Silke Rautenschlein
Clinic for Poultry
School of Veterinary Medicine
Hanover, Germany
Besides the ability of many widespread avian viruses to cause clinical diseases, a number of viruses are capable of causing immunosuppression. Immunosuppression has great economic importance for the poultry industry, because affected flocks are susceptible to secondary infections, respond poorly to vaccines, and they do not perform as good as non-affected birds.
Some of the economically significant immunosuppressive viruses are Marek's disease virus (MDV), hemorrhagic enteritis virus (HEV), chicken infectious anemia virus (CIAV), infectious bursal disease virus (IBDV) and reovirus (REOV). Although these viruses are immunosuppressive, the way they affect the immune system varies. While CAV and MDV affect significantly the cellular branch of the specific immune system, HEV and IBDV affect more the humoral branch. MDV reduces also functions of the innate immune system such as phagocytosis and natural killer cell activity. New advances in avian immunology research progress the understanding of immunosuppressive mechanisms of viruses.
In the following immunosuppressive mechanisms by avian viruses such as IBDV and CAV are discussed.
Immunosuppression
The cells of the specific immune system and the non-specific, also called innate, immune cells stay in close communication with each other (Figure 1). This communication can be either mediated by soluble factors, for example cytokines, or by cell-to-cell contact. Infections may destroy the equilibrium or functions of immune cells and the immune cell 'orchestra' will be out of balance, which results in immunosuppression.
Immunosuppression can be induced by a variety of events such as management problems and infectious agents. Some of the important immunosuppressive viral diseases are infectious bursal disease (Kim and Sharma, 2000; Lukert and Saif, 2003; Sharma et al., 2000); hemorrhagic enteritis (Pierson and Fitzgerald, 2003; Rautenschlein and Sharma, 2000); Marek's disease (Schat and Markowski-Grimsud, 2002; Witter and Schat, 2003); Reovirus (Rosenberger, 2003; Sharma et al., 1994) and Pneumovirus infection (Chary et al., 2002; Gough, 2003); and chicken infectious anemia (Schat, 2003).
In commercial poultry flocks, immunosuppression may be manifested clinically in a number of ways depending on age, the infectious agent, or genetic background. In general, the flock performance is affected. Specifically, immunosuppressed flocks tend to experience an increased incidence of secondary infections, poor feed conversion, reduced protective response to commonly used vaccines, and increased carcass condemnation rates at the processing plant.
In the following section the pathogenesis and immunosuppressive mechanisms of infectious bursal disease virus (IBDV) and chicken infectious anemia virus (CIAV) will be presented to demonstrate how manifold viruses can interact with and affect the avian immune system.
Infectious bursal disease virus (IBDV)
IBDV causes an acute, highly contagious and immunosuppressive disease in young chickens (Lukert and Saif, 2003). The virulence of the IBDV-strain, the genetic background and age of the chickens as well as the residual maternal antibodies may influence the outcome of IBDV immunopathogenesis. Recent studies have shown that the induction of pro-inflammatory cytokines following IBDV infection may vary depending on the strain of IBDV (Eldaghayes et al., 2004).
The cells of the specific and also of the innate immune system are temporary affected by IBDV (Figure 2). The main target cells for IBDV replication are the actively dividing B-lymphocytes. Destruction of the immunoglobulin-producing cells is the principal cause of IBDV-induced immunosuppression, which leads to significant impairment of the primary antibody response (Kim et al., 1999; Rosenberger and Gelb, 1978).
Recent studies indicate that the susceptibility of intrabursal B cell populations for IBDV may differ (Petkov et al., 2005). Depending on the virulence of the IBDV-strain, birds may recover from IBDV-inducted lesions. Parallel with the restoration of the morphological structure of the bursa to normal architecture the antibody production also will recover (Kim et al., 1999). It is speculated that large bursal follicles of recovering birds are the product of de-novo follicle formation due to proliferation of bursal stem cells that escaped destruction by IBDV, while small follicles are formed from a surviving population of medullary B cells with restricted Ig repertoire (Withers et al., 2004).
