The PRRSV genome is approximately 15 kbp in size and has a specific organization. The replicase genes are situated at the 5′-end of the genome, whereas the genes encoding structural proteins are found at the 3′-end (20, 21). The viral genome consists of more than 10 open reading frames (ORFs). Over 66% of the viral genome is made up of ORF1a and ORF1b, which encode nonstructural proteins that serve crucial functions including protease and replicase activities. These proteins also modulate host genes that are vital for the replication of the virus. Conversely, ORFs 2–7 encode the structural proteins required for virus formation (21).

PRRSV processes of eight structural proteins, which include a small non-glycosylated protein and a group of glycosylated proteins: Glycoprotein (GP) 2ab, GP3, GP4, GP5, GP5a, matrix (M), and nucleocapsid (N) (21, 22). The primary structural proteins encoded by ORFs 5, 6, and 7 are GP5, M, and N, respectively. While GP5 typically forms a heterodimer with M, there have been reports of GP5 homodimers (23). Among the surface glycoproteins, GP2, GP3, and GP4, derived from ORFs 2, 3, and 4, respectively, act as minor components. Additionally, two very small non-glycosylated proteins, designated as 2b or E and 5a, are translated from ORF2b and ORF5a, respectively (24, 25). The smooth exterior of the PRRSV virion is primarily attributed to the presence of short peptide sequences in the ectodomains of M and GP5. However, the larger ectodomains of GP2, GP3, and GP4 can also give rise to a few protrusions on the virus surface (21).

Macrophages are the primary target cells for PRRSV infection (10, 26–28), playing a crucial role in immune modulation and contributing to the respiratory distress observed in pigs affected by the porcine respiratory disease complex. The following section provides an overview of the recognition of the virus by recipient cells (Table 1) and the mechanisms involved.

CD163 serves as a crucial receptor for PRRSV and plays a critical role in determining cell susceptibility to the virus (29). It is a scavenger receptor glycoprotein predominantly found in mature macrophages and monocytes. The extracellular portion of CD163 comprises nine scavenger receptor cysteine-rich domains (SRCR) and two motifs rich in proline-serine–threonine (PST), which are repeated multiple times (56). The heterotrimeric GP2, GP3, and GP4 proteins of PRRSV bind to CD163, with GP2 and GP4 forming multiple interactions with different receptors (30, 56). Pigs with a CD163 gene knockout (KO) are non-permissive to PRRSV-2 infection (31), and their macrophages show resistance to PRRSV-1 and -2 (32). Recent studies show that CD163 SRCR5-deficient pigs are resistant to specific PRRSV-2 strains (33, 34). Genetically engineered pigs with a modified CD163 SRCR5 domain display normal growth under standard conditions (34, 35). This suggests that gene editing techniques targeting CD163 can potentially control and eradicate PRRS outbreaks.

CD163 participates in viral apoptotic mimicry, a strategy employed by certain viruses to infect host cells (57). This mechanism involves viruses disguising themselves as apoptotic debris and engaging receptors on the surface of phagocytes that recognize phosphatidylserine (PtdSer), a marker of apoptosis (58). These interactions activate signaling cascades and lead to actin rearrangements to facilitate endocytic engulfment, and subsequent degradation of viral particles (59). Viruses adopt distinct mechanisms of apoptotic mimicry, giving rise to the concepts of classical and nonclassical apoptotic mimicry (60). PRRSV capitalizes on viral apoptotic mimicry to induce macropinocytosis through the involvement of T cell immunoglobulin and mucin domain proteins TIM-1 and -4 (57). During PRRSV infection, CD163 plays a vital role in facilitating TIM-induced macropinocytosis (61). Consequently, PRRSV adopts an alternative route of infection via macrophage activity involving CD163.

Mammalian cells contain heparin sulfate (HS) as a glycosaminoglycan on their surface and in their extracellular matrix (62). Heparin sulfate plays an important role in adhesion during PRRSV infection by interacting with M and GP5-M proteins during PRRSV infection (37). Although not essential for PRRSV invasion of porcine alveolar macrophages (PAMs), HS enables PRRSV to adhere to non-susceptible cell lines without completing the subsequent infection steps (38). PRRSV-1 and -2 exhibit different sensitivities to HS (37). The treatment of PAMs with heparinase (which degrades HS) reduces PRRSV infection (37). Moreover, PRRSV infection can activate NF-κB and cathepsin L, resulting in heparinase upregulation and processing, reduction in HS surface expression, and promotion of viral replication and release (63).

