Attenuation of equine lentivirus alters mitochondrial protein expression profile from inflammation to apoptosis [Cellular Response to Infection]

Equine infectious anemia virus (EIAV) is an equine lentivirus similar to HIV-1, targets to host immune cells and causes life-long infection in horses. The Chinese live EIAV vaccine is attenuated from long-term passaging of a high virulent strain in vitro. The parent pathogenic strain (EIAVDLV34) induces a host inflammatory storm to cause severe pathological injury of animals. However, the vaccine strain (EIAVDLV121) induces a high level of apoptosis to eliminate the infected cells. To investigate how these processes are regulated, we performed a comparative proteomics analysis and functional study in equine monocyte-derived macrophages (eMDMs), and found that divergent mitochondrial protein expression profiles caused by EIAV strains with different virulence lead to disparate mitochondrial function, morphology and metabolism. This in turn promoted distinct transformation of macrophage inflammatory polarization and intrinsic apoptosis. In EIAVDLV34 infected cells, a high level of glycolysis and increased mitochondrial fragmentation were induced, resulting in M1-polarized pro-inflammatory type transformation of macrophages and subsequently producing a strong inflammatory response. Following infection with EIAVDLV121, the infected cells were transformed into M2-polarized anti-inflammatory macrophages by inhibition of glycolysis. In this case, decrease of mitochondrial membrane potential and impairment of electronic respiratory chain led to increased levels of apoptosis and ROS. These results are correlated with the viral pathogenicity loss and may help to understand the key mechanism of lentiviral attenuation.

IMPORTANCE

Following viral infection, the working pattern and function of the cell can be transformed through the impact on mitochondria. It still unknown how mitochondrial response changes in the cells infected with viruses in the process of virulence attenuation. EIAVDLV121 is the only effective lentiviral vaccine for large-scale use in world. EIAVDLV34 is a parent pathogenic strain. Unlike EIAVDLV34-induced inflammation storms, EIAVDLV121 can induce high levels of apoptosis. For the first time, we found that, after altering mitochondrial protein expression profile, EIAVDLV34 infected cells are transformed into M1-polarized type macrophages to cause inflammatory injury and the intrinsic apoptosis pathway is activated in EIAVDLV121 infected cells. These studies shed light on how the mitochondrial protein expression profile change from cells infected by pathogenic or attenuated lentivirus strains to drive different cellular response, especially from inflammation to apoptosis.

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