UC San Diego

Flaviviruses such as dengue, Zika, West Nile, and yellow fever are dangerous viruses that pose a significant global health burden and have massive epidemic potential. Annually, these viruses infect over 400 million individuals worldwide and have been responsible for several pandemics in recent years. Flavivirus infection can result in hepatitis, microcephaly, liver cirrhosis, hemorrhagic shock, and even death. Despite these severe consequences, there are no available therapeutics for the majority of these flaviviruses . The initial response to flavivirus infection is characterized by the mass production of pro-inflammatory molecules in the host’s attempt to defend against pathogen invasion, causing widespread tissue damage through a phenomenon known as a cytokine storm. Consequently, it is crucial to investigate the host immune regulators that govern inflammatory multi-protein complexes called inflammasomes. Previous studies have highlighted the role of Nod-Like Receptor Protein 10 (NLRP10) in suppressing inflammation by inhibiting another human protein called pro-caspase-1 (pro-CASP1), a key component of many inflammasome systems. Therefore, we sought to determine what role NLRP10 played in the context of flavivirus-associated inflammation. Our findings reveal that NLRP10 is cleaved by diverse flavivirus proteases at amino acid site 265. However, this cleavage did not result in the restoration of inflammasome activation. Despite this, we also discovered that flaviviruses also independently antagonize inflammasomes. Collectively, our results demonstrate that flaviviruses exert evolutionary pressures on many inflammasome-associated proteins such as NLRP10, highlighting the intricacy of virus-host dynamics on a broader pan-flavivirus scale.