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Amino acid starvation accelerates replication of Ibaraki virus
- Onishi, Keiko, Shibutani, Shusaku, Goto, Nanami, Maeda, Yuki, Iwata, Hiroyuki
- Virus research 2019 v.260 pp. 94-101
- Epizootic hemorrhagic disease virus, acidification, amino acids, autophagy, endosomes, lysosomes, rapamycin, virus replication
- Ibaraki virus (IBAV) is a strain of epizootic hemorrhagic disease virus 2 that belongs to the genus Orbivirus of the family Reoviridae. IBAV replication is suppressed by the inhibition of autophagy, and since mechanistic target of rapamycin complex 1 (mTORC1) is a key regulator of autophagy, we examined if mTORC1 inhibition by amino acid starvation or mTOR inhibitors (Torin 1 and rapamycin) affects IBAV replication. We found that IBAV replication is significantly enhanced after amino acid starvation of host cells, but not after treatment with mTOR inhibitors, during early stages of viral infection (0–1 hpi). Notably, inhibition of mTORC1 by amino acid starvation was reversible and thus restricted to 0–1 hpi, whereas mTOR inhibitors sustainably suppressed mTORC1 even after the 1-h treatment, suggesting that mTORC1 suppression itself does not affect IBAV replication. To investigate the mechanism of enhanced IBAV replication by amino acid starvation, we examined the endocytic pathway, since IBAV utilizes acidification of endosomes as a trigger for viral replication. Accordingly, we found that amino acid starvation, but not mTOR inhibitors, strongly induced acidification of endosomes/lysosomes and that inhibition of endosomal acidification by bafilomycin A1 effectively blocked enhancement of IBAV replication. Altogether, the inactivation of mTORC1 by amino acid starvation during early stages of infection enhances acidification of endosomes, which in turn enhances IBAV replication.