Sialoadhesin (Sn), also referred to as CD169 or SIGLIC-1, acts as a co-receptor for PRRSV invasion. The N-terminal immunoglobulin domain of porcine Sn is necessary and sufficient (39, 40). Cells expressing Sn facilitate PRRSV internalization, but do not promote viral uncoating (40). The collaboration between Sn and other receptors, such as CD163, sensitizes cells to PRRSV infection, promoting effective attachment, internalization, and disassembly of viral particles (41, 42). The absence of Sn in genetically-edited pigs does not disrupt PRRSV attachment/internalization or have any effect on disease progression or histopathology (64). This discrepancy between the in vitro and in vivo models of PRRSV receptors indicates conflicting outcomes. These findings suggest that Sn primarily plays a role in binding PRRSV to the macrophage surface rather than facilitating viral internalization.

Vimentin (VIM) is a crucial component of the PRRSV receptor complex and plays a key role in the intracellular replication and metastasis of PRRSV (45, 46). It forms a polymer with other fine-cell bone frame microfilaments and interacts with the PRRSV nucleocapsid protein (47). Vimentin can render normally non-susceptible cell lines susceptible to PRRSV infection. This highlights its involvement in the viral receptor complex (45). Following PRRSV entry, vimentin undergoes reorganization facilitated by Serine 38 phosphorylation by calcium calmodulin-dependent protein kinase II gamma (48). As a result of this reorganization, cage-like structures form around PRRSV replication complexes within the nucleus.

Tetraspanin superfamily member CD151 is an RNA-binding protein that interacts with the 3’-UTR of the PRRSV genome and functions as an RNA-binding protein (49). By silencing the CD151 gene in MARC-145 cells, PRRSV infection decreases significantly, and antibodies against CD151 prevent it entirely (49). CD151 expression can be regulated by microRNAs (such as miR-506) that lead to a decrease in CD151 mRNA and protein levels, thereby resulting in the inhibition of PRRSV replication and viral release in MARC-145 cells (50). CD151 possesses N-glycosylation and palmitoylation sites (65); their involvement in regulating PRRSV infection requires further investigation.

Non-muscle myosin heavy chain 9 (MYH9) plays various roles in cell adhesion, polarization, morphogenesis, and migration (66, 67). It interacts with PRRSV GP5, which is crucial for PRRSV internalization and intercellular spread. The C-terminal domain of MYH9 directly binds to the first ectodomain of viral GP5, and disruption of this interaction reduces PRRSV internalization (51). Specific amino acid residues within the MYH9 C-terminal domain are believed to be key binding sites for GP5 (52). Furthermore, MYH9 undergoes reorganization upon PRRSV infection, forming cage-like structures around the PRRSV replication complex (53). MYH9 co-expression with CD163 enhances PRRSV infection (51).

Heat shock protein member 8 (HSPA8) plays a role in various viral infections by regulating viral entry, replication, and assembly (68). Inhibition of endogenous HSPA8 reduces PRRSV replication by decreasing viral attachment and internalization (54). HSPA8 interacts with clathrin, and is involved in clathrin-mediated endocytosis (CME) (69). The PB domain of HSPA8 interacts with PRRSV GP4, and HSPA8 ATPase activity is required for PRRSV infection via CME (54). Moreover, HSPA8 co-localizes with PRRSV on the cell surface and facilitates viral fusion and entry (54). HSPA8-based therapies show promise in clinical trials and vaccine development for other diseases. For instance, recombinant HSPA8 fused with GP3 and GP4 boosts immune responses and confers protective effects against the highly pathogenic PRRSV infection in pigs (55). Therefore, HSPA8-based strategies have the potential for vaccine development.

The viral genome contains more than 10 ORFs. These ORFs encode nonstructural proteins crucial for viral replication. ORFs 2–7 encode structural proteins that play vital roles in viral formation, and are necessary for viral particle assembly. PRRSV uses multiple receptors for entry into host cells, including CD163, Sn, HS, VIM, MYH9, CD151, CD209, and HSPA8. Understanding the interactions between PRRSV and these receptors offers potential targets to control and eradicate PRRSV outbreaks, and to develop vaccines and therapeutic strategies.

