Induction of apoptosis in bone marrow neutrophil-lineage cells by classical swine fever virus

Abstract

The pathogenesis of bone marrow atrophy during classical swine fever (CSF) was investigated in vitro by using CSF virus (CSFV) infection of bone marrow haematopoietic cells (BMHC). The monocytic lineage had the highest susceptibility to CSFV infection, whereas the more mature SWC8+ granulocytic cells were not directly susceptible to infection. However, myelomonocytic precursors were targets for CSFV infection and continued to differentiate into SWC8+ granulocytic cells, which remained infected. This explains the occurrence of infected peripheral blood granulocytes during CSF. The infection of BMHC resulted in increased apoptosis and necrosis, mainly within the granulocytic lineage. Caspases 3 and 9 were particularly activated, relating to the mitochondrial pathway of apoptosis. Interestingly, the majority of infected cells were non-apoptotic, the apoptotic cells being primarily non-infected. This indicated an indirect mechanism for induction of apoptosis, but no role could be identified for bone marrow stroma cells such as macrophages or fibroblastoid cells. Furthermore, soluble factors including cytokines and reactive oxygen species were not primarily responsible. In contrast, contact between infected and non-infected BMHC was critical for increasing apoptosis in the latter. Taken together, these results in vitro relate to and help to explain further the apoptosis of BMHC that occurs in vivo during CSF. This experimental system will also be particularly useful for the study of CSFV gene products involved in leukocyte apoptosis.