Their research, published in the prestigious journal Molecular Cell, details the never-before-seen process of how the virus takes over the lung cells' machinery, hijacks their functions, and uses them to replicate itself, eventually causing extensive damage and cell death.
The researchers knew from earlier work that the virus uses a human cell's machinery, called the endoplasmic reticulum (ER), to make copies of itself. In healthy cells, the ER also makes proteins and lipids (fats) needed by the cell. However, how the virus gains control over the ER – in essence "hijacking" it – was not clear.
The team, led by Pei-Yong Shi, PhD, professor and chair of the Department of Biochemistry and Molecular Biology in the McGovern Medical School at UTHealth Houston, and co-led by Juan Jose Buey-Ramos, PhD, professor of virology in the Department of Infectious Diseases at MD Anderson, used cutting-edge imaging and other techniques to track the virus's entire life cycle in real-time inside lung cells.
They found that the virus induces the formation of specialized ER membrane structures, called spherules. These spherules become the hub and epicenter of the viral infection, where viral proteins are manufactured, and new copies of the virus are assembled.
"Using advanced microscopy and correlative light and electron microscopy, we found the virus reprograms the ER membrane, forcing the cell to make these unique spherules, which act like mini factories to facilitate efficient viral replication," said Shi, the corresponding author. "It was amazing to see the remarkable efficiency and speed at which the virus hijacks the ER and turns it into its primary replication center."
The spherules are formed around two viral proteins, called nsp6 and nsp7. These proteins are essential for viral replication and, when inhibited in previous experiments, severely impair viral replication.
The researchers also observed that excessive sphingomyelin, a type of lipid, accumulates within the spherules. Although the team does not yet fully understand the role of sphingomyelin, it is known to modulate membrane curvature and fluidity, and is essential for the formation of many small "transport vesicles" that bud from the spherules. These vesicles carry newly assembled viral RNA into nearby uninfected cells, ready to start the process anew.
"The remarkable transformation we observed of the ER into spherules has not been reported for other viruses. This unprecedented usurpation and transformation of the host ER, together with the presence of sphingomyelin, could potentially be targeted for therapeutic intervention," Shi said.
Further studies are needed to understand the precise role of the spherules and sphingomyelin in viral replication. However, this work provides critical new insights into viral pathogenesis and potential targets for the development of new antiviral drugs.
