Immune inhibitory receptor-mediated immune response, metabolic adaptation, and clinical characterization in patients with COVID-19.

Immune inhibitory receptors (IRs) play a critical role in the regulation of immune responses to various respiratory viral infections. However, in coronavirus disease 2019 (COVID-19), the roles of these IRs in immune modulation, metabolic reprogramming, and clinical characterization remain to be determined. Through consensus clustering analysis of IR transcription in the peripheral blood of patients with COVID-19, we identified two distinct IR patterns in patients with COVID-19, which were named IR_cluster1 and IR_cluster2. Compared to IR_cluster1 patients, IR_cluster2 patients with lower expressions of immune inhibitory receptors presented with a suppressed immune response, lower nutrient metabolism, and worse clinical manifestations or prognosis. Considering the critical influence of the integrated regulation of multiple IRs on disease severity, we established a scoring system named IRscore, which was based on principal component analysis, to evaluate the combined effect of multiple IRs on the disease status of individual patients with COVID-19. Similar to IR_cluster2 patients, patients with high IRscores had longer hospital-free days at day 45, required ICU admission and mechanical ventilatory support, and presented higher Charlson comorbidity index and SOFA scores. A high IRscore was also linked to acute infection phase and absence of drug intervention. Our investigation comprehensively elucidates the potential role of IR patterns in regulating the immune response, modulating metabolic processes, and shaping clinical manifestations of COVID-19. All of this evidence suggests the essential role of prognostic stratification and biomarker screening based on IR patterns in the clinical management and drug development of future emerging infectious diseases such as COVID-19.