, N.; Li, Y.; Rowland, B.; Renukaradhya, G.J. Porcine Reproductive and Respiratory Syndrome Virus (PRRSV): Pathogenesis and Interaction with the Immune System. Annu. Rev. Anim. Biosci. 2016, 4, 129–154. [Google Scholar] [CrossRef] [PubMed]
  14. Rowland, R.R.; Lawson, S.; Rossow, K.; Benfield, D.A. Lymphoid tissue tropism of porcine reproductive and respiratory syndrome virus replication during persistent infection of pigs originally exposed to virus in utero. Vet. Microbiol. 2003, 96, 219–235. [Google Scholar] [CrossRef]
  15. Ye, N.; Wang, B.; Feng, W.; Tang, D.; Zeng, Z. PRRS virus receptors and an alternative pathway for viral invasion. Virus. Res. 2022, 320, 198885. [Google Scholar] [CrossRef] [PubMed]
  16. Zhang, H.; Sha, H.; Qin, L.; Wang, N.; Kong, W.; Huang, L.; Zhao, M. Research Progress in Porcine Reproductive and Respiratory Syndrome Virus-Host Protein Interactions. Animals 2022, 12, 1381. [Google Scholar] [CrossRef]
  17. Liu, Y.; Li, R.; Chen, X.X.; Zhi, Y.; Deng, R.; Zhou, E.M.; Qiao, S.; Zhang, G. Nonmuscle Myosin Heavy Chain IIA Recognizes Sialic Acids on Sialylated RNA Viruses to Suppress Proinflammatory Responses via the DAP12-Syk Pathway. mBio 2019, 10, e00574-19. [Google Scholar] [CrossRef] [Green Version]
  18. Wang, L.; Li, R.; Geng, R.; Zhang, L.; Chen, X.X.; Qiao, S.; Zhang, G. Heat Shock Protein Member 8 (HSPA8) Is Involved in Porcine Reproductive and Respiratory Syndrome Virus Attachment and Internalization. Microbiol. Spectr. 2022, 10, e0186021. [Google Scholar] [CrossRef]
  19. Li, L.; Sun, W.; Hu, Q.; Wang, T.; Zhu, G.; Zhao, Q.; Zhou, E.M. Identification of MYH9 Key Domain Involved in the Entry of PRRSV Into Permissive Cells. Front. Microbiol. 2022, 13, 865343. [Google Scholar] [CrossRef]
  20. Hou, G.; Xue, B.; Li, L.; Nan, Y.; Zhang, L.; Li, K.; Zhao, Q.; Hiscox, J.A.; Stewart, J.P.; Wu, C.; et al. Direct Interaction Between CD163 N-Terminal Domain and MYH9 C-Terminal Domain Contributes to Porcine Reproductive and Respiratory Syndrome Virus Internalization by Permissive Cells. Front. Microbiol. 2019, 10, 1815. [Google Scholar] [CrossRef] [Green Version]
  21. Van Breedam, W.; Van Gorp, H.; Zhang, J.Q.; Crocker, P.R.; Delputte, P.L.; Nauwynck, H.J. The M/GP(5) glycoprotein complex of porcine reproductive and respiratory syndrome virus binds the sialoadhesin receptor in a sialic acid-dependent manner. PLoS Pathog. 2010, 6, e1000730. [Google Scholar] [CrossRef] [Green Version]
  22. Das, P.B.; Dinh, P.X.; Ansari, I.H.; de Lima, M.; Osorio, F.A.; Pattnaik, A.K. The minor envelope glycoproteins GP2a and GP4 of porcine reproductive and respiratory syndrome virus interact with the receptor CD163. J. Virol. 2010, 84, 1731–1740. [Google Scholar] [CrossRef] [Green Version]
  23. Kim, J.K.; Fahad, A.M.; Shanmukhappa, K.; Kapil, S. Defining the cellular target(s) of porcine reproductive and respiratory syndrome virus blocking monoclonal antibody 7G10. J. Virol. 2006, 80, 689–696. [Google Scholar] [CrossRef] [Green Version]
  24. Zheng, X.X.; Li, R.; Qiao, S.; Chen, X.X.; Zhang, L.; Lu, Q.; Xing, G.; Zhou, E.M.; Zhang, G. Vimentin rearrangement by phosphorylation is beneficial for porcine reproductive and respiratory syndrome virus replication in vitro. Vet. Microbiol. 2021, 259, 109133. [Google Scholar] [CrossRef]
  25. Wei, X.; Li, R.; Qiao, S.; Chen, X.X.; Xing, G.; Zhang, G. Porcine Reproductive and Respiratory Syndrome Virus Utilizes Viral Apoptotic Mimicry as an Alternative Pathway to Infect Host Cells. J. Virol. 2020, 94, e00709-20. [Google Scholar] [CrossRef] [PubMed]
