Porcine Parvovirus (PPV), an Ungulate parvovirus 1 in the Protoparvirus genus, was first recognized as a member of the Parvoviridae family and causative agent of SMEDI syndrome at the end of the 1960s (17). Seven distinct genotypes of PPV (PPV1-PPV7), which are prevalent worldwide, have been identified.

The Ministry of Agriculture in China has classified PPV as a Class II animal disease pathogen (18). In China, the positivity rate of PPV was significantly higher in pigs in the south-west, northern and southern parts of the country. For instance, in Haikou and Chongqing, China (2014), the serological positivity rate of PPV reached over 90% (19), while 85% of pig herds with reproductive dysfunction syndrome was positive for PPV in Yunnan Province (20). In Pakistan, Punjab (2016), the seroprevalence of PPV was 41.1% (21). In recent years, there has been an increase in the PPV variation and its co-infection with other pathogens. An epidemiological survey of the porcine reproductive syndrome in South-west China (2012) showed that the positive rate of PPV was 43.97%, while that of Pseudorabies virus (PRV) was 24.6%, and Chlamydia psittaci (Cps) was 36.98%. Of these, 39.6% were mono-infections, while 35.6% were mixed infections (22). It has been shown that PPV infection-induced cell apoptosis in pregnant sows is primarily caused by the non-structural protein NS1. This process is characterized by the induction of host cell DNA damage, reactive oxygen species (ROS) generation and mitochondrial damage (23). A consequence of PPV infection is the nuclear fragmentation and subsequent nucleus consolidation of the luteal cells, which damages the luteal tissue of sows. Moreover, PPV impedes progesterone synthesis in luteal cells by inhibiting the expression of StAR, 3β-HSD and P450scc and induces apoptosis in luteal cells by activating the p38, p53 and mitochondrial pathways (Figure 2), culminating in abortion and infertility (24). Additionally, PPV induces apoptosis in embryonic trophoblasts by regulating the expression levels of Fas/Fas L, Bax/Bcl-2 and p53, ultimately resulting in embryonic death (25).

PPV has a single serotype, and vaccine immunization has become the primary prevention and control strategy for the pathogen. The most commonly used vaccines in clinical settings are live and inactivated weakly-attenuated vaccines.

Porcine pseudorabies (PR), also known as Aujeszky’s disease, is caused by the pseudorabies virus (PRV), which has a wide host range. The family Suidae (true pigs) are the natural hosts and reservoirs of PRV (26–28). There are two types of PRV infections: overt and latent. Adult pigs are mostly latently infected and can continuously excrete the virus (29). Following PRV infection in boars, the virus can be excreted in semen and transmitted to sows, leading to various reproductive disorders. Serological tests showed that the positivity rate of PRV gE antibody in the 3,449 serum samples collected from the Hebei Province, China (2022), was 46.27% (30). In Greece (2019), 28.6% of 42 selected pig farms were positive for antibodies against the wild-type strains of PRV (31).

PRV can enter the blood circulation via leukocyte uptake, allowing it to reach all body parts, including the placental tissues, where it can cause stillbirth or miscarriage following fetal invasion (32). PRV-infected mononuclear cells can cross the endothelial cell (EC) barrier of the maternal vasculature (33), and widespread EC infection can lead to detachment of membranes in early gestation, abortions of virus-negative fetuses, or fetal reabsorptions in the sow. Secondary replication in the EC of the uterus of pregnant sows can cause vasculitis and multifocal thrombosis, and microscopic uterine vasculopathy may lead to abortion or stillbirths of virus-positive fetuses in mid and late pregnancy. Additionally, the induction of cytokines and hormones in the local environment during pregnancy may accelerate the adhesion of PRV-infected monocytes to ECs, further contributing to miscarriage in sows (29).

The gE gene deletion-engineered vaccines are widely used to immunize commercial pig herds and wildlife against PRV. Since 2011, outbreaks of PR caused by emerging PRV variants have occurred in Chinese pig herds immunized with the Bartha-K61 strain. The classical PRV attenuated vaccines have been demonstrated to provide incomplete protection for pigs (34, 35). Scientists have conducted research and developed genetically engineered vaccines against the novel 2011 PR. Currently, only two vaccine types have been licensed: a genetically modified inactivated vaccine against the PRV HeN1201 strain (2019) and a natural four-gene deletion (gI/gE/Us9/Us2) vaccine against the PRV C strain (2017) (36, 37). The active ingredients of certain herbs have also been demonstrated to act as PRV inhibitors. For example, resveratrol (trans-3,4,5-trihydroxystilbene; Res) has been shown to possess immunomodulatory, anti-inflammatory, and antiviral activities (38) and has been observed to protect rotavirus-infected piglets by reducing inflammatory responses and enhancing immune function (39).

