The NLRP3 inflammasome as a key pathway in the affective and chronic fatigue symptoms of Long COVID

Abstract The neuropsychiatric and somatic manifestations (physio-affective phenome) of Long COVID are substantially predicted by elevated peak body temperature (PBT) and diminished oxygen saturation (SpO 2 ) during the acute infectious stage. The latter is linked to the immune pathophysiology of Long COVID involving activation of the immune-inflammatory response system (IRS) and the NLRP3 inflammasome. Nevertheless, there is a lack of data indicating whether NLRP3 and its components are implicated in the physio-affective phenome of Long COVID. We enrolled 161 Long COVID patients 6 to 9 months after the acute phase and divided them into two groups based on the baseline PBT and SpO 2 levels, namely mild and severe acute COVID-19. We assessed serum NLRP3, caspase-1, C-reactive protein (CRP), interleukin (IL)-18, IL-1β, IL-10, fibronectin, and Gasdermin D (GSDMD) during Long COVID. All of the aforementioned indicators (with the exception of IL-10) were substantially higher in Long COVID patients who had previously experienced severe COVID-19 than in those who had mild acute COVID-19. The physio-affective phenome of Long COVID and the severity of the acute COVID-19 were significantly correlated with these IRS biomarkers, with the exception of fibronectin. The variance in the overall severity of Long COVID is accounted for (49.5%) by the combined influence of fibronectin, IL-10, SpO 2 , and PBT. In conclusion, the severity of Long COVID is strongly associated with IRS and NRLP3 activation and the severity of the inflammatory response during the acute infectious phase. NLRP3 activation is a drug target to treat Long COVID.