  26. Yu, P.; Wei, R.; Dong, W.; Zhu, Z.; Zhang, X.; Chen, Y.; Liu, X.; Guo, C. CD163(ΔSRCR5) MARC-145 Cells Resist PRRSV-2 Infection via Inhibiting Virus Uncoating, Which Requires the Interaction of CD163 with Calpain 1. Front. Microbiol. 2019, 10, 3115. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  27. Wells, K.D.; Bardot, R.; Whitworth, K.M.; Trible, B.R.; Fang, Y.; Mileham, A.; Kerrigan, M.A.; Samuel, M.S.; Prather, R.S.; Rowland, R.R.R. Replacement of Porcine CD163 Scavenger Receptor Cysteine-Rich Domain 5 with a CD163-Like Homolog Confers Resistance of Pigs to Genotype 1 but Not Genotype 2 Porcine Reproductive and Respiratory Syndrome Virus. J. Virol. 2017, 91, e01521-16. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  28. Burkard, C.; Opriessnig, T.; Mileham, A.J.; Stadejek, T.; Ait-Ali, T.; Lillico, S.G.; Whitelaw, C.B.A.; Archibald, A.L. Pigs Lacking the Scavenger Receptor Cysteine-Rich Domain 5 of CD163 Are Resistant to Porcine Reproductive and Respiratory Syndrome Virus 1 Infection. J. Virol. 2018, 92, JVI.00415-18. [Google Scholar] [CrossRef] [Green Version]
  29. Stoian, A.M.M.; Rowland, R.R.R.; Brandariz-Nuñez, A. Mutations within scavenger receptor cysteine-rich (SRCR) protein domain 5 of porcine CD163 involved in infection with porcine reproductive and respiratory syndrome virus (PRRS). J. Gen. Virol. 2022, 103, 001740. [Google Scholar] [CrossRef]
  30. Lee, Y.J.; Park, C.K.; Nam, E.; Kim, S.H.; Lee, O.S.; Lee, D.S.; Lee, C. Generation of a porcine alveolar macrophage cell line for the growth of porcine reproductive and respiratory syndrome virus. J. Virol. Methods 2010, 163, 410–415. [Google Scholar] [CrossRef]
  31. Frydas, I.S.; Nauwynck, H.J. Replication characteristics of eight virulent and two attenuated genotype 1 and 2 porcine reproductive and respiratory syndrome virus (PRRSV) strains in nasal mucosa explants. Vet. Microbiol. 2016, 182, 156–162. [Google Scholar] [CrossRef] [PubMed]
  32. Wang, K.; Yu, A.; Liu, K.; Feng, C.; Hou, Y.; Chen, J.; Ma, S.; Huang, L.; Dai, X. Nano-LYTACs for Degradation of Membrane Proteins and Inhibition of CD24/Siglec-10 Signaling Pathway. Adv. Sci. 2023, 10, e2300288. [Google Scholar] [CrossRef] [PubMed]
  33. Wills, R.W.; Zimmerman, J.J.; Yoon, K.J.; Swenson, S.L.; McGinley, M.J.; Hill, H.T.; Platt, K.B.; Christopher-Hennings, J.; Nelson, E.A. Porcine reproductive and respiratory syndrome virus: A persistent infection. Vet. Microbiol. 1997, 55, 231–240. [Google Scholar] [CrossRef]
  34. Rowland, R.R.; Morrison, R.B. Challenges and opportunities for the control and elimination of porcine reproductive and respiratory syndrome virus. Transbound Emerg. Dis. 2012, 59 (Suppl. 1), 55–59. [Google Scholar] [CrossRef] [PubMed]
  35. Pertich, A.; Barna, Z.; Makai, O.; Farkas, J.; Molnár, T.; Bálint, Á.; Szabó, I.; Albert, M. Elimination of porcine reproductive and respiratory syndrome virus infection using an inactivated vaccine in combination with a roll-over method in a Hungarian large-scale pig herd. Acta Vet. Scand. 2022, 64, 12. [Google Scholar] [CrossRef] [PubMed]
  36. Cifuentes-Munoz, N.; El Najjar, F.; Dutch, R.E. Viral cell-to-cell spread: Conventional and non-conventional ways. Adv. Virus Res. 2020, 108, 85–125. [Google Scholar] [CrossRef]
  37. Guo, R.; Davis, D.; Fang, Y. Intercellular transfer of mitochondria rescues virus-induced cell death but facilitates cell-to-cell spreading of porcine reproductive and respiratory syndrome virus. Virology 2018, 517, 122–134. [Google Scholar] [CrossRef]
  38. Guo, R.; Katz, B.B.; Tomich, J.M.; Gallagher, T.; Fang, Y. Porcine Reproductive and Respiratory Syndrome Virus Utilizes Nanotubes for Intercellular Spread. J. Virol. 2016, 90, 5163–5175. [Google Scholar] [CrossRef] [Green Version]
  39. Chen, X.X.; Zhou, X.; Guo, T.; Qiao, S.; Guo, Z.; Li, R.; Jin, Q.; Hu, X.; Xing, G.; Deng, R.; et al. Efficacy of a live attenuated highly pathogenic PRRSV vaccine against a NADC30-like strain challenge: Implications for ADE of PRRSV. BMC Vet. Res. 2021, 17, 260. [Google Scholar] [CrossRef]
