Apoptosis in Bovine Viral Diarrhea Virus (BVDV)–Induced Mucosal Disease Lesions

Abstract

Cattle persistently infected with a noncytopathic Bovine viral diarrhea virus (BVDV) are at risk of developing fatal “mucosal disease” (MD). The authors investigated the role of various apoptosis pathways in the pathogenesis of lesions in animals suffering from MD. Therefore, they compared the expression of caspase-3, caspase-8, caspase-9, and Bcl-2L1 (Bcl-x) in tissues of 6 BVDV-free control animals, 7 persistently infected (PI) animals that showed no signs of MD (non-MD PI animals), and 11 animals with MD and correlated the staining with the localization of mucosal lesions. Caspase-3 and -9 staining were markedly stronger in MD cases and were associated with mucosal lesions, even though non-MD PI animals and negative controls also expressed caspase-9. Conversely, caspase-8 was not elevated in any of the animals analyzed. Interestingly, Bcl-x also colocalized with mucosal lesions in the MD cases. However, Bcl-x was similarly expressed in tissues from all 3 groups, and thus, its role in apoptosis needs to be clarified. This study clearly illustrates ex vivo that the activation of the intrinsic, but not the extrinsic, apoptosis pathway is a key element in the pathogenesis of MD lesions observed in cattle persistently infected with BVDV. However, whether direct induction of apoptosis in infected cells or indirect effects induced by the virus are responsible for the lesions observed remains to be established.

PD-1-Mediated PI3K/Akt/mTOR, Caspase 9/Caspase 3 and ERK Pathways Are Involved in Regulating the Apoptosis and Proliferation of CD4+ and CD8+ T Cells During BVDV Infection in vitro

“…The PI3K/Akt pathway plays an anti-apoptotic role through inhibiting the caspase 9 signaling cascade (37). In BVDV infected cattle, the expression of caspase 9 and caspase 3 is involved in lymphoid tissues lesions, but whether it directly induces apoptosis in infected cells or whether it is related to the PD-1 pathway remains unclear (38). In our study, by measuring the levels of p-PI3K, p-Akt, p-mTOR, p-ERK, cleaved-caspase 9, and cleaved-caspase 3, we confirmed that CP BVDV infection can inhibit the proliferation of CD4 + and CD8 + T cells and induce apoptosis via PD-1-mediated repression of PI3K/Akt/mTOR and ERK pathways and activation of the caspase 9/caspase 3 pathway.…”

Border Disease Virus Infection of Bovine Placentas

“…To confirm the presence of antigen, immunohistochemical staining used in this study provided a highly specific and sensitive method to assess the presence of BDV in placental tissue and fetal organs such as thyroid gland, tongue, and skin. 7,9,20,22,41 All uteri, placentas, and fetuses were macroscopically normal, and no histologic abnormalities were found in the fetal organs. There was histological evidence of inflammation in the placentomes of the 3 heifers in which virus could be identified by immunohistochemical staining, which differs from the placentitis observed in sheep infected with noncytopathic BDV, in BVDV-infected ewes, 29,35,39 and also in BVDV-PI fetuses of pregnant cows, in which placentitis is absent.…”

“…A role for the adaptive intrinsic apoptosis pathway has been reported in persistent pestiviral infections, as described for mucosal disease–associated lesions . 20 During normal pregnancy, this pathway is also known to be activated, as the number of apoptotic cells increases significantly in the maternal crypt epithelium, maternal stroma, and fetal chorionic epithelium. 5 We were unable to detect any enhanced activation of the pathway in infected animals compared to controls, suggesting it is unlikely to be significantly involved.…”

“…Whether apoptosis would be advantageous to the virus in this scenario is unclear; depending on the virus tropism and multiplication pathway, apoptosis may enhance viral spread or conversely be detrimental by reducing availability of target cells. 20,34…”

“…To characterize inflammatory cells present in the placentome, various antibodies were used, as described in Table 1. 20,21,41 For all primary antibodies employed, the secondary antibodies used were the anti-mouse or anti-rabbit EnVision HRP System (code No. K4001/4003; Dako, Agilent Technologies, Glostrup, Denmark) or the Dako Real Detection, anti-rabbit or anti-mouse (code No.…”