[초청강연] Discovery of innate immune sensors in viral infections

Discovery of innate immune sensors in viral infections

SangJoon Lee

Department of Immunology, St. Jude Children’s Research Hospital, Memphis, USA.

Inflammasomes are important sentinels of innate immune defense, sensing pathogens
and inducing cell death in infected cells. There are several inflammasome sensors that
each detect and respond to a specific pathogen- or damage-associated molecular pattern
(PAMP or DAMP), respectively. Influenza A virus (IAV) infection triggers
inflammatory responses in the respiratory mucosa, but the mechanisms of
inflammasome activation are poorly understood. Using genome-wide high-content
shRNA library screening and proteomics analysis, we previously identified MxA as a
functional inflammasome sensor in respiratory epithelial cells and MxA inflammasome
contributes to IAV resistance by triggering a rapid inflammatory response in infected
respiratory epithelial cells (S. Lee et al., Science Immunology, 2019). During human
herpes simplex virus-1 (HSV1) infection, we found that AIM2 regulates the innate
immune sensors Pyrin and ZBP1 to drive inflammatory signaling and a form of
inflammatory cell death and provide host protection (S. Lee et al., Nature, 2021).

Regarding SARS-CoV-2, the cytosolic innate immune sensors that sense SARS-CoV-
2 to initiate inflammatory cell death are largely unknown. Using genome-wide

CRISPR/CAS9 knockout screening and RNAseq analyses from human patients, we
identified NLRPx as an inflammasome sensor that drives inflammatory cell death
during SARS-CoV-2 infection (S. Lee et al., Nature, under the revision). Overall, our
results improve our fundamental understanding of innate immune responses and
disease pathogenesis by identifying an innate immune sensor-dependent inflammasome
and inflammatory cell death pathway and by defining its contribution to the
pathological and life-threatening inflammation.