Chinese Dapulian pigs (DPL) exhibit increased resistance to PRRSV when compared to commercial Duroc×Landrace×Yorkshire (DLY) crossbred pigs, as evidenced by lower rectal temperatures and serum PRRSV copy numbers (70). Analysis of lung tissue samples from PRRSV-uninfected DPL and DLY pigs show varied expression patterns of five PRRSV mediator genes (NMMHC-IIA, SIGLEC1, CD163, HSPG2, and VIM), with significantly higher mRNA expression levels of SIGLEC1, NMMHC-IIA, CD163, and VIM in DLY pigs than those in DPL pigs (70). Another study revealed that the mRNA level of CD163 in PAMs of Dingyuan pigs is significantly lower than that of Jiangquhai pigs within 24 h post-infection (hpi); this may account for the high resistance of Jiangquhai pigs to PRRSV (71). Moreover, Sn expression in PAMs from Dingyuan pigs increase at a faster rate than that in PAMs from Jiangquhai pigs following viral infection (71). This finding corresponds to the high PRRSV content in PAMs from Dingyuan pigs (71). The increased mRNA expression levels of CD163 and Sn may contribute to more rapid viral invasion and wider penetration sites in vivo and in vitro (72). Viral receptor expression varies among different pig breeds after PRRSV infection, and there are variations in the expression of PRRSV receptors (HS, Sn, CD163, CD151, and VIM) in the lung tissues of different pig breeds, even under normal physiological conditions (47, 71, 73).

Variations in receptor expression and RNA abundance can lead to activation or inhibition of various pathways, resulting in distinct responses to PRRSV infection in different pig breeds. Further exploration of the mechanisms underlying these susceptibility differences could pave the way for the development of innovative approaches to control PRRSV infection in swine populations.

The clinical manifestations of PRRS are influenced by multiple factors, including the virus strain, age and immune status of the host, production environment, productive state, and specific PRRSV strains. The typical symptoms during the acute phase of the disease include loss of appetite, weakness, fever, and respiratory difficulties. Respiratory dyspnea is commonly observed across all the age groups of pigs, although infected pregnant sows may exhibit more severe symptoms.

Pregnant sows are highly susceptible to PRRSV infection and may exhibit various clinical symptoms. This includes loss of appetite, abortions, transient discoloration of the ears (commonly known as blue ear disease, which affects approximately 2% of sows), early farrowing, prolonged anestrus, delayed return to heat after weaning, coughing, and respiratory signs (74).

Symptoms in weaned and fattened piglets can be significant and may include hair loss, slight loss of appetite, mild respiratory problems (such as coughing), and localized skin redness. The mortality rate during this stage ranges from 10 to 20% and is influenced by hygiene and operational management. The presence of other microorganisms within a herd can increase mortality rates. Pigs aged 4–12 weeks born by infected sows exhibit clinical symptoms similar to those of suckling pigs, including loss of appetite, malabsorption, wasting, coughing, and pneumonia, and a 12% higher post-weaning mortality rate (75, 76). Secondary bacterial infections can lead to lung and systemic abscesses, abscess-related lameness, or poor growth (77, 78).

A range of clinical symptoms indicates potential issues in farrowing sows. These symptoms include anorexia, decreased water intake, reduced milk production, mastitis, premature delivery of piglets, discoloration of the skin (such as, verticillium wilt or blue vulva and ears), pressure sores, lethargy, respiratory symptoms (such as, coughing and pneumonia), mummified piglets, stillborn piglets, and weak piglets at birth (77, 79).

Severe respiratory diseases and decreased survival rates are the most common issues in piglets. Other clinical symptoms included eyelid swelling, conjunctivitis, listlessness, significant weight loss, diarrhea, rough and unkempt fur, purple ear discoloration, and abnormal behavior (76, 77).

Artificial infection of TC pigs and LW pigs with HP-PRRSV results in similar symptoms of high fever. LW pigs have a temperature above 40.5°C from 0 to 3 days post-contact (dpc) and above 41.0°C from 4 to 7 dpc, while TC pigs have a temperature above 40.5°C from 1 to 3 dpc and above 41.0°C from 4 to 6 dpc (18). However, the clinical signs are less severe in TC pigs than those in LW pigs, showing changes in lying behavior, less depression, deep breathing, skin flushing, and reduced food intake. Furthermore, TC pigs have significantly less inflammatory exudation (p < 0.01) and alveolar wall thickening (p < 0.05) when compared with LW pigs. Post-mortem analysis revealed varying degrees of swelling and bleeding in the brain, liver, and spleen, with jagged edges in the spleen (18).

