Type I Interferonopathy among Non-Elderly Female Patients with Post-Acute Sequelae of COVID-19, 2024, Xu, Qin

SNT Gatchaman · Sep 29, 2024

Type I Interferonopathy among Non-Elderly Female Patients with Post-Acute Sequelae of COVID-19
Xu, Donghua; Qin, Xuebin

The pathophysiological mechanisms of the post-acute sequelae of COVID-19 (PASC) remain unclear. Sex differences not only exist in the disease severity of acute SARS-CoV-2 infection but also in the risk of suffering from PASC. Women have a higher risk of suffering from PASC and a longer time to resolution than men. To explore the possible immune mechanisms of PASC among non-elderly females, we mined single-cell transcriptome data from peripheral blood samples of non-elderly female patients with PASC and acute SARS-CoV-2 infection, together with age-and gender-matched non-PASC and healthy controls available from the Gene Expression Omnibus database.

By comparing the differences, we found that a CD14+ monocyte subset characterized by higher expression of signal transducers and activators of transcription 2 (STAT2) (CD14+STAT2high) was notably increased in the PASC patients compared with the non-PASC individuals. The transcriptional factor (TF) activity analysis revealed that STAT2 and IRF9 were the key TFs determining the function of CD14+STAT2high monocytes. STAT2 and IRF9 are TFs exclusively involving type I and III interferon (IFN) signaling pathways, resulting in uncontrolled IFN-I signaling activation and type I interferonopathy. Furthermore, increased expression of common interferon-stimulated genes (ISGs) has also been identified in most monocyte subsets among the non-elderly female PASC patients, including IFI6, IFITM3, IFI44L, IFI44, EPSTI1, ISG15, and MX1.

This study reveals a featured CD14+STAT2 high monocyte associated with uncontrolled IFN-I signaling activation, which is indicative of a possible type I interferonopathy in the non-elderly female patients with PASC.

Link | PDF (Viruses) [Open Access]

SNT Gatchaman · Sep 29, 2024

Enhanced transcriptional activity of STAT2 can result in uncontrolled IFN-I signaling and type I interferonopathy [19,22].
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[22] has a thread at Severe type I interferonopathy and unrestrained interferon signaling due to a homozygous germline mutation in STAT2 (2019, Science Immunology)

Hutan · Sep 30, 2024

This study included a total of 41 female participants, consisting of 15 acute COVID-19 infection patients, 15 healthy controls, eight PASC patients, and three non-PASC controls from seven publications [8,9,10,11,12,13,14]
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Unfortunately, small sample sizes - only 8 PASC. And with the data coming from samples from seven publications, there could be problems with the selection of the people contributing the samples.

After integrating all sample datasets and quality control, a total of 207,563 immune cells were obtained from 41 scRNA-seq data of PBMC samples.
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I've got to say that it is impressive that there is a database that can offer this sheer quantity of data though.

There was no obvious difference in the percentages of monocytes, B cells, T cells, and NK cells between PASC and non-PASC controls (Figure 1D,E).
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but

Furthermore, no significant difference was observed for the percentages of monocytes, B cells, T cells, and NK cells between acute COVID-19 infection and healthy controls (Figure 1D,E). However, obvious differences in the percentages of monocytes, B cells, and NK cells between PASC and healthy controls were found (Figure 1D,E), which were likely to be caused by bias from the non-biological batch effect or technical variation among different experiments. There was alsoa significant difference in the percentages of NK cells between non-PASC controls and healthy controls (Supplementary Figure S1), which were likely to be biased by non-biological batch effects. There were significant differences in the percentages of B cells, monocytes, and NK cells between PASC patients and acute COVID-19 infection cases, which may also be attributed to non-biological batch effects or technical variations across different study cohorts (Supplementary Figure S1). Therefore, we mainly used outcomes of the comparison between the PASC group and the non-PASC group, which were from the same study cohort and could exclude the impact of those non-biological batch effects, and outcomes of the comparison between the acute infection group and the healthy control group, which had a low risk of non-biological batch effects.
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So yes, the authors were also concerned about 'non-biological batch effects', although perhaps the comparisons between the PASC group and nonPASC groups are ok. But, that means the comparisons are between 8 PASC and 3 non-PASC.

SNT Gatchaman · Sep 30, 2024

A previous study has suggested that PASC was associated with high expression of STING, cGAS, and IFN-α [25], which supports the findings in our study. In our study, increased expression of common ISGs has been identified in most peripheral monocyte subsets and other major immune cells from non-elderly female PASC patients, suggesting the crucial role of uncontrolled type I IFN signaling and/or type I interferonopathy in PASC. This finding provides new insights into the pathophysiological mechanisms of PASC.
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[25] is Severe COVID-19 and long COVID are associated with high expression of STING, cGAS and IFN-α (2024, Nature Scientific Reports)

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Type I Interferonopathy among Non-Elderly Female Patients with Post-Acute Sequelae of COVID-19, 2024, Xu, Qin

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