Research progress on the mechanisms by which porcine circovirus type 2 infection causes immunosuppression

Circovirus infection is a newly discovered infectious disease. The disease has a relatively high infection rate in pigs and occurs widely throughout the world, having become one of the infectious diseases that seriously affect the development of the @#@227@#@ industry. Circovirus mainly attacks the pig immune system, interfering with and destroying the body's production and maintenance of immune antibodies against disease, resulting in reduced resistance and making pigs susceptible to secondary or concurrent other diseases. In recent years, scholars at home and abroad have conducted a great deal of research on the mechanisms by which porcine circovirus invades the immune system, and certain progress has been made in the virus replication mechanism, its effects on cytokines and lymphocytes, and its relationship with porcine dermatitis and nephropathy syndrome, laying the foundation for the prevention and treatment of porcine circovirus infection.

At present, most scholars believe that porcine circovirus type 2 (Porcinecircovirus2, PCV-2) is the main cause of postweaning multisystemic wasting syndrome (Postweaningmultisystemicwastingsyndrome, PMWS). PMWS was first discovered in western Canada in the mid-1990s, and was subsequently found in the United States, France, Germany, New Zealand, India, Korea, Japan and Hungary, among other countries. At the end of 2001, PMWS occurred in large-scale pig farms in some regions of southern China, and the epidemic broke out in 2002; it has now spread to almost all large-scale pig farms in the country. Retrospective antibody testing of archived sera from Europe showed that PCV-2 infection in pigs has a history of at least 30 years, and PMWS has existed in pig herds for at least 15 years, but no major changes have been found in the PCV-2 genome over the past 10 years.

PCV-2 requires some other predisposing factors or pathogens to assist it in promoting the occurrence of PMWS and causing infected pigs to develop extensive clinical symptoms and pathological changes. Examples include temperature factors (low temperature, high temperature), environmental factors (ammonia, endotoxin), stress factors (mixing of pigs, long-distance transport), immune stimulation (vaccines, adjuvants), and co-infection with pathogens (porcine reproductive and respiratory syndrome virus, pseudorabies virus, Haemophilus parasuis, Streptococcus, Pasteurella multocida and Salmonella) [1]. PCV-2-related PMWS in pigs has occurred and become epidemic worldwide, with mortality rates ranging from 10% to 30%; in more severely affected areas, such as porcine reproductive and respiratory syndrome (PRRS)-positive pig farms, the death and culling rate is as high as about 40%. PCV-2 also has immunosuppressive properties, which can prevent infected pigs from producing an effective immune response to other pathogens, making them susceptible to concurrent infection with other pathogens (such as Mycoplasma, bacteria, viruses, parasites, etc.), further complicating diseases on large-scale pig farms. Because of the harm caused by PCV-2 infection and the significant economic losses, the disease has been recognized by veterinarians and pig producers around the world as an important newly discovered swine infectious disease after PRRS, and has become a research hotspot for scholars in various countries; in particular, studying the immunosuppressive effect of PCV-2 will be of great significance for elucidating the pathogenesis of PMWS, preventing and controlling diseases on intensive pig farms, and developing PCV-2 vaccines.

1 PCV-2 can infect monocytes-macrophages and dendritic cells, but does not replicate within them.

PCV-2 is a monocyte-macrophage-tropic virus. Although PCV-2 antigen and its nucleotides can be detected in the cytoplasm of antigen-presenting cells, and even in lymphocytes, these cells are not the target cells for virus replication. Meehan BM et al. [2] observed the surface antigens of monocytes and monocytes-macrophages infected with PCV-2 by flow cytometry and found that the surface of these PCV-2-infected immune cells did not carry viral antigen. Comparing PCV-2-infected lymphocytes with PK-15 cells, PCV-2 progeny virus and intermediate products of viral replication were found in PK-15 cells, but no such analogues were found in lymphocytes. This indicates that these lymphocytes are not the target cells in which PCV-2 first replicates.

Dendritic cells (dendriticcell, DC) are the professional antigen-presenting cells (APC) with the strongest antigen-presenting function in the body. DC differ from other antigen-presenting cells in that their greatest feature is the ability to significantly stimulate the proliferation of naive T cells (naiveTcell), whereas B cells and macrophages can only stimulate already activated or memory T cells. Therefore, DC are the initiators of the immune response in the body. Studies have shown [3] that 80% to 90% of the interactions between DC and PCV-2 occur in the early stage of infection. Although no PCV-2 replication has been found in DC, the virus can persist in DC without losing infectivity and without causing DC death. When DC phagocytose PCV-2, they do not induce changes in surface antigens such as MHC class I molecules, MHC class II molecules, CD80/80L and CD25. PCV-2-infected DC will not re-infect homologous T lymphocytes with the virus, even if the T cells have been activated. Co-culturing T lymphocytes with PCV-2-infected DC does not cause PCV-2 replication or apoptosis of T lymphocytes and DC.

The pattern of PCV-2 infection of DC allows it not only to evade host immunity, but also to avoid causing DC apoptosis. Because DC can migrate within the host body, they can serve as a transport vehicle to assist PCV-2 in moving within the host body. Therefore, the depletion of lymphocytes in PMWS is not caused by direct virus replication in lymphocytes, and other factors should also be involved.

Even on day 125 after animals are inoculated with PCV-2, the virus can still be isolated from various tissues or viral DNA can be detected [4]. This ability to persist and continuously shed virus means that even after the host recovers, the immune system still cannot completely clear the virus. Therefore, on the surface PCV-2 appears harmless to the immune system, but viral infection is directly related to clinical symptoms. Chang HW et al. [5] found that co-infection with Gram-negative bacteria is an important promoting factor for PCV-2 replication and at least plays a certain role in the development of PMWS. Widespread infection of lymphoid follicle DC and other antigen-presenting cells by PCV-2 is a major feature of PMWS, but how great the impact of PCV-2 on lymphocyte depletion and destruction of their function is remains unclear.