RIG-I-Mediated Antiviral Responses to Single-Stranded RNA Bearing 5'-Phosphates

The ability of viral infected cells to detect and initiate an antiviral response before the activation of immune responses is central to the control of intracellular infections. Recently, Hornung (1) and Pichlmair (3) showed that RIG-I can scan viral ssRNA to produce type I interferon that may block viral replication in infected cells. However, both studies used influenza ssRNA to transfect human HEK293 or mice NIH 3T3 cells to trigger RIG-I mediated antiviral response. Although these cell types clearly have the ability to detect and mount antiviral responses, they are not the preferred host target cells for virus attachment and infection. In vivo, influenza viruses primarily infect ciliated airway epithelial cells lining the respiratory tracts of mice and humans (4). Considering that an early antiviral response mounted by epithelial tissues would inhibit the spread of infection well before the involvement of immune cells, it is important to consider the expression pattern of RIG-I in lung tissues.

Using the serial analysis of gene expression (SAGE) method, which generates short, transcript-specific tags that can be sequenced at high throughput (5), the expression pattern of RIG-I gene was checked in a total of ten leukocytes and lung tissues. Surprisingly, a low level expression of RIG-I was detected in SAGE libraries prepared from the lung tissues. In contrast, SAGE libraries prepared from leukocyte cells showed moderate to high expression that coincides with their ability to detect and initiate antiviral responses. The detection of moderate and high numbers of RIG-I transcript in libraries of comparable sizes prepared from leukocyte cells confirmed that the low level expression of RIG-I tag was not the result of inadequate sampling or tag misidentification (6).

This result may explain why influenza viruses prefer to replicate in lung epithelial tissues. The evolutionary pressure may have shaped the virus to successfully co-opt host cell processes for replicating in epithelial lung tissues because of the low expression of RIG-I gene. In order to design therapeutic regimes, for augmenting RIG-I mediated antiviral responses, focus should be directed toward the selective induction of RIG-I expression in airway epithelial tissues.

References:

1. V. Hornunget al., Science 314, 994 (2006).

2. A. Pichlmair et al., Science 314, 997 (2006).

3. A. Ibricevic et al., J. Virol. 80, 7469 (2006).

4. V. E. Velculescu et al., Science 270, 484 (1995).

5. J. Stollberg et al., Genome Res. 10, 1241 (2000).

6. E. J. Evans et al., Immunity 19, 213 (2003).