Ancient Cellular Pathway Important in Fighting Viruses

Akiko Iwasaki and Heung Kyu Lee

Autophagy, or self-cannabalism, plays a major role in the body’s antiviral immune response, according to a report in Science by Yale School of Medicine researchers.

“Our results imply that facilitating autophagy may be a benefit in antiviral therapies for certain single-stranded RNA viruses, such as the Rhabdoviruses and Paramyxoviruses, families that cause rabies and measles,” said Akiko Iwasaki, Ph.D., associate professor in the Department of Immunobiology and senior author of the study.

Autophagy is an evolutionarily conserved pathway that allows cells to digest organelles and materials in the cytosol, or cytoplasm, to survive starvation conditions.

Iwasaki said she and her colleagues found that this process in which parts of the cell are digested and recycled has a significant role in antiviral immune responses of plasmacytoid dendritic cells. The recycling process allows the immune system to recognize viral replication intermediates. It also allows secretion of type I interferons to combat viral replication.

Plasmacytoid dendritic cells are specialized for detecting infections by viruses. These cells have Toll-like receptor 7 (TLR7) that detect single-stranded RNA viruses in the lysosomes, which are organelles that act like a digestive tract within the cell. Previous studies indicated that TLR7 detects the single-stranded RNA (ssRNA) viruses as the engulfed viruses are degraded in the lysosomes.

“However,” Iwasaki said, “our study found that not all ssRNA viruses are detected in this way. Instead, for certain ssRNA viruses, such as the vesicular stomatitis virus (a Rhabdovirus) and Sendai virus (a Paramyxovirus), the plasmacytoid dendritic cells detect replication intermediates that are made when the virus reproduces in the cytosol.”

To understand the difference, the researchers looked at the autophagy pathway. They hypothesized that the process could be used by the plasmacytoid dendritic cells to transport cytosolic replication intermediates into the lysosomes to be detected by Toll-like receptor 7.

“By using plasmacytoid dendritic cells that are deficient in autophagy, we showed that recognition of vesicular stomatitis virus is diminished in these cells,” Iwasaki said. “We also discovered that autophagy is required for the secretion of type I interferons, which are key defense molecules against virus infections.”

Co-authors include Heung Kyu Lee of Yale; Jennifer Lund, now at the University of Washington; Balaji Ramanathan, now at the University of Prince Edward Island, and Noboru Mizushima of Tokyo Medical and Dental University.

The study was supported by the National Institutes of Health.

Science Express: February 1, 2007