T cells are also affected by IBDV. The in vitro mitogenic proliferation of splenic and peripheral blood T cells is severely compromised. This suppression in mitogenic response is mediated most probably by macrophages. Macrophages are activated by IBDV to release soluble factors such as cytokines and nitric oxide, which may mediate suppressive effects on other immune cells such as T cells (Khatri et al., 2005; Kim et al., 1998). But T cells are not only suppressed in their functions during IBDV-infection. Replication of IBDV in the bursa is accompanied by an influx of activated T cells at the site of virus replication (Poonia and Charan, 2004; Rautenschlein et al., 2002a; Tanimura and Sharma, 1997). Our studies suggest that these intrabursal T cells not only control IBDV-replication in the early phase of infection but also promote bursal tissue damage and delay tissue recovery through the release of inflammatory cytokines and cell-mediated cytotoxic effects (Kim and Sharma, 2000; Rautenschlein et al., 2002a; Rautenschlein and Haase, 2005).
Following infection with IBDV, the repopulation of bursa follicles was faster in T cell-deficient birds than in T cell-intact ones (Figure 3).
Besides IBDV-induced activation of macrophages, these cells are also susceptible to infection by IBDV (Sharma et al., 2005), which may result in reduced phagocytic activities contributing to immunosuppression. Earlier data suggest that the NK cell activity remained unaffected by exposure to IBDV (Sharma and Lee, 1983).
Chicken infectious anemia virus (CIAV)
Vertical transmission of the CIAV through the egg to the progeny chicks results in severe disease characterised by a generalised lymphoid atrophy, increased mortality, severe anemia and hemorrhages (Schat, 2003). Infection of older birds may be mainly immunosuppressive with reduced resistance to other pathogens (Smyth et al., 2001). The main target cells of CIAV are erythroid and lymphoid progenitor cells in the bone marrow and thymus, respectively (Figure 4). Although the virus is mostly lymphotropic, there is also evidence that CIAV can be present in the reproductive system (Brentano et al., 2005; Cardona et al., 2000). The B cells are not susceptible to CIAV infection. Destruction of erythroid progenitors in bone marrow results in severe anemia, and depletion of granulocytes and thrombocytes. Destruction of precursor T cells in the thymus cortex results in depletion of mature cytotoxic and helper T cells with consequent immunosuppressive effects (Adair, 2000; Markowski-Grimsrud and Schat, 2003). Interference of CIAV infections with the transcription of cytokines such as interferons was described (Ragland et al., 2001). Sixteen to eighteen days following infection, granulopoiesis and erythropoiesis activity is restored, and the immunocompetence of chickens returns to levels of their uninfected hatch mates (Smyth et al., 1993).
The appearance of CIAV-antibodies in the serum coincides with the disappearance of the virus from the blood and other lymphoid organs, and ultimately with the recovery of the infected chicken (Yuasa et al., 1993). But recent studies indicate that transmission to the progeny may occur irrespectively of the CIAV-antibody levels in hens (Brentano et al., 2004).
Veterinary intervention
The ultimate goal is the prevention of economic losses due to immunosuppressive viral infections. This will be achieved mainly through carefully chosen vaccination strategies. Flock management is essential, not only to reduce the risk of primary viral infections but also to prevent secondary infection, which are the main reason for economic losses due to immunosuppressive diseases. Treatments against viral diseases in poultry are not available so far. With recent cloning of avian cytokine genes the utilisation of cytokines as therapeutic agents for viral diseases in poultry as well as for vaccine adjuvants has become more feasible in the future (Asif et al., 2004; Li et al., 2004; Lillehoj et al., 2005; Lowenthal et al., 1998). Furthermore, some immunomodulary products have been experimentally tested and shown to reduce the severity of some viral induced lesions and consequently immunosuppression (Colledge et al., 2000; Rautenschlein et al., 2000; 2002b; Sun et al., 2005; Wang et al., 1993).
References are available on request
This paper was firstly presented at the 11th European Poultry Conference, Bremen, Germany and appears in the Proceedings.