Porcine reproductive and respiratory syndrome (PRRS), also referred to as porcine blue ear disease, is caused by the porcine reproductive and respiratory syndrome virus (PRRSV). Infected sows exhibit reproductive disorders, which are primarily manifest in abortion, mummified fetus, weak fetuses and stillbirths. During the late gestation period, the abortion rate can exceed 30.0%, and the piglets exhibit severe respiratory disorders, with a mortality rate of 35.0% ~ 40.0%. Infected sows can be detoxified through excretion in feces, saliva, milk, and so forth, but the detoxification cycle is lengthy (40).

PRRSV primarily infects macrophages and cells of the monocyte lineage, including dendritic cells (DCs) (40). Infection in a breeding pig results in significantly reduced immunity, leading to the development of mixed and secondary infections, further exacerbating the disease severity. PRRSV can modulate various inflammatory cytokines (Figure 3), including interferon-α (IFN-α), tumor necrosis factor-α (TNF-α), as well as interleukins such as IL-1, IL-8 and IL-10, to regulate the host innate immune response (41). PRRSV infection also reduces the expression of major histocompatibility complex (MHC) class II molecules on the surface of antigen-presenting cells. Additionally, the virus has been shown to induce the death of host cells through both apoptotic and necrotic mechanisms, thus inhibiting the functions of DCs and evading the host’s adaptive immune response (42, 43). It is also possible that PRRSV may reach the endometrial connective tissue by infecting endometrial vascular migrating mononuclear cells. Viral replication leads to local cellular infection and peripheral cell death, which in turn causes fetal detachment from the placenta or cellular degeneration, ultimately causing fetal death (44). Furthermore, PRRSV infection may result in inflammatory damage to the endometrium, placenta, blood vessels, and myometrium of pregnant sows. This may reduce the intensity of vascular endothelial growth factor (VEGF) immunostaining, which could affect cell proliferation at the maternal-fetal interface and submucosal angiogenesis and impact fetal viability (45, 46).

The primary objective of controlling PRRS is to prevent infection, establish optimal herd immunity, and minimize the risk of infection, which is a systematic process. PRRS vaccines can be broadly classified into live attenuated and inactivated vaccines. Two categories of live attenuated vaccines exist: those derived from classical strains and those derived from highly pathogenic strains (47). Given that PRRSV is an RNA virus, its high variability and rapid evolution pose significant challenges for the design and development of PRRS vaccines. Currently, attenuated applications are widely employed but face challenges such as revertant mutations, virulence enhancement, and strain recombination. Precise knowledge of the antibody titer of PRRS can ascertain the existence and severity of the disease, determine the immune status of the herd, and inform the improvement of the immunization strategy as needed, thereby reducing the clinical infection rate of PRRS and gradually achieving the goal of disease purification.

Epidemic encephalitis B is a zoonotic infection caused by the mosquito-borne Japanese encephalitis virus (JEV), which targets the central nervous system of both humans and animals. In its natural habitat, JEV primarily infects humans and animals via the “pig-mosquito-human” cycle. Pigs serve as “amplifying hosts” and represent the largest reservoir, multiplier and disperser of the virus. The virus can multiply in large quantities in pigs, resulting in overt viremia (48). JEV viral particles proliferate primarily in tissues, including connective tissue, skeletal muscle, cardiac muscle, smooth muscle, lymphoreticular tissue, and endocrine and exocrine glands, among others. The virus can also cross the blood–brain barrier to access the central nervous system, infecting neuronal cells. The pro-inflammatory and chemotactic factors released from the infected neuronal cells can activate microglia to produce more inflammatory factors, leading to an “inflammatory storm” in the central nervous system, which ultimately causes viral encephalitis and massive neuronal death (49, 50). Infection with encephalitis B in pigs is largely asymptomatic, although it can cause several other clinical signs, including high fever in fattening pigs, abortion in pregnant sows, stillbirth, mummified fetuses, and premature or delayed delivery, among other symptoms. It can also cause acute inflammation of the testes in boars, resulting in enlarged testes on one or both sides, followed by atrophy, hardening, and, ultimately, the loss of breeding capacity (51).