  40. Madapong, A.; Saeng-Chuto, K.; Chaikhumwang, P.; Tantituvanont, A.; Saardrak, K.; Pedrazuela Sanz, R.; Miranda Alvarez, J.; Nilubol, D. Immune response and protective efficacy of intramuscular and intradermal vaccination with porcine reproductive and respiratory syndrome virus 1 (PRRSV-1) modified live vaccine against highly pathogenic PRRSV-2 (HP-PRRSV-2) challenge, either alone or in combination with of PRRSV-1. Vet. Microbiol. 2020, 244, 108655. [Google Scholar] [CrossRef]
  41. Qiu, M.; Li, S.; Ye, M.; Li, J.; Sun, Z.; Li, X.; Xu, Y.; Xiao, Y.; Li, C.; Feng, B.; et al. Systemic Homologous Neutralizing Antibodies Are Inadequate for the Evaluation of Vaccine Protective Efficacy against Coinfection by High Virulent PEDV and PRRSV. Microbiol. Spectr. 2022, 10, e0257421. [Google Scholar] [CrossRef]
  42. Nam, B.; Mekuria, Z.; Carossino, M.; Li, G.; Zheng, Y.; Zhang, J.; Cook, R.F.; Shuck, K.M.; Campos, J.R.; Squires, E.L.; et al. Intrahost Selection Pressure Drives Equine Arteritis Virus Evolution during Persistent Infection in the Stallion Reproductive Tract. J. Virol. 2019, 93, e00045-19. [Google Scholar] [CrossRef] [Green Version]
  43. Wang, G.; Yu, Y.; Cai, X.; Zhou, E.M.; Zimmerman, J.J. Effects of PRRSV Infection on the Porcine Thymus. Trends Microbiol. 2020, 28, 212–223. [Google Scholar] [CrossRef] [PubMed]
  44. Rahe, M.C.; Murtaugh, M.P. Mechanisms of Adaptive Immunity to Porcine Reproductive and Respiratory Syndrome Virus. Viruses 2017, 9, 148. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  45. Wu, Q.; Han, Y.; Wu, X.; Wang, Y.; Su, Q.; Shen, Y.; Guan, K.; Michal, J.J.; Jiang, Z.; Liu, B.; et al. Integrated time-series transcriptomic and metabolomic analyses reveal different inflammatory and adaptive immune responses contributing to host resistance to PRRSV. Front. Immunol. 2022, 13, 960709. [Google Scholar] [CrossRef] [PubMed]
  46. Loving, C.L.; Osorio, F.A.; Murtaugh, M.P.; Zuckermann, F.A. Innate and adaptive immunity against Porcine Reproductive and Respiratory Syndrome Virus. Vet. Immunol. Immunopathol. 2015, 167, 1–14. [Google Scholar] [CrossRef]
  47. Tian, Y.; Hao, Y.; Dong, M.; Li, S.; Wang, D.; Jiang, F.; Wang, Q.; Hao, X.; Yang, Y.; Chen, N.; et al. Development of a Monoclonal Antibody to Pig CD69 Reveals Early Activation of T Cells in Pig after PRRSV and ASFV Infection. Viruses 2022, 14, 1343. [Google Scholar] [CrossRef]
  48. Ruedas-Torres, I.; Gómez-Laguna, J.; Sánchez-Carvajal, J.M.; Larenas-Muñoz, F.; Barranco, I.; Pallarés, F.J.; Carrasco, L.; Rodríguez-Gómez, I.M. Activation of T-bet, FOXP3, and EOMES in Target Organs from Piglets Infected with the Virulent PRRSV-1 Lena Strain. Front. Immunol. 2021, 12, 773146. [Google Scholar] [CrossRef]
  49. Kick, A.R.; Amaral, A.F.; Cortes, L.M.; Fogle, J.E.; Crisci, E.; Almond, G.W.; Käser, T. The T-Cell Response to Type 2 Porcine Reproductive and Respiratory Syndrome Virus (PRRSV). Viruses 2019, 11, 796. [Google Scholar] [CrossRef] [Green Version]
  50. Li, Y.; Díaz, I.; Martín-Valls, G.; Beyersdorf, N.; Mateu, E. Systemic CD4 cytotoxic T cells improve protection against PRRSV-1 transplacental infection. Front. Immunol. 2022, 13, 1020227. [Google Scholar] [CrossRef]
  51. Cao, J.; Grauwet, K.; Vermeulen, B.; Devriendt, B.; Jiang, P.; Favoreel, H.; Nauwynck, H. Suppression of NK cell-mediated cytotoxicity against PRRSV-infected porcine alveolar macrophages in vitro. Vet. Microbiol. 2013, 164, 261–269. [Google Scholar] [CrossRef]
