The cytosolic sensor NLRP1 identifies viruses as non-self and triggers inflammatory responses
How epithelial cells ward off viruses
Among the proteins which recognize intruders is a class known as inflammasome sensors. Once activated, these sensors form inflammasome complexes, which then trigger a range of inflammatory responses that can in some cases lead to the death of the infected cell. A group of researchers at TUM, LMU and MPIB has now demonstrated that one such sensor found in skin cells binds directly to a specific molecular structure that arises during the replication of certain RNA viruses. The new findings underline the importance of epithelial cells as a barrier against invasive pathogens.
The NRLP1 protein was the first inflammasome sensor to be discovered and characterized. However, up to now it had remained unclear whether NLRP1 really functions as a direct sensor for non-self molecules, In humans, NLRP1 is found primarily in cells called keratinocytes, which form the outer layers of the skin and serve as a physical barrier against bacteria and viruses. The authors of the new study first tested how these cells react to viruses that differ in their modes of replication, and identified one – Semliki Forest Virus (SFV) – which strongly activated NLRP1. Other cells known to have barrier functions, such as cells of the bronchial epithelia, also responded to this virus by activating NLRP1, so this seemed to be a general phenomenon.
The Semliki Forest virus is found mainly in rodents and is an important model for research on viruses. In most of the cases – e.g. the Semliki Forest virus – the process of virus replication entails the synthesis of a complementary strand, which pairs with the parental strand to yield a double-stranded RNA. This makes them good candidates for recognition by the innate immune system: biochemical experiments have now confirmed that NRLP1 binds specifically to double-stranded RNA. “This type of sensor is difficult to work with, because they have a tendency to form aggregates,” explains first author Stefan Bauernfried. “Nevertheless, we were able to purify an NLRP1 construct, and we went on to show that is directly binds to and gets activated by double-stranded RNA.”
“Our findings suggest that NLRP1 is a key factor in the recognition of viral infections in barrier tissues like the skin,” says Andreas Pichlmair, Professor for Viral Immunopathology at the Institute for Virology at TUM. “It may be particularly important for the detection of viruses that are not optimally adapted to the potential host. Whether, and to what extent, it is also involved in the detection of other viruses which are pathogenic to humans remains unclear.” Last author Prof. Veit Hornung from LMU adds: “It’s not altogether unlikely that well adapted viruses have acquired the ability to inhibit this particular response mechanism.” The research team intends to explore this issue in future studies.
Stefan Bauernfried, Matthias J. Scherr, Andreas Pichlmair, Karl E. Duderstadt and Veit Hornung: Human NLRP1 is a sensor for double-stranded RNA. In: Science, 26 November 2020. DOI: 10.1126/science.abd0811