Материал: Bovine Viral Diarrhea Virus Diagnosis, Management, and Control

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INTRODUCTION

Clinical manifestations of BVDV may include inapparent, acute, or persistent subclinical infections; fetal death and congenital abnormalities; wasting disease; severe acute disease (which may progress to hemorrhagic syndrome); or mucosal disease. The clinical outcome of infection depends on the immune status of the animal and time of infection. A complete understanding of the immune processes and immunogens of BVDV, as given in the next section, should be helpful in designing better preventive strategies for BVDV infections.

IMMUNE RESPONSES TO BVDV

BVDV strains vary in their tropism for bovine tissues. Hence, the effect of different strains of BVDV on the immune system also differs and may affect the type of disease exhibited. The natural route of transmission of BVDV is oronasal by contact with suspended droplets or mucus, although genital transmission may also occur. The virus first replicates in the nasal mucosa and tonsils from where white blood cells help spread the virus throughout the body by binding to surface receptors (Bruschke et al., 1998a, 1998b). Although the biochemical nature of BVDV receptors is not well understood, a 50 kDa protein is believed to be the viral receptor (Xue et al., 1997).

Pestivirus infections are associated with leukopenia, immunosuppression, and in some cases, hemorrhages. In general, the immunosuppressive properties of BVDV lead to a reduction in local defense mechanisms, thereby predisposing calves to other respiratory pathogens. Immune responses to BVDV may develop following vaccination, infection, exposure to cross-reactive pestiviruses, or by passively acquiring BVDV-specific antibodies from colostrum.

INNATE IMMUNE RESPONSE

The innate/natural (non–antigen-specific) immune response can influence the outcome of BVDV infection. BVDV can infect cells of the innate immune system (e.g., neutrophils, monocytes, macrophages, and dendritic cells) and affect their function (Potgieter, 1995; Glew et al., 2003; Lambot et al., 1998; Peterhans et al., 2002). Infection with BVDV may result in impairment of microbicidal, chemotatic, and antibody-dependent cell-mediated cytotoxicity of neutrophils (Potgieter, 1995). In monocytes, infection with cp BVDV may lead to apoptosis (Glew et al., 2003; Lambot et al., 1998). A 30–70% decrease in monocyte numbers may occur following infection of calves with virulent BVDV (Archambault et al., 2000). In vitro or in vivo infection of alveolar macrophages (AM) with BVDV may lead to decreases in phagocytosis, expression of Fc (FcR) and complement receptors (C3R), microbicidal activity, and chemotatic factors (Welsh et al., 1995; Liu et al., 1999; Peterhans et al., 2002). Infection of AM also causes increased LPS-induced (lipopolysaccharide) procoagulant activity, which can lead to bacterial colonization and may adversely affect the normal defense mechanism of the lung (Olchowy et al., 1997).

Cytokines can mediate the effects of both innate and specific immunity (Nobiron et al., 2001). Cytokines are small soluble proteins secreted by certain cells. They alter not only the function of cells producing them but also of other cells on which they might act. Tumor necrosis factor - (TNF- ) is a cytokine produced mainly by macrophages. It plays an important role in the activation of the immune response by modulating the production and activity of many other cytokines (Chase, 2004). Infection of AM with BVDV leads to a decrease in superoxide anion and TNF, enhanced nitric oxide (NO) synthesis in re-

sponse to LPS (Potgieter, 1995; Adler et al., 1994; Adler et al., 1997), stimulation of prostaglandin E2 synthesis (Van Reeth and Adair, 1997; Welsh and Adair, 1995), induction of IL-1 inhibitors (Jensen and Schultz, 1991), and a decrease in cytokine-induced chemotaxis (Ketelsen et al., 1979). Certain soluble factors released by infected monocytes and macrophages induce apoptosis when added to uninfected cells (Lambot et al., 1998; Adler et al., 1997). Apoptosis is the process that commits cells to programmed cell death to eliminate an infected cell and is believed to be the cause of lymphoid tissue pathology seen in mucosal disease and in disease caused by highly virulent BVDV (Liebler-Tenorio et al., 2003; LieblerTenorio and Ridpath, 2002; Stroffregen et al., 2000). Cytokines such as IL-2 and granulocyte-macrophage colony-stimulating factor enhance both humoral and cellular immune responses against BVDV and play a critical role in fetal-maternal interface by ensuring that pregnancy proceeds successfully (Graham et al., 1992). IL-1 is one of the endogenous pyrogens that act upon the hypothalamus to alter the regulation of body temperature.

