In coronavirus disease (COVID-19), the nucleotide-binding domain, leucine-rich repeat and pyrin domain-containing protein 3 (NLRP3) inflammasome is activated in response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Acute infections are accompanied by a sickness symptom complex (SSC) which is highly conserved and protects against infections and hyperinflammation. The aim of this study is to delineate the associations of COVID-19, SSC and NLPR3 rs10157379 T > C and NLPR3 rs10754558 C > G variants; and the protective role of SSC in SARS-CoV-2 infection. We recruited COVID-19 patients, 308 with critical, 63 with moderate and 157 with mild disease. Increased SSC protects against SARS, critical disease, and death due to COVID-19. Increasing age, male sex and rs10754558 CG significantly reduce SSC protection. The rs10157379 CT and rs10754558 GG genotypes are positively associated with SARS. Partial Least Squares analysis shows that a) 41.8% of the variance in critical COVID-19 symptoms is explained by SSC and oxygen saturation (inversely associated), inflammation, chest computed tomography abnormalities, increased body mass index, SARS and age (positively associated); and b) the effects of the NLRP3 rs10157379 and rs10754558 variants on critical COVID-19 are mediated via SSC (protective) and SARS (detrimental). SSC includes anosmia and dysgeusia, and maybe gastrointestinal symptoms. In conclusion, intersections among the rs10754558 variant , age, and sex increase risk towards critical COVID-19 by attenuating SSC. NLRP3 variants play an important role in SARS, and severe and critical COVID-19 especially in elderly male individuals with reduced SSC and with increased BMI, hypertension, and diabetes type 2.

No abstract

No abstract

No abstract

The early stage of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, may be accompanied by high activity of the nucleotide-binding domain, leucine-rich repeat and pyrin domain-containing protein 3 (NLRP3) inflammasome and a cytokine storm. The aim of the study was to construct Machine Learning (ML) models that predict critical disease, severity of Coronavirus Disease 2019 (COVID-19), and death due to COVID-19. This cross-sectional study recruited 528 COVID-19 patients divided into those with critical (n = 308) and non-critical (n = 220) disease. The ML models included baseline imaging, demographic, and inflammatory data as well as NLRP3 (rs10754558 and rs10157379) and IL18 (rs360717 and rs187238) genetic variants. Partial least squares analysis showed that 49.5% of the variance in severity of critical COVID-19 can be explained by SpO2 and the sickness symptom complex (SSC) (inversely associated), chest computed tomography alterations (CCTA), inflammatory biomarkers, severe acute respiratory syndrome (SARS), body mass index (BMI), type 2 diabetes mellitus (T2DM), and age (all 7 positively associated). In this model, the four NLRP3/IL18 gene variants showed significant indirect effects on critical COVID-19 which were completely mediated by inflammatory biomarkers, SARS, and SSC. Neural network models, which entered SSC, SARS, CCTA, SpO2, age, T2DM, hypertension, inflammatory biomarkers and gene variants, yielded a significant prediction of critical disease and death due to COVID-19 with an area under the receiving operating characteristic curve of 0.930 and 0.927, respectively. Our ML methods increase the accuracy of predicting the severity, critical illness, and mortality caused by COVID-19 and show that the genetic variants contribute to the predictive power of the ML models.