Identification of an Immunological Signature of Long COVID Syndrome

Gisella Guerrera,Manolo Sambucci,Eleonora Timperi,Mario Picozza, Andrea Misiti,Roberta Placido, Silvia Corbisiero,Silvia D'Orso,Andrea Termine,Carlo Fabrizio,Francesca Gargano, Sharon Eleuteri,Luisa Marchioni,Veronica Bordoni, Luigi Coppola,Marco Iannetta,Chiara Agrati,Giovanna Borsellino,Luca Battistini

FRONTIERS IN IMMUNOLOGY（2025）

Santa Lucia Fdn IRCCS | Bambino Gesu Pediat Hosp | Policlin Tor Vergata Rome | Tor Vergata Univ

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Abstract

IntroductionAcute COVID-19 infection causes significant alterations in the innate and adaptive immune systems. While most individuals recover naturally, some develop long COVID (LC) syndrome, marked by persistent or new symptoms weeks to months after SARS-CoV-2 infection. Despite its prevalence, there are no clinical tests to distinguish LC patients from those fully recovered. Understanding the immunological basis of LC is essential for improving diagnostic and treatment approaches.MethodsWe performed deep immunophenotyping and functional assays to examine the immunological profiles of LC patients, individuals with active COVID-19, recovered patients, and healthy donors. This analysis assessed both innate and adaptive immune features, identifying potential biomarkers for LC syndrome. A Binomial Generalized Linear Model (BGLM) was used to pinpoint immune features characterizing LC.ResultsCOVID-19 patients exhibited depletion of innate immune cell subsets, including plasmacytoid and conventional dendritic cells, classical, non-classical, and intermediate monocytes, and monocyte-derived inflammatory dendritic cells. Elevated basal inflammation was observed in COVID-19 patients compared to LC patients, whose immune profiles were closer to those of healthy donors and recovered individuals. However, LC patients displayed persistent immune alterations, including reduced T cell subsets (CD4, CD8, Tregs) and switched memory B cells, similar to COVID-19 patients. Through BGLM, a unique adaptive immune signature for LC was identified, featuring memory CD8 and gd T cells with low proliferative capacity and diminished expression of activation and homing receptors.DiscussionThe findings highlight a unique immunological signature associated with LC syndrome, characterized by persistent adaptive immune dysregulation. While LC patients displayed recovery in innate immune profiles comparable to healthy and Recovered individuals, deficits in T cell and memory B cell populations were evident, differentiating LC from full recovery. These findings provide insights into LC pathogenesis and may support the development of diagnostic tools and targeted therapies.

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Key words

SARS-CoV-2 infection,Long COVID,immune response,immunological signature,post-acute sequelae of COVID19,immune dysregulation

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【要点】：论文发现了一种与长期COVID（LC）综合症相关的免疫学特征，这可能有助于LC的诊断和治疗。

【方法】：研究使用了深度免疫表型分析和功能测试，通过Binomial Generalized Linear Model（BGLM）来确定LC患者的免疫特征。

【实验】：实验对LC患者、活动性COVID-19患者、康复患者和健康捐赠者的免疫学特征进行了比较分析，使用了BGLM模型识别LC的免疫学特征，具体数据集名称未在摘要中提及。