PD-1 Blockade Restores the Proliferation of Peripheral Blood Lymphocyte and Inhibits Lymphocyte Apoptosis in a BALB/c Mouse Model of CP BVDV Acute Infection

Abstract

Acute infection of bovine viral diarrhea virus (BVDV) is associated with immune dysfunction and can cause peripheral blood lymphopenia and lymphocyte apoptosis. Our previous study has confirmed that programmed death-1 (PD-1) blockade inhibits peripheral blood lymphocytes (PBL) apoptosis and restores proliferation and anti-viral immune functions of lymphocytes after BVDV infection in vitro. However, the situation in vivo remains to be further studied and confirmed. Therefore, in this study, we established a BALB/c mouse model of acute BVDV infection with cytopathic (CP) BVDV (strain NADL) and non-cytopathic (NCP) BVDV (strain NY-1). Then, we examined the mRNA and protein levels of PD-1 and programmed death-ligand 1 (PD-L1) in peripheral blood mononuclear cells (PBMC) from BVDV-infected mice and analyzed the effects of PD-1 blockade on the proportions of CD3+, CD4+, and CD8+ T cell subsets, the apoptosis and proliferation of PBL, and the production of IL-2 and IFN-γ. We found that leukopenia, lymphocytopenia, and thrombocytopenia were developed in both CP and NCP BVDV-infected mice at day 7 of post-infection. The mRNA and protein expression of PD-1 and PD-L1 were significantly upregulated in CP and NCP BVDV-infected mice. Moreover, PD-1/PD-L1 upregulation was accompanied by leukopenia and lymphopenia. Additionally, PD-1 blockade inhibited PBL apoptosis and virus replication, restored the proportions of CD3+, CD4+, and CD8+ T cell subsets, and increased IFN-γ production and p-ERK expression in BVDV-infected mice. However, blocking PD-1 did not significantly affect PBL proliferation and IL-2 production in NCP BVDV-infected mice. Our findings further confirmed the immunomodulatory role of PD-1 in peripheral blood lymphocytopenia in vivo and provided a scientific basis for exploring the molecular mechanism of immune dysfunction caused by acute BVDV infection.

In Vivo and In Vitro Antiviral Activity of Phlorizin Against Bovine Viral Diarrhea Virus

“…The anti-CP BVDV effects of phlorizin were significant. In previous studies, we have successfully established the mouse model of BVDV infection and confirmed that the viral load in the tissues and blood of mice was high and the histopathological change was evident at 7 d post-infection . In the present study, the protective effects of phlorizin on CP BVDV-infected mice were explored, taking the mouse as a model.…”

“…The mouse model of BVDV infection was established according to our previous reports . In the present study, BALB/c mice were randomly equally divided into six groups of six mice each to explore the effects of phlorizin on CP BVDV infection as follows: control group, BVDV group, phlorizin (6.25, 12.5, and 25 mg/kg) + BVDV groups, and phlorizin (25 mg/kg) group.…”

Integrative Transcriptomics and Proteomics Analysis Provide a Deep Insight Into Bovine Viral Diarrhea Virus-Host Interactions During BVDV Infection

“…A previous study reported that classical swine fever virus (CSFV) could induce lymphocyte apoptosis during infection ( 40 ). Recently, researchers have confirmed that BVDV could promote the expression of PD-1 to induce peripheral blood lymphocyte apoptosis ( 41 ). In this study, we observed that certain anti-apoptotic proteins such as BCL2A1, BIRC3, and NGF were significantly down-regulated in the BVDV-infected MDBK cells compared to their levels in the mock-infected MDBK cells.…”

Quercetin Inhibits Hsp70 Blocking of Bovine Viral Diarrhea Virus Infection and Replication in the Early Stage of Virus Infection

“…In our previous studies, we established a mouse model of BVDV infection [1]. In this study, we divided the mice into cp BVDV infection group, ncp BVDV infection group, control group, 50 mg/kg quercetin administration group, 100 mg/kg quercetin administration group, DMSO control group, 50 mg/kg quercetin + cp BVDV group, 50 mg/kg quercetin + ncp BVDV group, 100 mg/kg quercetin + cp BVDV group, and 100 mg/kg quercetin + ncp BVDV group.…”

“…Bovine viral diarrhea virus (BVDV), a positive-strand RNA virus of the genus Pestivirus in the Flaviviridae family, is the causative agent of viral diarrheal disease in bovines. Flaviviridae also includes critical human pathogens, such as West Nile virus (WNV), hepatitis C virus (HCV), yellow fever virus (YFV), dengue virus (DV), and Saint Louis encephalitis virus (SLEV) [1]. Acute infection of BVDV is associated with immune dysfunction and can cause peripheral blood lymphopenia and apoptosis.…”