Vaccination has been demonstrated to provide a beneficial protective effect on infectious diseases such as Japanese encephalitis (JE), which are zoonotic and transmitted by insect vectors. However, it is not feasible to eradicate these diseases through vaccination alone. The three major types of vaccine currently in use worldwide are the inactivated mouse brain vaccine, the inactivated cellular vaccine, and the live attenuated encephalitis vaccine. The inactivated mouse brain vaccine is the most widely produced and used vaccine and is the only inactivated Japanese encephalitis B vaccine approved by the World Health Organization (WHO) and commercialized for human use (52). Therefore, it is necessary to implement a comprehensive strategy that includes industrial structure adjustment, mosquito control, intermediate host prevention, and final host immunization to effectively control JE epidemics.

Porcine circovirus (PCV) is a single-stranded circular DNA virus with four identified genotypes (PCV1 - PCV4) (53). PCV2 is the predominant genotype associated with postweaning multisystemic wasting syndrome (PMWS) and reproductive disorders in sows (54). PCV2 infection in sows can result in increased rates of return to estrus, abortion, and stillbirths. Furthermore, PCV2 can be vertically transmitted from the mother to the fetus, causing myocarditis and interstitial pneumonia. In severe cases, fetal mummification and death may occur (55). Epidemiological surveys conducted in Italy (2013–2018) revealed a rising prevalence of PCV2d detection in domestic pigs, with a similar trend observed in wild boars (56).

PCV2 can bind to cellular receptors via its capsid protein. Given the diversity of viral attachment receptors, PCV2 has the ability to infect multiple tissues and organs in pigs. Studies have shown that the likelihood of PCV2 infection varies among different pig breeds, indicating that pig genetics can influence the infectivity of PCV2 in the host (57). PCV2 can penetrate mature oocytes through a compromised zona pellucida and has the capacity to reduce the developmental competence of oocytes (58). In embryos with compromised zona pellucida, PCV2 infection significantly reduces survival rates, with only 6.4% of infected embryos surviving compared to 65.4% of negative controls (59).

Panax notoginseng saponins and arctigenin (ACT) can alleviate oxidative stress in mice infected with PCV2, thereby partially suppressing viral replication (60, 61). These findings offer novel therapeutic perspectives for PCV diseases (PCVD). Commercial PCV2 vaccines currently available include inactivated vaccines (Fostera^™ PCV, Circovac^®) and subunit vaccines (Porcilis^® PCV, Circumvent^®, Ingelvac CircoFLEX^®) (62).

Classical Swine Fever (CSF), an acute and highly contagious disease caused by Classical Swine Fever Virus (CSFV), poses a significant threat to pig health and the swine industry. CSFV, a single-stranded RNA virus, belongs to the genus Pestivirus within the family Flaviviridae (63).

CSF is endemic in regions of Central and South America, Eastern Europe, Asia, and Africa. While the prevalence of highly virulent CSFV strains has diminished in recent years, infections caused by moderately virulent strains persist. Morbidity can reach 100%, while mortality rates fluctuate according to viral strain virulence (64).

The effects of CSFV on sow reproduction are highly dependent on the gestational stage at which infection occurs. Early gestation infections may cause abortions, stillbirths, or fetal mummification. In contrast, infections during mid-to-late gestation that result in the live birth of persistently infected piglets can induce neurological disorders and growth retardation. CSFV exhibits immunosuppressive properties, causing a significant reduction in white blood cells in infected pigs, with apoptosis primarily occurring in the thymus, spleen, lymph nodes, and bone marrow (65). Moreover, CSFV can inhibit the host’s antiviral response through activation of the IL-10-STAT1 pathway (66).

Vaccination is a crucial strategy for CSF prevention. However, inactivated whole virus vaccines are neither effective nor available. Live attenuated vaccines (LAV) are extensively used in CSF-endemic regions but cannot distinguish between natural infection and vaccination. Conversely, the E2 subunit vaccine (Porcilis® Pesti) and the chimeric virus vaccine (Suvaxyn CSF Marker) have DIVA (differentiation of infected from vaccinated animals) capabilities, making them appropriate for settings where such differentiation is necessary (67).

Brucellosis is a zoonotic infection caused by the bacterium Brucella spp. (68), with approximately 500,000 new cases resulting from animal-to-human transmission occurring globally each year (69). The prevalence of Brucella in pig herds has been reported worldwide, with the infection rate in Europe being 17.4% (70). In the European Union, North America and Australia, the prevalence of Brucella suis (B. suis) in domestic pigs is lower due to the implementation of eradication programs. However, the risk of pathogen reintroduction in wild pigs persists (71), as shown by the higher prevalence in feral pigs (15.0%) than in domestic pigs (1.1%).

