Host Response to SARS-CoV-2 Infection and Its Role in PASC

Introduction: Post-Acute Sequelae of SARS-CoV-2 (PASC) syndrome or "Long COVID" represents a widespread health challenge that necessitates the development of novel diagnostic approaches and targeted therapies that can be readily deployed. Immune dysregulation has been reported as one of the hallmarks of Long COVID, but the extent of immune dysregulation in patients over time remains unclear.

Objective: The objective of the study was to analyze immune responses over time in Long COVID patients as well as patients who had fully recovered from a SARS-CoV-2 infection.

Methods: We therefore assessed SARS-CoV-2-specific antibody responses, peripheral immune cell profiles, autoantibody profiles and circulating cytokines for up to 6 months in participants with a SARS-CoV-2 infection who either convalesced or developed Long COVID. Compared to convalescent, Long COVID participants with a broad mix of Long COVID symptoms showed evidence of persistent increases in circulating antibodies against the SARS-CoV-2 virus even though the acute infection symptoms had resolved. Importantly, the increased levels in Long COVID participants were seen for antibodies which targeted the viral Envelope and Nucleocapsid proteins, but not the Spike protein which is targeted by vaccines. We also studied distinct immune cell populations in the blood using CyTOF analysis.

Results: We observed elevated numbers of circulating T follicular helper cells (cTFH) as well as mucosa-associated invariant T cells (MAIT), in Long COVID participants. Persistent immune activation was accompanied by augmented serum cytokine profiles with LIF, IL-11, Eotaxin-3, and HMGB-1 in Long COVID participants, who also demonstrated significantly higher rates of autoantibodies.

Conclusion/Discussion: These findings highlight the persistence of immune dysregulation in Long COVID as seen in the persistence of circulating antibodies targeting viral proteins and the presence of autoantibodies for up to 6 months. Our findings suggest that such immune dysregulation can be identified in the peripheral blood which could facilitate the diagnosis and monitoring of Long COVID in the outpatient setting. The presence of persistent anti-viral antibodies virus underscores the need to explore targeted therapies addressing viral persistence as well as dysregulated antibody production.

Key Topics:

• Assay and in vitro studies to gain mechanistic insights
• Chronic immune dysfunction
• Long-term follow-up of the RECOVER Cohorts
• Viral persistence/reactivation