The acute phase of COVID-19 and the development of post-acute sequelae is reflected in blood gene expression


Two years into the SARS-CoV-2 pandemic, the post-acute sequelae of infection are compounding the global health crisis. Often debilitating, these sequelae are clinically heterogeneous and of unknown molecular etiology.

Here, a transcriptome-wide investigation of this new condition was performed in a large cohort of acutely infected patients followed clinically into the post-acute period.

Gene expression signatures of post-acute sequelae were already present in whole blood during the acute phase of infection, with both innate and adaptive immune cells involved.

Plasma cells stood out as driving at least two distinct clusters of sequelae, one largely dependent on circulating antibodies against the SARS-CoV-2 spike protein and the other antibody-independent. Altogether, multiple etiologies of post-acute sequelae were found concomitant with SARS-CoV-2 infection, directly linking the emergence of these sequelae with the host response to the virus.

Since the outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), over 232 million individuals have developed coronavirus disease 2019 (COVID-19) worldwide.

The post-acute sequelae of SARS-CoV-2 infection (PASC) comprise a broad array of symptoms that emerge after recovery in up to 30% of individuals, and over 40% of those requiring hospitalization1,2.

These symptoms include, among others, overall fatigue, dyspnea, smell and taste problems, and often last over long periods of time3-6. Elements of the immune response during the acute phase of COVID-19 have been shown to be associated with certain PASC outcomes6-10.

However, sample sizes to date have been small and the scope of molecular profiling limited. There is therefore a need to comprehensively characterize the molecular processes occurring upon infection that associate with subsequent development of PASC.

Here, whole-blood gene expression and antibody titers were profiled in a large cohort of hospitalized COVID-19 patients followed clinically into the post-acute period11. Multiple distinct acute phase gene expression signatures were identified, linking several immune cell types to post-acute sequelae.

At least two independent etiologies of PASC were found, distinguished by their dependence on the titers of antibodies against the SARS-CoV-2 spike surface protein.

Together, our results show that the molecular processes leading to PASC are already detectable during the acute phase of COVID-19, establish multiple distinct etiologies leading to different long- term outcomes, and directly link the emergence of these symptoms to the host-response to SARS-CoV-2 infection.


This report presents a transcriptome-wide investigation showing that processes leading to PASC have already started during hospitalization for acute COVID-19. At least two divergent etiologies for different sets of symptoms were identified, one dependent and one independent from the antibody response to the SARS-CoV-2 spike protein.

These two points, taken together, suggest that study designs capturing only the post-acute phase risk missing a critical window into the pathogenesis of PASC. The association between acute-phase DE signatures and PASC introduces the potential for discovery of predictive molecular biomarkers.

Controlling for the clinical presentation of COVID-19 demonstrates that the molecular processes leading to PASC are not explained simply by acute severity.

This is consistent with the reported occurrence of PASC across the range of severity for SARS-CoV-2 infection1,2. Additional studies will be required to determine if our findings generalize to mild COVID-19 and asymptomatic infections. It is also anticipated that future studies of the relationship between acute infection and PASC will define additional symptom clusters with common underlying mechanisms. Knowledge of symptom- specific mechanisms will present opportunities to investigate precision treatment and prevention strategies.

Plasma cells are identified as playing a key role in PASC. The downregulation of genes involved in antibody production and function in the pulmonary symptom cluster was independent of the anti-spike antibody titers. The latter are representative of the specific immune response to SARS-CoV-2, thus suggesting a non-specific downregulation of humoral activity underlying pulmonary symptoms.

Conversely, the upregulation of genes involved in the same processes in the miscellaneous symptom cluster is largely dependent on the anti-spike antibody response, directly linking the symptoms in this cluster to the immune response to the virus.

This antibody dependency could be explained by cross-reactivity of antibodies against SARS-CoV-212. Interestingly, two symptoms in this cluster (skin rash and smell/taste problems) also had separate titer-independent DE signatures, suggesting additional divergent etiologies for these symptoms. Beyond plasma cells, associations with PASC symptoms were seen for CD8+ and memory CD4+

T cells. The complex pattern of associations seen between cell-type DEGs and symptoms support the hypothesis that PASC is a complex set of traits with multiple etiologies.

Figure 1: Study workflow

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