Immunopathogenesis, prevention and control of Bovine viral diarrhea virus
Type of Degreedissertation
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Bovine viral diarrhea virus (BVDV) is an important infectious agent that affects cattle worldwide (Baker, 1995; Houe, 1999). Acute infections with some strains of BVDV may cause immunosuppression and clinical signs of gastrointestinal, reproductive, and respiratory disease (Fulton et al., 2005a; Makoschey et al., 2001). Strategies to prevent and control BVDV include quarantine and other biosecurity measures to control the spread of infection within and between herds, identification and slaughter of persistently infected cattle, and vaccination (Brock, 2004; Kelling et al., 2000; Reber et al., 2006). An important factor in the evaluation of BVDV vaccine efficacy is rapidity in eliciting an adequate immune response to protect cattle from negative outcomes when exposed to the virus within a few days after vaccination. It was hypothesized that a single dose of a commercial modified-live virus (MLV) vaccine (containing BVDV type 1a and 2 strains) would protect cattle from acute BVDV infection when experimentally inoculated with a NY-1 BVDV soon after vaccination (3, 5, or 7 days post-vaccination). Our results indicated that modified-live BVDV vaccine administered 5 or 7 days before challenge prevented fever, viremia, and leukopenia in calves inoculated with NY-1 BVDV. However, a high proportion of calves vaccinated 3 days before challenge shed BVDV after inoculation. Infection of pregnant cattle with BVDV may result in abortions, stillbirths, or the birth of calves with congenital defects or persistently infected with BVDV (Baker, 1995). Persistent infections occur if a susceptible pregnant cow is infected with a noncytopathic (ncp) BVDV strain at 30 to 125 days of gestation (Brock et al., 2005). At this time of gestation the fetal immune system is not completely developed and not able to recognize BVDV as a foreign antigen; thus the fetus becomes immunotolerant of the infecting BVDV strain. Such calves continually shed large amounts of BVDV, representing a risk to susceptible herdmates (McClurkin et al., 1984). The efficacy of modified-live BVDV vaccines to prevent fetal infections and the development of PI animals has been previously evaluated, reporting values between 57.9 and 100% (Brock and Cortese, 2001; Brock et al., 2006; Cortese et al., 1998a; Dean et al., 2003; Fulton, 2005; Leyh et al., 2011; Rodning et al., 2010a). A major concern of MLV BVDV vaccines is the potential risk for contamination with foreign virulent strains becoming a source of spread of BVDV infections (Nuttall et al., 1977). In the second study of this investigation we showed evidence of abortions and BVDV fetal persistent infections following off-label immunization of pregnant heifers with a contaminated modified-live ncp BVDV vaccine. Even though the contaminated vaccine contained both ncp BVDV-1 and BVDV-2, qRT-PCR and nucleotide sequencing analysis revealed that vaccinated heifers developed only BVDV-2 PI fetuses. Furthermore, BVDV was apparently shed to unvaccinated heifers causing fetal infections from which only BVDV-1 was detected. The virulence of the BVDV strain has been correlated with the ability of the virus to cause a decrease in lymphocyte counts (Kelling et al., 2002b; Liebler-Tenorio et al., 2003a; Liebler-Tenorio et al., 2003b) and impair leukocyte function. Thus, highly virulent BVDV induce a significantly more severe and longer lymphopenia and lymphoid tissue depletion than less virulent BVDV (Kelling et al., 2002b; Liebler-Tenorio et al., 2002; Liebler-Tenorio et al., 2003b). The third and fourth studies of this research were focused on the evaluation of the early immune response (through the mRNA gene expression) following inoculation in beef calves with high or low virulence BVDV strains. These studies were performed to determine a possible association between BVDV virulence and the mechanisms by which this virus causes immunosuppression in susceptible cattle. The results demonstrated an up-regulation of type I interferon-induced antiviral state in spleen and tracheo-bronchial lymph nodes of calves inoculated with high and low virulence BVDV strains. A significant up-regulation of caspase-8 and -9 was observed in tracheo-bronchial lymph nodes in the calves inoculated with the low virulence BVDV (P=0.01), but not in those inoculated with the highly virulent BVDV-2 1373. There was a differential expression of some interferon-induced genes (OAS-1 and ISG-15) and pro-apoptosis markers based on BVDV virulence and genotype. In addition, experimental inoculation with BVDV-2 1373 stimulated a significant mRNA expression of both pro-inflammatory (TNF-α, IL-1β, IFN-γ, IL-2, IL-12, IL-15), and anti-inflammatory (IL-4, IL-10, TGF-β) cytokines. However, inoculation with BVDV-1 SD-1 only resulted in up-regulation of IL-12 and IL-15 mRNA, which are associated with activation of macrophages and NK cells during the innate immune response. The observed differential expression of early immune response after infection with low or high virulence BVDV might reflect differences in viral pathogenesis and could possibly determine the clinical outcome. The analysis of cytokine expression during the early events of immune response to BVDV could have important implications for selection of BVDV strains to be used for new vaccine production, since the efficacy of a vaccine will depend on how efficiently it stimulates the innate and early adaptive immune response.