  52. Crisci, E.; Fraile, L.; Montoya, M. Cellular Innate Immunity against PRRSV and Swine Influenza Viruses. Vet. Sci. 2019, 6, 26. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  53. Xiao, Z.; Batista, L.; Dee, S.; Halbur, P.; Murtaugh, M.P. The level of virus-specific T-cell and macrophage recruitment in porcine reproductive and respiratory syndrome virus infection in pigs is independent of virus load. J. Virol. 2004, 78, 5923–5933. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  54. Nedumpun, T.; Sirisereewan, C.; Thanmuan, C.; Techapongtada, P.; Puntarotairung, R.; Naraprasertkul, S.; Thanawongnuwech, R.; Suradhat, S. Induction of porcine reproductive and respiratory syndrome virus (PRRSV)-specific regulatory T lymphocytes (Treg) in the lungs and tracheobronchial lymph nodes of PRRSV-infected pigs. Vet. Microbiol. 2018, 216, 13–19. [Google Scholar] [CrossRef] [PubMed]
  55. Nedumpun, T.; Techakriengkrai, N.; Thanawongnuwech, R.; Suradhat, S. Negative Immunomodulatory Effects of Type 2 Porcine Reproductive and Respiratory Syndrome Virus-Induced Interleukin-1 Receptor Antagonist on Porcine Innate and Adaptive Immune Functions. Front. Immunol. 2019, 10, 579. [Google Scholar] [CrossRef] [PubMed]
  56. Chaudhari, J.; Liew, C.S.; Riethoven, J.M.; Sillman, S.; Vu, H.L.X. Porcine Reproductive and Respiratory Syndrome Virus Infection Upregulates Negative Immune Regulators and T-Cell Exhaustion Markers. J. Virol. 2021, 95, e0105221. [Google Scholar] [CrossRef] [PubMed]
  57. Ruedas-Torres, I.; Rodríguez-Gómez, I.M.; Sánchez-Carvajal, J.M.; Guil-Luna, S.; Larenas-Muñoz, F.; Pallarés, F.J.; Carrasco, L.; Gómez-Laguna, J. Up-Regulation of Immune Checkpoints in the Thymus of PRRSV-1-Infected Piglets in a Virulence-Dependent Fashion. Front. Immunol. 2021, 12, 671743. [Google Scholar] [CrossRef]
  58. Ruedas-Torres, I.; Sánchez-Carvajal, J.M.; Carrasco, L.; Pallarés, F.J.; Larenas-Muñoz, F.; Rodríguez-Gómez, I.M.; Gómez-Laguna, J. PRRSV-1 induced lung lesion is associated with an imbalance between costimulatory and coinhibitory immune checkpoints. Front. Microbiol. 2022, 13, 1007523. [Google Scholar] [CrossRef]
  59. Bautista, E.M.; Suárez, P.; Molitor, T.W. T cell responses to the structural polypeptides of porcine reproductive and respiratory syndrome virus. Arch. Virol. 1999, 144, 117–134. [Google Scholar] [CrossRef]
  60. Chung, C.J.; Cha, S.H.; Grimm, A.L.; Ajithdoss, D.; Rzepka, J.; Chung, G.; Yu, J.; Davis, W.C.; Ho, C.S. Pigs that recover from porcine reproduction and respiratory syndrome virus infection develop cytotoxic CD4+CD8+ and CD4+CD8- T-cells that kill virus infected cells. PLoS ONE 2018, 13, e0203482. [Google Scholar] [CrossRef] [Green Version]
  61. Pan, X.; Zhang, N.; Wei, X.; Jiang, Y.; Chen, R.; Li, Q.; Liang, R.; Zhang, L.; Ma, L.; Xia, C. Illumination of PRRSV Cytotoxic T Lymphocyte Epitopes by the Three-Dimensional Structure and Peptidome of Swine Lymphocyte Antigen Class I (SLA-I). Front. Immunol. 2019, 10, 2995. [Google Scholar] [CrossRef] [PubMed]
  62. Tian, D.; Subramaniam, S.; Heffron, C.L.; Mahsoub, H.M.; Sooryanarain, H.; Wang, B.; Cao, Q.M.; Hassebroek, A.; LeRoith, T.; Foss, D.L.; et al. Construction and efficacy evaluation of novel swine leukocyte antigen (SLA) class I and class II allele-specific poly-T cell epitope vaccines against porcine reproductive and respiratory syndrome virus. J. Gen. Virol. 2020, 101, 1191–1201. [Google Scholar] [CrossRef] [PubMed]
  63. Liang, C.; Xia, Q.; Zhou, J.; Liu, H.; Chen, Y.; Liu, Y.; Ding, P.; Qi, Y.; Wang, A. Identification of potential SLA-I-restricted CTL epitopes within the M protein of porcine reproductive and respiratory syndrome virus. Vet. Microbiol. 2021, 259, 109131. [Google Scholar] [CrossRef] [PubMed]