Interferon (IFN) is the most important innate defense antiviral cytokine. Type I interferons are two serologically distinct proteins including IFN - produced by phagocytes and IFN-ß produced by fibroblasts. Viral infections, including BVDV infections, strongly signal the induction of type I IFN, which increases the cytotoxic potential of natural killer (NK) cells. Treatment of cells with high doses (104 units/ml) of human IFN - prevented the replication of both ncp and cp BVDV in vitro while that with human INF- , TNFor TNF-ß did not (Sentsui et al., 1998). Infection of the fetus with cp BVDV leads to IFN production, which probably prevents the establishment of persistent infection. Infection of the fetus with ncp BVDV does not induce IFNproduction although it did induce abundant amounts of all IFN ( , ß, and ) in gnotobiotic calves (Charleston et al., 2001a, 2002). These responses were associated with depressed levels of transforming growth factor beta (TGF-ß) in serum. These results indicate that the immunosuppression caused by ncp BVDV may not be associated with low interferon responses or elevated levels of TGF-ß (Charleston et al., 2001a).

Antigen-presenting cells (APC; dendritic cells, macrophages, and monocytes) internalize the viral antigen and present it to T-helper cells with assistance from IFNand IL-12. However, infection of APC with BVDV causes a reduction in Fc and C3 receptor expression, receptors that are required for

phagocytic activity (Welsh et al., 1995; Adler et al., 1996). It also reduces the ability of monocytes to present antigen to T-helper cells (Glew et al., 2003). Dendritic cells, the most important APC in the lymph node, on the other hand, were not affected in their ability to present antigen to T-helper cells or in surface marker expression (Glew et al., 2003).

HUMORAL IMMUNE RESPONSE

Although both active and passive humoral immune responses are protective, they differ in longevity and their ability to potentiate an immune response following a subsequent exposure. Antibody response to BVDV is detectable 2–3 weeks postinfection and may plateau in approximately 10–12 weeks postinfection (Howard et al., 1992). Humoral immunity, as detected by serum antibodies against BVDV, may result from an active immune response following an exposure to BVDV antigen (active immunity) or the ingestion of antibody present in colostrum (passive immunity). Three glycoproteins of BVDV (gp 53/E2, gp 48/E0, and gp 25/E1) induce neutralizing antibodies, with E2 protein being immunodominant (Bolin and Ridpath, 1990). Antibodies against several other viral proteins (115, 90, 48, and 25 kDa) have also been detected in some cattle (Bolin and Ridpath, 1990; Boulanger et al., 1991).

Colostral antibodies

Antibodies do not cross the placenta of cattle as they do in humans. Thus, calves receive passive immunity by absorption, through the gastrointestinal tract, of immunoglobulins contained in the ingested colostrum. However, calves can absorb colostral antibodies only during the first 24–48 hrs of life when their gastrointestinal tract is permissive to the transfer of these molecules across the mucosal epithelium, a phenomenon called “the open gut.” The highest concentration of BVDV antibodies in colostrum occurs only in the first few days of lactation after parturition. After that, the colostrum changes to normal milk and the amount of antibodies decreases rapidly.

Passive antibodies play an important role in protection from BVDV infection in the neonatal calf. However, the presence of high concentrations of maternal antibody in animals may block the induction of active B-cell immune response to BVDV vaccination. This has led to the suggestion that vaccination should be administered when passively acquired antibodies are declining (Ellis et al., 2001). However, T-cell immune responses have been observed when calves were infected intranasally with BVDV in the presence of maternal antibodies