Genome-Wide Gene Expression Analysis Identifies the Proto-oncogene Tyrosine-Protein Kinase Src as a Crucial Virulence Determinant of Infectious Laryngotracheitis Virus in Chicken Cells

Li, Hai; Wang, Fengjie; Han, Zongxi; Gao, Qi; Li, Huixin; Shao, Yuhao; Sun, Nana; Liu, Shengwang

Targeting the host molecular network that governs the responses of host cells to ILTV infection is a promising strategy for controlling ILT in a way that is independent of host immunity. The underlying mechanisms governing ILTV-host interactions largely remain unclear, but they are important for developing novel strategies to control ILT. In the current study, we identified the Src-FAK interaction to be an essential determinant of ILTV-associated cell death in LMH cells. Based on our findings, we suggest a model where, upon ILTV infection, Src and FAK are phosphorylated and form a positive-feedback loop, thus subsequently re-ducing ILTV-induced host cell death but maintaining ILTV replication at high levels in host cells. However, in cells where either Src or FAK is inhibited, the phosphorylation of Src and FAK is disrupted, thereby disrupting the Src-FAK positive-feedback loop. This has the subsequent effect of enhancing the virulence of ILTV by making host cells more susceptible to ILTV-induced cell death, but it also limits ILTV replication. Furthermore, our in ovo studies revealed that Src inhibition induced death only in heavily infected embryos and not in embryos with mild infections, although significant reductions in the levels of viral replication were obtained in both cases (Fig. 5) . We speculate that in chickens with minor ILTV infections, Src or FAK inhibition can help to quickly clear infected cells and delay disease progression, thereby limiting pathological damage. In turn, this might provide sufficient time for the activation of a host anti-ILTV immune response, thus improving the clearance of residual infected cells. However, in chickens heavily infected with ILTV, the inhibition of host Src or FAK could exacerbate the pathological effects and even increase the likelihood of death, although viral replication might still be repressed. Further investigations of the molecular basis of the regulation of ILTV replication and ILTV-induced cell death by the Src-FAK interaction are required to develop strategies that can improve ILT control and reduce economic losses during therapy.