B. suis is currently subdivided into five biovars, with the primary biovars responsible for brucellosis in pigs being biovars 1, 2, and 3 (71). In regions outside of Europe, the main causative agents of swine brucellosis are biovars 1 and 3 (72), whereas in Europe, pigs are mainly infected with biovars 2 (73). Brucella is a facultative intracellular parasitic bacterium capable of evading the host’s innate and adaptive immune responses (74) and resistant to some antibiotics, thereby causing a characteristic pathological manifestation in the infected host. Cellular immunity plays a major role in eradication of the intercellular infection, while serum antibodies can only act against extracellular Brucella spp. Consequently, the immunity produced by immunization with inactivated vaccines is markedly weak. Currently, live attenuated vaccines are the most commonly used worldwide for preventing and controlling swine brucellosis. These include the live B. suis. Vaccine (S2 strain) developed in China, and the live B. abortus vaccine (SRB51 strain) developed in the United States (75, 76). These vaccines can be administered orally, subcutaneously, or intramuscularly to pigs. However, these live vaccines are inadequate for protecting swine against B. suis infection and pose a risk of infection to humans. Furthermore, it is difficult to differentiate between vaccine immunity and natural infection. At present, there are no commercially available vaccines for protecting domestic or feral swine against B. suis infection. Although not a feasible solution in all situations, whole-herd depopulation is the most effective regulatory mechanism for controlling swine brucellosis (71).

Listeriosis is a sporadic infectious disease of humans, livestock, and poultry caused by Listeria monocytogenes. The Centers for Disease Control and Prevention (CDC) estimates that there are approximately 1,600 infection cases and 260 deaths related to the disease annually (77). L. monocytogenes can invade various eukaryotic cells, including epithelial cells, fibroblasts and macrophages, among others (78) and disseminate to the placenta, fetus, and neonates, with approximately 14% of clinically confirmed cases occurring during pregnancy. In pigs, infection with L. monocytogenes is primarily associated with the development of meningitis, septicemia, and mononucleosis, as well as abortion in pregnant sows.

Once it has entered enterocytes, L. monocytogenes spreads throughout the body and subsequently crosses the placental and the blood–brain barriers, entering phagocytic and non-phagocytic epithelial cells and proliferating within these cells. Access to specialized phagocytic cells, such as macrophages, is a passive process, and active entry into non-phagocytic cells, such as intestinal cells, fibroblasts, endothelial cells, hepatocytes, and epithelial cells, necessitates the presence of two surface proteins, InlA and InlB (79). There is currently no effective vaccine available to prevent this disease. Treatment with antibiotics is usually needed for the control of the infection caused by Listeriosis (80). The administration of high doses of streptomycin, penicillin, gentamicin, and sulfonamides in pigs at the initial stages of the disease can result in favorable therapeutic outcomes. Nevertheless, treatment of suckling pigs with neurological symptoms often proves ineffective (81). In addition, certain Listeria strains have demonstrated resistance to commonly employed antibiotics (penicillin, gentamicin, and sulfonamides), complicating future control and treatment efforts (82).

Chlamydia is a febrile, chronic, and contact infectious disease caused by Chlamydia infection in pigs. Four species of Chlamydia can infect pigs: Chlamydia suis, C. psittaci (Cps), C. abortus, and C. pecorum (Cpe). The most prevalent form of cross-infection is between C. suis and C. abortus (83). Pregnant sows infected with Chlamydia tend to be asymptomatic, and the disease occurs most frequently in primiparous sows, with abortion rates ranging from 40.0 to 90.0%.

The pathogenic mechanisms of C. abortus and C. suis remain unknown. The infectious elementary body (EB) enters cells to form phagosomes, and Chlamydia’s major outer membrane protein family (MOMP) prevents phagosomes from fusing with lysosomes, thus facilitating the replication of Chlamydia within the phagosome and the destruction of host cells. Additionally, Chlamydia can produce endotoxin-like substances analogous to those produced by Gram-negative bacteria. These substances inhibit host cell metabolism and directly destroy host cells. The infected organism elicits a delayed hypersensitivity reaction, which results in immunopathological damage to tissue cells. Following infection, C. abortus induces the production of cytokines, including IFN-γ, TNF-α, IL-4, and IL-10, which can alter the infected cells and result in miscarriage (84). A recent study has demonstrated that host animals infected with C. abortus exhibit gut microbial dysbiosis, which may also contribute to abortion in animals (85).

