mTOR Signaling as a Central Regulator of Coronavirus Replication: Mechanistic Insights and Translational Opportunities

Abstract

Coronaviruses comprise a diverse group of enveloped, positive-sense single-stranded RNA viruses capable of causing high morbidity in humans and livestock. The repeated emergence of severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and SARS-CoV-2 underscores the critical need for broad-spectrum countermeasures. Mounting evidence demonstrates that successful coronavirus infection depends on the manipulation of host cellular pathways governing translation, metabolism, autophagy, and survival. The mechanistic target of rapamycin (mTOR) is an evolutionarily conserved serine/threonine kinase that functions via the mammalian target of rapamycin complex 1 (mTORC1) and complex 2 (mTORC2) to integrate extracellular and intracellular signals. Rather than remaining passive metabolic bystanders, coronaviruses actively exploit and rewrite host PI3K/Akt/mTOR networks to facilitate structural translation, assemble double-membrane replication organelles, suppress autophagic clearance, and reprogram protective innate and adaptive immune landscapes. This review provides a comprehensive synthesis of the molecular mechanisms dictating coronavirus–mTOR interactions across human pathogens and high-impact veterinary models. We detail the clinical consequences of dysregulated mTOR signaling—including immunometabolic perturbations, long-term metabolic memory, and tissue-specific complications—and evaluate the therapeutic potential of allosteric rapalogs, dual ATP-competitive inhibitors, and natural compounds as host-directed platforms designed to complement conventional antiviral regimens and enhance global pandemic preparedness.