  64. Cao, Q.M.; Tian, D.; Heffron, C.L.; Subramaniam, S.; Opriessnig, T.; Foss, D.L.; Calvert, J.G.; Meng, X.J. Cytotoxic T lymphocyte epitopes identified from a contemporary strain of porcine reproductive and respiratory syndrome virus enhance CD4+CD8+ T, CD8+ T, and γδ T cell responses. Virology 2019, 538, 35–44. [Google Scholar] [CrossRef]
  65. Mötz, M.; Stas, M.R.; Hammer, S.E.; Duckova, T.; Fontaine, F.; Kiesler, A.; Seitz, K.; Ladinig, A.; Müller, A.C.; Riedel, C.; et al. Identification of MHC-I-Presented Porcine Respiratory and Reproductive Syndrome Virus (PRRSV) Peptides Reveals Immunogenic Epitopes within Several Non-Structural Proteins Recognized by CD8(+) T Cells. Viruses 2022, 14, 1891. [Google Scholar] [CrossRef] [PubMed]
  66. Huang, J.; Liu, H.; Wang, M.; Bai, X.; Cao, J.; Zhang, Z.; Wang, Q. Mannosylated gelatin nanoparticles enhanced inactivated PRRSV targeting dendritic cells and increased T cell immunity. Vet. Immunol. Immunopathol. 2021, 235, 110237. [Google Scholar] [CrossRef]
  67. Lee, J.; Kim, Y.M.; Kim, J.H.; Cho, C.W.; Jeon, J.W.; Park, J.K.; Lee, S.H.; Jung, B.G.; Lee, B.J. Nasal delivery of chitosan/alginate nanoparticle encapsulated bee (Apis mellifera) venom promotes antibody production and viral clearance during porcine reproductive and respiratory syndrome virus infection by modulating T cell related responses. Vet. Immunol. Immunopathol. 2018, 200, 40–51. [Google Scholar] [CrossRef]
  68. Welner, S.; Ruggli, N.; Liniger, M.; Summerfield, A.; Larsen, L.E.; Jungersen, G. Reduced Virus Load in Lungs of Pigs Challenged with Porcine Reproductive and Respiratory Syndrome Virus after Vaccination with Virus Replicon Particles Encoding Conserved PRRSV Cytotoxic T-Cell Epitopes. Vaccines 2021, 9, 208. [Google Scholar] [CrossRef]
  69. Tang, T.; Wang, C.; Pu, Q.; Peng, J.; Liu, S.; Ren, C.; Jiang, M.; Tian, Z. Vaccination of Mice with Listeria ivanovii Expressing the Truncated M Protein of Porcine Reproductive and Respiratory Syndrome Virus Induces both Antigen-Specific CD4+ and CD8+ T Cell-Mediated Immunity. J. Mol. Microbiol. Biotechnol. 2019, 29, 74–82. [Google Scholar] [CrossRef]
  70. Bernelin-Cottet, C.; Urien, C.; Stubsrud, E.; Jakob, V.; Bouguyon, E.; Bordet, E.; Barc, C.; Boulesteix, O.; Contreras, V.; Barnier-Quer, C.; et al. A DNA-Modified Live Vaccine Prime-Boost Strategy Broadens the T-Cell Response and Enhances the Antibody Response against the Porcine Reproductive and Respiratory Syndrome Virus. Viruses 2019, 11, 551. [Google Scholar] [CrossRef] [Green Version]
  71. Cao, Q.M.; Ni, Y.Y.; Cao, D.; Tian, D.; Yugo, D.M.; Heffron, C.L.; Overend, C.; Subramaniam, S.; Rogers, A.J.; Catanzaro, N.; et al. Recombinant Porcine Reproductive and Respiratory Syndrome Virus Expressing Membrane-Bound Interleukin-15 as an Immunomodulatory Adjuvant Enhances NK and γδ T Cell Responses and Confers Heterologous Protection. J. Virol. 2018, 92, e00007-18. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  72. Montaner-Tarbes, S.; Del Portillo, H.A.; Montoya, M.; Fraile, L. Key Gaps in the Knowledge of the Porcine Respiratory Reproductive Syndrome Virus (PRRSV). Front. Vet. Sci. 2019, 6, 38. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  73. Wang, H.; Xu, Y.; Feng, W. Porcine Reproductive and Respiratory Syndrome Virus: Immune Escape and Application of Reverse Genetics in Attenuated Live Vaccine Development. Vaccines 2021, 9, 480. [Google Scholar] [CrossRef] [PubMed]
  74. Osorio, F.A.; Galeota, J.A.; Nelson, E.; Brodersen, B.; Doster, A.; Wills, R.; Zuckermann, F.; Laegreid, W.W. Passive transfer of virus-specific antibodies confers protection against reproductive failure induced by a virulent strain of porcine reproductive and respiratory syndrome virus and establishes sterilizing immunity. Virology 2002, 302, 9–20. [Google Scholar] [CrossRef] [Green Version]
