The immunopathology of post-acute sequelae of SARS-CoV-2 infection: highlighting the knowledge gaps

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In a recent article published in eLife, researchers highlighted the knowledge gaps in the immunopathology of post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (PASC), or long COVID and acute coronavirus disease 2019 (COVID-19).

The aim of the research was to help design studies and direct research efforts in this area, which, in turn, could help develop preventive strategies and therapeutics for both.

They focused on three salient mechanisms underlying various clinical PASC phenotypes – immunopathology, viral persistence, and tissue damage while reviewing the role of the innate and adaptive immune systems in the pathogenesis of acute SARS-CoV-2 infection and PASC.

Study: Immune mechanisms underlying COVID-19 pathology and post-acute sequelae of SARS-CoV-2 infection (PASC). Image Credit: tilialucida/Shutterstock.comStudy: Immune mechanisms underlying COVID-19 pathology and post-acute sequelae of SARS-CoV-2 infection (PASC). Image Credit: tilialucida/


Understanding the mechanisms underlying PASC is crucial for the development of appropriate precision therapies which could help restore healthy immune function in PASC patients. Though not released simultaneously, both granulocyte-macrophage colony-stimulating factor (GM-CSF) and cytokines are involved in the immune response to SARS-CoV-2 and possibly play a role in COVID-19 severity.

In most cases, after the virus clearance, the population of all immune cells activated in response to virus proliferation, e.g., T cells, decline and return to a resting state.

However, in some people, a subset of immune cells persists, leading to chronic inflammation, tissue damage, and other long-COVID symptoms.

Thus, the presence of viral RNA in plasma is an early indicator of PASC sequelae. The persistence of the virus in other sites, e.g., the gastrointestinal (GI) tract, olfactory system, or the brain, also drives PASC symptoms via activation of local immunity; however, it remains unclear whether there is a mechanistic tie between the two.

Innate and adaptive immunity in COVID-19 and PASC: role of neutrophils, macrophages, mast cells, and autoantibodies

Excessive neutrophil activation is an important predictor of whether the disease trajectory would take a more severe course. Researchers Kaiser et al. and Vanderbeke et al. have implicated the amplification of inflammatory and pro-thrombotic loops via interactions with other immune cells resulting in cytokine storms that govern neutrophil activation.

Likewise, neutrophil extracellular traps (NET) formation promotes severe COVID-19. NETs, released by neutrophils, are coated with cytosolic and granular proteins, such as calprotectin and neutrophil elastase, respectively.

Researchers have observed the maladaptive roles of NET formation in several respiratory diseases, e.g., asthma; thus, NETs formation is the second crucial prognostic information for risk-stratifying patients. Further research is needed to clarify which components of NETs drive the development of more severe PASC phenotype.

Some key questions to address include: i) does chronic and excessive neutrophil activation and an increased spontaneous NET formation in PASC augments further upon encountering de novo infectious and non-infectious stimuli; ii) also, whether it is possible to trace back changes in PASC neutrophil phenotype to their differentiation or maturation in the bone marrow.

A dysregulated monocyte/macrophage inflammatory response to SARS-CoV-2 possibly contributes to disease severity and mortality in COVID-19 patients. However, data on aberrant activation of monocytes and macrophages in PASC is scarce.

Furthermore, many PASC patients show symptoms that emulate mast cell activation syndrome (MASC). Wechsler et al. showed a significant elevation in active tryptase levels in sera (also correlated with IL-6 levels) during PASC compared to healthy controls. Thus, antihistamine drugs to treat MCAS could be effective.

The role of T-cells in COVID-19 is well-characterized; however, that is not the case with PASC. In acute and convalescent COVID-19 patients, it likely contributes to virus clearance, correlates with antibody responses, and helps protect against re-infection.

In individuals with PASC vs. other recovered COVID-19 patients, researchers observed lower and quickly waning SARS-CoV-2 nucleocapsid-specific CD8+ T cells. Conversely, another study documented that patients with pulmonary PASC have interferon-gamma (IFNγ)-producing SARS-CoV-2-specific T cells in much higher numbers.

A few studies also investigated longitudinal changes in T cell profiles and T cell dynamics in patients with PASC.

Large-scale, multi-omics analyses of patients with and without PASC have correlated PASC with the expansion of SARS-CoV-2-specific CD8+ and CD4+ T cell populations.

Deep immunophenotyping revealed that PASC was associated with increased adaptive immune cell populations, including activated B cells and interleukin-secreting CD4+ T cells.

The T-cell dynamics change in patients with other PASC syndromes, like multisystem inflammatory syndrome in children and adults, MIS-C, and MIS-A.

Thus, children with MIS-C have lower SARS-CoV-2-specific CD4+ and CD8+ T cell responses to SARS-CoV-2 antigens, e.g., spike (S) protein. Cheng et al. observed a shift toward TRBV genes in adults with severe acute COVID-19, but information on TCR repertoire shifts in adult patients with long COVID is scarce.

Nonetheless, several studies have found that T cell repertoire in patients of PASC syndromes has higher CD4+ and CD8+ T cells expressing the TRBV gene.

In severe COVID-19, multiple mechanisms govern the production of autoantibodies. In one scenario, genetically determined neutralizing autoantibodies against type I IFNs, may precede infection with SARS-CoV-2 and trigger new-onset rheumatic autoimmune diseases via bystander activation triggered by NETs formation and the cytokine storm.

It highlighted the need to define whether preexisting autoantibodies predispose COVID-19 patients to develop more severe forms of PASC immunopathology.

In a second scenario, IgG autoantibodies are produced de novo during infection, indicating that severe COVID-19 can break tolerance to self. Accordingly, Woodruff et al. found enrichment of extrafollicular B cells in subjects with severe and fatal COVID-19.

In a third scenario, reactivation of latent herpesviruses, e.g., Epstein-Barr virus (EBV), in tissues might give rise to autoantibodies in acute COVID-19 patients. However, the extent to which latent viral reactivation plays a role in autoimmunity and PASC warrants further investigation.

Similarly, the occurrence of PASC has links to autoimmunity. A study demonstrated high antinuclear antibodies (ANA) titers and neurocognitive symptoms in ~44% of patients a year after COVID-19 symptom onset.

Multiple other studies have documented a correlation between PASC and autoantibodies against G-protein-coupled receptors.

However, some studies, like those exploring autoantibodies against calprotectin, suggested a protective – rather than pathogenic – role for these autoantibodies, thus, raising the need for further investigation of the role of antibodies in PASC immunopathology.


The current understanding of PASC immunopathology is limited. Yet, scientists have ascertained that PASC has a complex immunopathology involving excessive activation and interplay between the adaptive and innate immune systems.

Thus, analysis of data from cohort studies like Researching COVID to Enhance Recovery (RECOVER) could help identify subjects with PASC who might benefit from immune-modulating therapies without compromising host defense.

Launched in February 2021, RECOVER engages >100 researchers across the United States (U.S.) studying PASC with the help of electronic health records and patient-completed surveys.

Journal reference:
Neha Mathur

Written by

Neha Mathur

Neha is a digital marketing professional based in Gurugram, India. She has a Master’s degree from the University of Rajasthan with a specialization in Biotechnology in 2008. She has experience in pre-clinical research as part of her research project in The Department of Toxicology at the prestigious Central Drug Research Institute (CDRI), Lucknow, India. She also holds a certification in C++ programming.


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