In COVID-19, NLRP3 inflammasome genetic variants are associated with critical disease and these effects are partly mediated by the sickness symptom complex: a nomothetic network approach

Abstract

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.

Lowered oxygen saturation and increased body temperature in acute COVID-19 largely predict chronic fatigue syndrome and affective symptoms due to LONG COVID: a precision nomothetic approach

“…It should be stressed that during the initial phase of COVID-19 infection, a sickness behavioral complex (SBC) is present, which includes physiosomatic symptoms such as muscle pain and tension, loss of appetite, fatigue, headache and probably also dysgeusia and anosmia (Maes, Tedesco Junior et al 2022). This SBC protects against severe and critical COVID-19 disease and is partly mediated by NLRP3 (nucleotide-binding domain, leucine-rich repeat and pyrin domain-containing protein 3 inflammasome) gene variants (Maes, Tedesco Junior et al 2022).…”

“…It should be stressed that during the initial phase of COVID-19 infection, a sickness behavioral complex (SBC) is present, which includes physiosomatic symptoms such as muscle pain and tension, loss of appetite, fatigue, headache and probably also dysgeusia and anosmia (Maes, Tedesco Junior et al 2022). This SBC protects against severe and critical COVID-19 disease and is partly mediated by NLRP3 (nucleotide-binding domain, leucine-rich repeat and pyrin domain-containing protein 3 inflammasome) gene variants (Maes, Tedesco Junior et al 2022). Nevertheless, the SBC is a beneficial short-lasting response confined to the acute phase of inflammation and should be discriminated from the affective and chronic fatigue symptoms which accompany the chronic inflammatory phase (Maes, Berk et al 2012, Morris, Anderson et al 2013).…”

The tryptophan catabolite or kynurenine pathway in COVID-19 and critical COVID-19: a systematic review and meta-analysis

“…Most importantly, during SARS-CoV-2 infection, the cytokine network is activated, with elevated levels of many pro-inflammatory cytokines such as interleukin (IL)-1β, IL-18, IL-6, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ [7][8][9][10]. Mild COVID-19 may progress into SARS with pneumonia (and lowered oxygen saturation and lung lesions on chest computerized tomography scan), intravascular coagulation, multisystem failure, and death if these pro-inflammatory cytokines are overproduced during a cytokine storm [2,7,8]. Profound tissue damage, even extending to organ failure, may be the consequence of enduring increases in IFN-γ secretion [11].…”

Combined effects of nucleotide-binding domain-like receptor protein 3 polymorphisms and environmental metals exposure on chronic kidney disease

“…These results imply that subjects with NLRP3 rs10157379 T allele may be associated with renal damage than those with C allele. In addition, a recent study found that the NLRP3 rs10157379 CT genotype was associated with the severity of severe acute respiratory syndrome (SARS) 44 . NLRP3 may also be related to host immunity and susceptibility to inflammation disorders 45 .…”