  75. Crotty, S. T Follicular Helper Cell Biology: A Decade of Discovery and Diseases. Immunity 2019, 50, 1132–1148. [Google Scholar] [CrossRef]
  76. Lopez, O.J.; Osorio, F.A. Role of neutralizing antibodies in PRRSV protective immunity. Vet. Immunol. Immunopathol. 2004, 102, 155–163. [Google Scholar] [CrossRef]
  77. Luo, Q.; Zheng, Y.; Zhang, H.; Yang, Z.; Sha, H.; Kong, W.; Zhao, M.; Wang, N. Research Progress on Glycoprotein 5 of Porcine Reproductive and Respiratory Syndrome Virus. Animals 2023, 13, 813. [Google Scholar] [CrossRef]
  78. Vu, H.L.; Kwon, B.; Yoon, K.J.; Laegreid, W.W.; Pattnaik, A.K.; Osorio, F.A. Immune evasion of porcine reproductive and respiratory syndrome virus through glycan shielding involves both glycoprotein 5 as well as glycoprotein 3. J. Virol. 2011, 85, 5555–5564. [Google Scholar] [CrossRef] [Green Version]
  79. Ansari, I.H.; Kwon, B.; Osorio, F.A.; Pattnaik, A.K. Influence of N-linked glycosylation of porcine reproductive and respiratory syndrome virus GP5 on virus infectivity, antigenicity, and ability to induce neutralizing antibodies. J. Virol. 2006, 80, 3994–4004. [Google Scholar] [CrossRef] [Green Version]
  80. Paploski, I.A.D.; Makau, D.N.; Pamornchainavakul, N.; Baker, J.P.; Schroeder, D.; Rovira, A.; VanderWaal, K. Potential Novel N-Glycosylation Patterns Associated with the Emergence of New Genetic Variants of PRRSV-2 in the U.S. Vaccines 2022, 10, 2021. [Google Scholar] [CrossRef]
  81. Zhang, X.; Li, Y.; Xiao, S.; Yang, X.; Chen, X.; Wu, P.; Song, J.; Ma, Z.; Cai, Z.; Jiang, M.; et al. High-frequency mutation and recombination are responsible for the emergence of novel porcine reproductive and respiratory syndrome virus in northwest China. Arch. Virol. 2019, 164, 2725–2733. [Google Scholar] [CrossRef] [PubMed]
  82. Liu, X.; Zhou, X.; Noor, A.U.; Zhang, X.; Song, C.; Sun, H. Enhancing half-life and cytotoxicity of porcine respiratory and reproductive syndrome virus soluble receptors by taming their Fc domains. Vet. Microbiol. 2022, 273, 109526. [Google Scholar] [CrossRef] [PubMed]
  83. Zhang, L.; Wang, H.; Li, W.; Feng, X.; Han, F.; Zhang, Y.; Chen, J.; Liu, D.; Xia, P. Activating Fc Gamma Receptors and Viral Receptors Are Required for Antibody-Dependent Enhancement of Porcine Reproductive and Respiratory Syndrome Virus Infection. Vet. Sci. 2022, 9, 470. [Google Scholar] [CrossRef] [PubMed]
  84. Shi, P.; Zhang, L.; Wang, J.; Lu, D.; Li, Y.; Ren, J.; Shen, M.; Zhang, L.; Huang, J. Porcine FcεRI Mediates Porcine Reproductive and Respiratory Syndrome Virus Multiplication and Regulates the Inflammatory Reaction. Virol. Sin. 2018, 33, 249–260. [Google Scholar] [CrossRef] [PubMed]
  85. Zhang, L.; Li, W.; Sun, Y.; Kong, L.; Xu, P.; Xia, P.; Zhang, G. Antibody-Mediated Porcine Reproductive and Respiratory Syndrome Virus Infection Downregulates the Production of Interferon-α and Tumor Necrosis Factor-α in Porcine Alveolar Macrophages via Fc Gamma Receptor I and III. Viruses 2020, 12, 187. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  86. Wan, B.; Chen, X.; Li, Y.; Pang, M.; Chen, H.; Nie, X.; Pan, Y.; Qiao, S.; Bao, D. Porcine FcγRIIb mediated PRRSV ADE infection through inhibiting IFN-β by cytoplasmic inhibitory signal transduction. Int. J. Biol. Macromol. 2019, 138, 198–206. [Google Scholar] [CrossRef] [PubMed]
  87. Xu, P.; Li, W.; Zhao, S.; Cui, Z.; Chen, Y.; Zhang, Y.N.; Chen, J.; Xia, P. Proteomic Characterization of PAMs with PRRSV-ADE Infection. Viruses 2022, 15, 36. [Google Scholar] [CrossRef]
  88. Bao, D.; Wang, R.; Qiao, S.; Wan, B.; Wang, Y.; Liu, M.; Shi, X.; Guo, J.; Zhang, G. Antibody-dependent enhancement of PRRSV infection down-modulates TNF-α and IFN-β transcription in macrophages. Vet. Immunol. Immunopathol. 2013, 156, 128–134. [Google Scholar] [CrossRef]
