Host mTORC1 signaling regulates andes virus replication.

Area of Science:

• Virology
• Molecular Biology
• Cellular Biology

Background:

• Hantavirus Pulmonary Syndrome (HPS) is a severe, often fatal respiratory illness caused by New World hantaviruses.
• Andes virus (ANDV) infects lung microvascular endothelial cells and hijacks host translation machinery by scavenging mRNA 5'-caps.
• The mammalian target of rapamycin (mTOR) pathway regulates cellular translation based on nutrient and energy availability.

Purpose of the Study:

• To investigate the potential of mTOR pathway inhibitors as a therapeutic strategy against HPS.
• To determine if inhibiting mTORC1 can reduce Andes virus replication and protein expression.

Main Methods:

• Treatment of primary human microvascular endothelial cells with temsirolimus, an FDA-approved mTOR inhibitor.
• Assessing viral protein expression, virion release, and host protein synthesis.
• Knockdown of mTORC1 components and analysis of viral replication.
• Examining ANDV replication in fibroblasts from a tuberous sclerosis patient with elevated mTORC1 activity.

Main Results:

• Temsirolimus treatment inhibited ANDV protein expression and virion release without affecting viral entry or host protein synthesis.
• Inhibition of mTORC1, but not mTORC2, components reduced ANDV replication.
• Elevated ANDV protein expression in tuberous sclerosis fibroblasts was reversed by temsirolimus.
• ANDV glycoprotein Gn was found to colocalize with mTOR and lysosomes in infected cells.

Conclusions:

• mTORC1 signaling is essential for Andes virus replication.
• The hantavirus Gn protein may interact with mTOR and lysosomal pathways to dysregulate host translation.
• mTORC1 inhibitors like temsirolimus represent a promising therapeutic avenue for Hantavirus Pulmonary Syndrome.