The Interplay of NLRP3, Gasdermin-D, and C-Reactive Protein in Predicting Depression in Long-COVID

Abstract

Patients with COVID-19 are at risk for long-COVID (LC) symptoms after recovery. LC is associated with neuropsychiatric disorders and inflammatory symptoms. Depression is an important symptom that affects the everyday life of patients. In the present study, we recruited the leucine-rich-containing family, pyrin domain-containing-3 (NLRP3), Gasdermin-D (GSDMD), and C-reactive protein as tools for prediction of depression in LC patients. Leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome overactivation brought on by severe acute respiratory syndrome in certain instances, cytokine storm is also caused by coronavirus 2 (SARS-CoV-2). Gasdermin-D (GSDMD) is cleaved by caspase-1 upon caspase-1 activation, which causes pyroptosis, an anticipated cell death. Patients with COVID-19 also have elevated levels of CRP, another biomarker. In patients with COVID-19, elevated CRP levels have been linked to higher mortality, inflammatory alterations in chest CT scans, and severe infection. A vital initial line of defense against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is innate immunity one However, dysregulated innate immune responses can be harmful, leading to an overabundance of proinflammatory cytokines that worsen tissue damage. As an intravascular effector of innate immunity, immunothrombosis refers to complicated networks of molecular pathways and cellular interactions functioning to restrict the survival and spread of pathogens. When pro-inflammatory cytokines like interleukin-6 (IL-6) are stimulated, the liver is the primary source of the acute-phase protein known as C-reactive protein (CRP). It is a proven biomarker for tracking COVID-19 patients' rates of inflammation. By attaching itself to pathogen surfaces and injured cells, CRP plays a crucial part in triggering the innate immune response. Serum levels of NLRP3, GSDMD, were measured using the ELISA technique. Depression symptoms were estimated using the Hamilton depression (HAMD).  Results indicate a substantial rise (p<0.001) in median CRP levels in LC+Dep and LC groups compared to the control group.  Serum NLRP3 levels were considerably higher (p<0.001) in the LC+Dep group compared to LC patients and the control group.  The LC+Dep and LC groups had considerably greater GSDMD levels (p<0.001) than the control group, which had the lowest value. The partial correlation study among the study groups after controlling for age, weight, height, BMI, and smoking in LC patients showed significant correlation between total HAMD score and CRP, GSDRMD, and NLRP3. GSDMD has the best diagnostic ability for depression in LC patients at a cut-off value of 60.98 pg/ml indicating that the subjects may predict depression in LC patients with a significant sensitivity (69.8%) and specificity (69.9%).  The present study revealed the importance of inflammation and NLRPs and GSDMD in the pathophysiology of the LC symptoms. DSDRMD is the best predictor for depression in LC patients.