  89. Gu, W.; Guo, L.; Yu, H.; Niu, J.; Huang, M.; Luo, X.; Li, R.; Tian, Z.; Feng, L.; Wang, Y. Involvement of CD16 in antibody-dependent enhancement of porcine reproductive and respiratory syndrome virus infection. J. Gen. Virol. 2015, 96, 1712–1722. [Google Scholar] [CrossRef]
  90. Sautter, C.A.; Trus, I.; Nauwynck, H.; Summerfield, A. No Evidence for a Role for Antibodies during Vaccination-Induced Enhancement of Porcine Reproductive and Respiratory Syndrome. Viruses 2019, 11, 829. [Google Scholar] [CrossRef] [Green Version]
  91. Rahe, M.C.; Murtaugh, M.P. Effector mechanisms of humoral immunity to porcine reproductive and respiratory syndrome virus. Vet. Immunol. Immunopathol. 2017, 186, 15–18. [Google Scholar] [CrossRef] [Green Version]
  92. Paudyal, B.; Mwangi, W.; Rijal, P.; Schwartz, J.C.; Noble, A.; Shaw, A.; Sealy, J.E.; Bonnet-Di Placido, M.; Graham, S.P.; Townsend, A.; et al. Fc-Mediated Functions of Porcine IgG Subclasses. Front. Immunol. 2022, 13, 903755. [Google Scholar] [CrossRef]
  93. Gunn, B.M.; Yu, W.H.; Karim, M.M.; Brannan, J.M.; Herbert, A.S.; Wec, A.Z.; Halfmann, P.J.; Fusco, M.L.; Schendel, S.L.; Gangavarapu, K.; et al. A Role for Fc Function in Therapeutic Monoclonal Antibody-Mediated Protection against Ebola Virus. Cell Host Microbe 2018, 24, 221–233.e225. [Google Scholar] [CrossRef]
  94. Flórez-Álvarez, L.; Hernandez, J.C.; Zapata, W. NK Cells in HIV-1 Infection: From Basic Science to Vaccine Strategies. Front. Immunol. 2018, 9, 2290. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  95. Astorga-Gamaza, A.; Grau-Expósito, J.; Burgos, J.; Navarro, J.; Curran, A.; Planas, B.; Suanzes, P.; Falcó, V.; Genescà, M.; Buzon, M.J. Identification of HIV-reservoir cells with reduced susceptibility to antibody-dependent immune response. Elife 2022, 11, e78294. [Google Scholar] [CrossRef]
  96. Vietzen, H.; Danklmaier, V.; Zoufaly, A.; Puchhammer-Stöckl, E. High-affinity FcγRIIIa genetic variants and potent NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC) responses contributing to severe COVID-19. Genet. Med. 2022, 24, 1449–1458. [Google Scholar] [CrossRef]
  97. Goldberg, B.S.; Ackerman, M.E. Antibody-mediated complement activation in pathology and protection. Immunol. Cell. Biol. 2020, 98, 305–317. [Google Scholar] [CrossRef]
  98. Costers, S.; Delputte, P.L.; Nauwynck, H.J. Porcine reproductive and respiratory syndrome virus-infected alveolar macrophages contain no detectable levels of viral proteins in their plasma membrane and are protected against antibody-dependent, complement-mediated cell lysis. J. Gen. Virol. 2006, 87, 2341–2351. [Google Scholar] [CrossRef]
  99. Nelson, C.S.; Huffman, T.; Jenks, J.A.; Cisneros de la Rosa, E.; Xie, G.; Vandergrift, N.; Pass, R.F.; Pollara, J.; Permar, S.R. HCMV glycoprotein B subunit vaccine efficacy mediated by nonneutralizing antibody effector functions. Proc. Natl. Acad. Sci. USA 2018, 115, 6267–6272. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  100. Baraniak, I.; Kropff, B.; Ambrose, L.; McIntosh, M.; McLean, G.R.; Pichon, S.; Atkinson, C.; Milne, R.S.B.; Mach, M.; Griffiths, P.D.; et al. Protection from cytomegalovirus viremia following glycoprotein B vaccination is not dependent on neutralizing antibodies. Proc. Natl. Acad. Sci. USA 2018, 115, 6273–6278. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Viruses 15 01442 g001 550
Figure 1. Schematic diagram of PRRSV infection of susceptible cells. The four steps of viral infection in cells are attachment, internalization, replication assembly, and release. This diagram primarily shows how viral membrane proteins and nucleocapsid proteins interact with receptor proteins to enter the cell.
