Pancreatic Acinar Cell-Specific Autophagy Disruption Reduces Coxsackievirus Replication and Pathogenesis In Vivo

Alirezaei M, Flynn CT, Wood MR, Whitton JL

Cell Host & Microbe 11:298-305, March 15, 2012

Speaker: Szu-Han Kuo (郭思含)                                  Time: 2012/9/19, 2:00-3:00 PM

Commentator: Dr. Ching-Chuan Liu (劉清泉教授)     Location: Room 601

Abstract

Autophagy plays different roles under various conditions. For example, it can protect the host from many infectious agents by inducing the lysosomal-mediated degradation of the pathogens. However, it is not an inevitable outcome, several viruses such as enterovirus, dengue virus had developed strategies by evading or even exploiting this homeostatic pathway to facilitate their replication. According to the previous study, coxsackievirus B3 (CVB3) which belongs to Enterovirus can induce autophagosome-like structures but blocks maturation to autolysosomes through unknown mechanism, so that it may increases viral replication and yield(Wong et al., 2008). In this paper, the authors took a genetic manner to study the effects of autophagy on CVB3 replication and pathogenesis, they generated Atg5^f/f/Cre⁺ and Atg5^f/f/Cre^- mice, which selectively deleting the autophagy essential gene Atg5 in pancreatic acinar cell with Cre recombinase gene knockout or not. EM studies confirm that the most acinar cells in Atg5^f/f/Cre⁺ mice are autophagy deficient but retain relatively normal cell morphology and the function is sufficient to permit normal host development, and the mice remain healthy. Under the CVB3 infection conditions, Atg5 gene deletion prevent pancreatic acinar cells form CVB3-induced pathology. In addition to autophagy, Atg5^f/f/Cre⁺ mice showed an ~2,000 fold lower viral titer in the pancreas as compared with theAtg5^f/f/Cre^- mice. In summary, CVB3 RNA replication and protein translation in Atg5^f/f/Cre⁺ acinar cells are reduced, but the subsequent steps in the virus life cycle are close to normal. It may be some residual autophagy carried out by a nonconventional, alternative, pathway(Nishida et al., 2009). Although, the authors claim that the inhibition of acinar cell autophagy by some specific compounds may shed light on the therapy to moderate the damaging effects of CVB3 in pancreas.

References

1. Nishida, Y., Arakawa, S., Fujitani, K., Yamaguchi, H., Mizuta, T., Kanaseki, T., Komatsu, M., Otsu, K., Tsujimoto, Y., and Shimizu, S. (2009). Discovery of Atg5/Atg7-independent alternative macroautophagy. Nature 461, 654-658.

2. Wong, J., Zhang, J., Si, X., Gao, G., Mao, I., McManus, B.M., and Luo, H. (2008). Autophagosome supports coxsackievirus B3 replication in host cells. J.Virol 82, 9143-9153.