Chlamydia is a multisymptomatic contact zoonosis that represents a significant public health concern. The implementation of an efficacious vaccination program has the potential to mitigate the morbidity and post-illness severity observed in animal populations while also serving to impede the further regional dissemination of C. abortus and the emergence of antibiotic resistance. Currently, commercial vaccines for swine chlamydiosis are not widely used in the pig industry and are largely confined to laboratory development and preclinical trials. The CPAF protein of Chlamydia trachomatis has recently been shown to be highly immunogenic in pigs (86). An experimental subunit vaccine targeting C. abortus has demonstrated protective immunity in piglets (87). However, the commercial C. abortus 1B vaccine strain for ruminants (Cevac® Chlamydia, Ceva Animal Health Ltd.) may still induce abortions in vaccinated animals, potentially facilitating the spread of C. abortus (88).

Leptospira spp. are spiral-shaped bacteria capable of surviving in diverse environments, particularly in warm and humid conditions (89). These bacteria can infect a wide range of animals, including pigs, and cause various diseases. Transmission occurs through contact with contaminated urine, water, or soil (90). In pigs, the most important serovars associated with reproductive issues include Bratislava, Pomona, and Tarassovi (91). These serovars can induce lesions in the uterus and placenta, impairing fertilization and embryo implantation, ultimately resulting in infertility or reduced conception rates (92, 93).

Leptospira spp. can rapidly enter the bloodstream, causing leptospirosis bacteremia, which induces a robust inflammatory response, leading to tissue damage and organ dysfunction. Additionally, these bacteria can evade the host immune system, resulting in persistent damage. Regular vaccination can effectively reduce the incidence of leptospirosis (94). Furthermore, enhancing the hygiene management of pig pens and preventing contact with contaminated water and soil can significantly lower the risk of transmission (95).

Campylobacteriosis, caused by Campylobacter spp., can significantly affect the reproductive system of sows, with the specific manifestations and severity varying depending on the bacterial strain and the host’s immune status.

Campylobacter is a genus of Gram-negative, spiral-shaped bacteria that are highly motile and obligate microaerophilic (96). The most common species associated with swine are Campylobacter coli and Campylobacter jejuni (97, 98). Although, these bacteria primarily colonize the gastrointestinal tract of pigs, their potential to cause reproductive disorders remains less well-documented than their effects on the digestive system.

In sows, Campylobacter infection can cause reproductive tract inflammation, including endometritis and cervicitis (99). Such inflammation can disrupt normal reproductive processes, leading to early embryonic loss, reduced fertility, and prolonged inter-estrus intervals (100). However, the specific pathological changes in the reproductive system of sows due to Campylobacter infection are less well-documented compared to those in cattle.

The pathogenicity of Campylobacter spp. is attributed to several virulence factors, including their ability to adhere to and invade host cells, produce toxins such as cytolethal distending toxin (CDT), and evade the host immune system (101, 102). Their spiral shape and motility facilitate penetration and colonization of mucosal surfaces, including those of the reproductive tract (103). In the context of reproductive disorders, these bacteria can trigger immune responses that cause inflammation and tissue damage, ultimately impairing reproductive function.

Preventing and controlling Campylobacter infections in swine requires a comprehensive approach. Regular monitoring of pig herds for Campylobacter presence facilitates early detection and management of infections. In cases of clinical infection, appropriate antibiotic treatment is essential; however, it should be used judiciously to prevent the development of antibiotic-resistant strains.

Erysipelothrix rhusiopathiae, a Gram-positive bacterium, is the primary etiological agent of swine erysipelas (SE) and can adversely affect sow reproductive performance. The bacterium comprises multiple serotypes, among which types 1a, 1b, and 2 are predominant in causing disease in pigs (104).

Surface proteins of E. rhusiopathiae, including SpaA, promote bacterial adhesion to host cells and recruit host plasminogen, thereby enhancing pathogenicity (105). The pathogenesis of E. rhusiopathiae in sows involves its capacity to induce systemic infections or septicemia, causing inflammation and tissue damage in multiple organs, including the reproductive system (106). The bacterium disseminates through the bloodstream, inducing lesions in the placenta and fetal tissues, which can lead to fetal death and abortion (107). Chronic infections may also result in endocarditis and arthritis, further impairing the sow’s overall health and reproductive performance (108).

Vaccination is essential for controlling erysipelas, with live attenuated vaccines or bacterins being commonly used (109). Pre-farrowing vaccination of sows boosts maternal antibody levels in piglets, offering enhanced protection against the disease.