SARS-CoV-2 infection induces a long-lived pro-inflammatory transcriptional profile, 2023, Zhang et al.

[SNT Gatchaman]

SARS-CoV-2 infection induces a long-lived pro-inflammatory transcriptional profile
Zhang, Jia-Yuan; Whalley, Justin P.; Knight, Julian C.; Wicker, Linda S.; Todd, John A.; Ferreira, Ricardo C.

The immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in COVID-19 patients has been extensively investigated. However, much less is known about the long-term effects of infection in patients and how it could affect the immune system and its capacity to respond to future perturbations. Using a targeted single-cell multiomics approach, we have recently identified a prolonged anti-inflammatory gene expression signature in T and NK cells in type 1 diabetes patients treated with low-dose IL-2.

Here, we investigated the dynamics of this signature in three independent cohorts of COVID-19 patients: (i) the Oxford COVID-19 Multi-omics Blood Atlas (COMBAT) dataset, a cross-sectional cohort including 77 COVID-19 patients and ten healthy donors; (ii) the INCOV dataset, consisting of 525 samples taken from 209 COVID-19 patients during and after infection; and (iii) a longitudinal dataset consisting of 269 whole-blood samples taken from 139 COVID-19 patients followed for a period of up to 7 months after the onset of symptoms using a bulk transcriptomic approach. We discovered that SARS-CoV-2 infection leads to a prolonged alteration of the gene expression profile of circulating T, B and NK cells and monocytes. Some of the genes affected were the same as those present in the IL-2-induced anti-inflammatory gene expression signature but were regulated in the opposite direction, implying a pro-inflammatory status. The altered transcriptional profile was detected in COVID-19 patients for at least 2 months after the onset of the disease symptoms but was not observed in response to influenza infection or sepsis. Gene network analysis suggested a central role for the transcriptional factor NF-κB in the regulation of the observed transcriptional alterations.

SARS-CoV-2 infection causes a prolonged increase in the pro-inflammatory transcriptional status that could predispose post-acute patients to the development of long-term health consequences, including autoimmune disease, reactivation of other viruses and disruption of the host immune system-microbiome ecosystem.

Link | PDF (Genome Medicine)

 

[SNT Gatchaman]

Selected quotes from the discussion —

we show that SARS-CoV-2 infection leads to a long-lived alteration of the transcriptional landscape of immune cells in blood for over 2 months [...] a core set of co-regulated immune response genes display a pronounced and specific inverted expression profile from original discovery in an anti-inflammatory context (T1D patients treated with low-dose IL-2) compared to COVID-19 patients.

we provide evidence for a prolonged alteration of a systematic set of co-regulated genes that can be detected months after the resolution of acute symptoms. The long-term alteration of the immune system during the post-acute phase of the disease is usually asymptomatic, but it could affect the likelihood of PASC development

Our study supports the hypothesis that the transcription factor NF-kB plays a critical role in the establishment and maintenance of the observed transcriptional alteration. [...] Further work is therefore warranted to better understand the exact mechanism and combination of factors that contribute to the prolonged activation of the NF-kB signalling pathway observed in this study.

One hypothesis is that the cytokines produced during the acute phase of the disease have a longer period of biological activity in tissues. This could be caused by the maintenance of higher local concentrations of cytokines in the site of infection and associated immune tissues through the binding of cytokines to the extracellular matrix. Several pro-inflammatory cytokines, most notably TNF, have been previously shown to bind to the extracellular matrix, which could promote a much longer period of biological activity in tissues, thereby inducing the transcriptional signature detected in this study. A long-lasting immune alteration that also possibly reflects a continuing inflammatory stimulus or long-lived pro-inflammatory cytokines on the extracellular matrix has been reported in mild COVID-19 patients, with infection inducing a pro-inflammatory response in monocyte-derived macrophages that continues to be detected 3–5 months following SARS-CoV-2 infection.