Host mTORC1 Signaling Regulates Andes Virus Replication.

McNulty S, Flint M, Nichol ST, Spiropoulou CF.

Source

Viral Special Pathogens Branch, The Centers for Disease Control and Prevention, Atlanta, GA.

Abstract

Hantavirus pulmonary syndrome (HPS) is a severe respiratory disease characterized by pulmonary edema with a fatality of 35-45%. Disease occurs following infection by pathogenic New World hantaviruses, such as Andes virus (ANDV), which targets lung microvascular endothelial cells. During replication the virus scavenges 5' m(7)G-caps from cellular mRNA to ensure efficient translation of viral proteins by the host-cell cap-dependent translation machinery. In cells, mammalian target of rapamycin (mTOR) regulates the activity of host cap-dependent translation by integrating amino acid, energy, and oxygen availability signals. Since there is no approved pharmacological treatment for HPS, we investigated whether inhibitors of the mTOR pathway could reduce hantavirus infection. Here, we demonstrate that treatment with an FDA-approved rapamycin analogue (temsirolimus, CCI-779) blocks ANDV protein expression and virion release, but not entry into primary human microvascular endothelial cells. This effect was specific to viral proteins, as temsirolimus treatment did not block host protein synthesis. We confirmed that temsirolimus targeted host mTOR complex 1 (mTORC1) and not a viral protein as knockdown of mTORC1 and mTORC1 activators, but not mTOR complex 2 components reduced ANDV replication. Additionally, primary fibroblasts from a patient with tuberous sclerosis exhibited increased mTORC1 activity and increased ANDV protein expression, which was blocked following temsirolimus treatment. Finally, we show that ANDV glycoprotein Gn co-localizes with mTOR and lysosomes in infected cells. Together, these data demonstrate that mTORC1 signaling regulates ANDV replication and suggest that the hantavirus Gn protein may modulate mTOR and lysosomal signaling during infection, thus bypassing the cellular regulation of translation.