Long-term perturbation of the peripheral immune system months after SARS-CoV-2 infection

Abstract

Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly infectious respiratory virus which is responsible for the coronavirus disease 2019 (COVID-19) pandemic. It is increasingly clear that recovered individuals, even those who had mild COVID-19, can suffer from persistent symptoms for many months after infection, a condition referred to as “long COVID”, post-acute sequelae of COVID-19 (PASC), post-acute COVID-19 syndrome, or post COVID-19 condition. However, despite the plethora of research on COVID-19, relatively little is known about the molecular underpinnings of these long-term effects. Methods We have undertaken an integrated analysis of immune responses in blood at a transcriptional, cellular, and serological level at 12, 16, and 24 weeks post-infection (wpi) in 69 patients recovering from mild, moderate, severe, or critical COVID-19 in comparison to healthy uninfected controls. Twenty-one of these patients were referred to a long COVID clinic and > 50% reported ongoing symptoms more than 6 months post-infection. Results Anti-Spike and anti-RBD IgG responses were largely stable up to 24 wpi and correlated with disease severity. Deep immunophenotyping revealed significant differences in multiple innate (NK cells, LD neutrophils, CXCR3+ monocytes) and adaptive immune populations (T helper, T follicular helper, and regulatory T cells) in convalescent individuals compared to healthy controls, which were most strongly evident at 12 and 16 wpi. RNA sequencing revealed significant perturbations to gene expression in COVID-19 convalescents until at least 6 months post-infection. We also uncovered significant differences in the transcriptome at 24 wpi of convalescents who were referred to a long COVID clinic compared to those who were not. Conclusions Variation in the rate of recovery from infection at a cellular and transcriptional level may explain the persistence of symptoms associated with long COVID in some individuals.

Immune phenotypes that predict COVID-19 severity

“…CD95 expression was significantly elevated in both subsets from critical COVID-19 compared to all other groups (Bonferroni-adjusted P-value range 0.00965 -1.43*10 -7 ). In conclusion several immune traits in severe COVID-19 required prolonged time -up to 100 days after symptom onset -to reach baseline levels which can be several months which agrees with previous studies (19,20).…”

“…Most immune perturbations caused by COVID-19 disappear within 60 days post-infection, but some immune perturbations persist for weeks after viral clearance (19,20). In our study, the majority of immune traits were at baseline in recovered patients (Fig.…”

“…Thus, we looked for traits postrecovery and selected those traits for analysis which might be most informative based on GWAS. COVID-19 induced immune perturbations can persist after viral clearance and recovery (19,20). We hypothesized that immune cells could experience different fates during acute COVID-19 including i) not affected and remaining at baseline, ii) affected and deviating from healthy individuals only during active viral disease or iii) persistently affected even after viral clearance.…”

“…The latter results in delayed normalization back to baseline levels. We first aimed to identify these persisting immune perturbations which may contribute to long-lasting COVID19-related symptoms known as long COVID (19).…”

High-affinity FcγRIIIa genetic variants and potent NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC) responses contributing to severe COVID-19

“…These findings are of special interest because the immune exhaustion in convalescent patients with COVID-19 was recently proposed as a potential risk factor for “long-COVID,” a multi-symptomatic condition characterized by long-term sequelae appearing after the convalescence period of COVID-19. 19 …”