Similarly, a study involving 4-6-week-old piglets of Tibetan, ZangMei black (ZM), and LW piglets challenged with HP-PRRSV (JXA1) showed that LW piglets had a significant increase in rectal temperature from 2 dpi that remained elevated until 15 dpi (40.4°C ± 0.55). ZM piglets exhibit a significant increase in rectal temperature for 4 days (2–5 dpi) with no readings above 40°C, and Tibetan piglets did not show any rectal temperature readings above 40°C. Anorexia, sneezing, coughing, and diarrhea appeared in the affected ZM and LW piglets within 2–3 dpi; however, LW piglets experienced more severe symptoms, including increased shivering, hyperspasmia, and respiratory rates from 6 to 8 dpi. Some of the challenged LW piglets died at 9, 11, and 13 dpi, whereas Tibetan piglets did not exhibit typical signs or death throughout the 28-day period (80). The observed clinical signs were aligned with corresponding changes in temperature and body weight gain. LW piglets showed decreased body weight during the second week following challenge, ZM piglets experienced weight loss during the first week, and Tibetan piglets showed consistent weight gain throughout the 4 weeks (80).

Porcine reproductive and respiratory syndrome virus infection has a notable effect on the clinical presentation and growth performance of pigs, which can significantly vary among breeds. For example, LW pigs experience weight loss and mortality after PRRSV infection, whereas ZM pigs show no weight changes. In contrast, Tibetan pigs (known for their robust disease resistance) continue to exhibit weight gain throughout the infection (80).

TC pigs display significantly lower viral loads than LW pigs after artificial HP-PRRSV infection. Moreover, TC pigs display a reduced peak viral load and maintain a steady decline throughout the infection period. The maximum quantity of PRRSV particles in TC pigs is 0.4 times that found in LW pigs; this suggests a superior ability to control viral replication in TC pigs (18).

A study of 100 pigs from NEI (a Large White-Landrace composite population) and 100 pigs from a cross between Hampshire and Duroc line (HD) inoculated with PRRSV (97–7895 strain) indicated that the viremia titer was greater in HD pigs than that in NEI pigs on days 4, 7, and 14, whereas the viral titers in the lungs and bronchial lymph nodes were significantly higher in HD pigs (14).

A study involving seven Miniature (MI) pigs and eight commercial Pietrain (PI) pigs challenged with an attenuated PRRSV strain shows that viremia peaks at 6 dpi, with 100% viremia observed in PI pigs and at 12 dpi, with 87% viremia noted in MI pigs (81). MI pigs have a reduced duration of viremia. Different genetic susceptibilities to PRRSV may contribute to variations in antibody production (81).

Inoculation of eight purebred boars (two Landrace, three Yorkshire, and three Hampshire) with VR-2332 detected PRRSV RNA in the serum and PBMC between 4 and 11 dpi. The virus is not detected in the lymphoid tissues of Landrace pigs at 47 and 88 dpi, whereas Yorkshire and Hampshire pigs show varying viral loads in lymphoid tissues. Yorkshire and Hampshire boars exhibit higher resistance to PRRSV shedding in semen than Landrace boars (82).

In 2015, Tibetan, Zang Mei, and Large White piglets were challenged with HP-PRRSV (JXA1). During the challenge, the serum viral load in LW piglets peaked at 7 dpi, which gradually decreased until 28 dpi. Zang Mei piglets had their viral peak virus at 4 dpi, which decreased rapidly, resulting in significantly lower viral loads when compared to LW piglets at 14 and 21 dpi (80). Tibetan pigs consistently exhibited lower viral loads than the other two breeds throughout the challenge (80).

The virus titer and mRNA abundance in PAM supernatants following inoculation with PRRSV NJGC in vitro show similar trends among Landrace, Erhualian, Suzhong, Jiangquhuai, Dingyuan, and Meishan breeds (71).

Different breeds exhibit significant variations in clinical features, growth performance, and viral titers owing to genetic variations that ultimately affect their ability to combat PRRSV. Some breeds, such as Meishan and Tongcheng, demonstrate a genetic advantage in fighting the virus that results in a reduction in the duration of viremia.