Figure 1. Schematic diagram of PRRSV infection of susceptible cells. The four steps of viral infection in cells are attachment, internalization, replication assembly, and release. This diagram primarily shows how viral membrane proteins and nucleocapsid proteins interact with receptor proteins to enter the cell.
Viruses 15 01442 g001
Viruses 15 01442 g002 550
Figure 2. Illustration of the impact of ADE on PRRSV infection. PRRSV particles can be neutralized by high titer specific neutralizing antibodies. Within the influence of ADE, the level of PRRSV infection dramatically increases as compared to the infection stage without antibodies. Additionally, PRRSV binds to non-neutralizing or sub-neutralizing antibodies to create immune complexes (ICs), which enter cells via FcRs receptors to influence innate immune function and to obstruct anti-inflammatory signaling molecules, thereby facilitating virus reproduction.
Figure 2. Illustration of the impact of ADE on PRRSV infection. PRRSV particles can be neutralized by high titer specific neutralizing antibodies. Within the influence of ADE, the level of PRRSV infection dramatically increases as compared to the infection stage without antibodies. Additionally, PRRSV binds to non-neutralizing or sub-neutralizing antibodies to create immune complexes (ICs), which enter cells via FcRs receptors to influence innate immune function and to obstruct anti-inflammatory signaling molecules, thereby facilitating virus reproduction.
Viruses 15 01442 g002
Table
Table 1. Research progress in the design of novel vaccines using cellular immune response properties.
Table 1. Research progress in the design of novel vaccines using cellular immune response properties.
Design SystemIngredientsTest ResultsReference
MnGNPMannose-modified gelatin nanoparticles (MnGNP) as a carrier to encapsulate inactivated PRRSV virusImproves T-cell activation, proliferation, and immunity[66]
CH/AL-BVChitosan/sodium alginate (CH/AL) nanoparticle-encapsulated bee venom (BV)Effectively induces Th1-related immune responses, stimulates T cells to secrete IFN-γ, and reduces immunosuppressive effects[67]
VRPsExpression of PRRSV cytotoxic T cell epitopes using viral replicon particles (VRPs) of swine fever virusSignificantly reduces viral load in the lung tail and improves cell-mediated immune response[68]
LI-M’Integration of the hydrophilic structural domain of the PRRSV M protein into Listeria monocytogenesSignificantly enhances CD8+ T cell-mediated immunity[69]
DNA-MLVDNA vaccines encoding conserved B and T cell epitopes among European subtype 1 strains and known strainsAn expanded T-cell response and enhanced antibody response[70]
IL-15-MLVInterleukin-15 (IL-15) and MLV fused with glycosylphosphatidylinositol (GPI)Enhances NK and T cell immune responses and provides some allogenic protection[71]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Cai, H.; Zhang, H.; Cheng, H.; Liu, M.; Wen, S.; Ren, J. Progress in PRRSV Infection and Adaptive Immune Response Mechanisms. Viruses 2023, 15, 1442. https://doi.org/10.3390/v15071442

AMA Style

Cai H, Zhang H, Cheng H, Liu M, Wen S, Ren J. Progress in PRRSV Infection and Adaptive Immune Response Mechanisms. Viruses. 2023; 15(7):1442. https://doi.org/10.3390/v15071442

Chicago/Turabian Style

Cai, Huanchang, Hewei Zhang, Huai Cheng, Min Liu, Shubo Wen, and Jingqiang Ren. 2023. "Progress in PRRSV Infection and Adaptive Immune Response Mechanisms" Viruses 15, no. 7: 1442. https://doi.org/10.3390/v15071442

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop