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

The pathogenesis of bone marrow atrophy during classical swine fever (CSF) was investigated in vitro by using CSF virus (CSFV) infection of bone marro w haematopoietic cells (BMHC), The monocytic lineage had the highest suscep tibility to CSFV infection, whereas the more mature SWC8(+) granulocytic ce lls were not directly susceptible to infection. However, myelomonocytic pre cursors were targets for CSFV infection and continued to differentiate into SWC8+ granulocytic cells, which remained infected. This explains the occur rence of infected peripheral blood granulocytes during CSF, The infection o f BMHC resulted in increased apoptosis and necrosis, mainly within the gran ulocytic lineage. Caspases 3 and 9 were particularly activated, relating to the mitochondrial pathway of apoptosis, Interestingly, the majority of inf ected cells were non-apoptotic, the apoptotic cells being primarily non-inf ected. This indicated an indirect mechanism for induction of apoptosis, but no role could be identified for bone marrow stroma cells such as macrophag es or fibroblastoid cells, Furthermore, soluble factors including cytokines and reactive oxygen species were not primarily responsible. In contrast, c ontact between infected and noninfected BMHC was critical for increasing ap optosis 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 C SF, This experimental system will also be particularly useful for the study of CSFV gene products involved in leukocyte apoptosis.