Integrated immune, hormonal, and transcriptomic profiling reveals sex-specific dysregulation in long COVID patients with ME/CFS, 2025, Shahbaz et al.

[Chandelier]

https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(25)00522-1

Spoiler: Authors

Shima Shahbaz1 ∙ Mohammed Osman2,3,4,7 ∙ Hussain Syed5 ∙ Andrew Mason5 ∙ Rhonda J. Rosychuk6 ∙ Jan Willem Cohen Tervaert2 ∙ Shokrollah Elahi

Highlights​

• Female long COVID (LC) patients show heightened immune activation and inflammation
• Disrupted sex hormone levels differ between male and female LC patients
• Neuroinflammatory gene signatures may explain cognitive symptoms in females
• Sex-specific biomarkers suggest need for tailored LC therapies

Summary​

Long COVID (LC) manifests with sex-specific differences, particularly in those with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Our study reveals that female LC patients (LCF) with ME/CFS show a shift toward myelopoiesis, reduced lymphocytes, increased neutrophils/monocytes, and depleted regulatory T cells—suggesting persistent immune activation.
Elevated CD71+ erythroid cells and disrupted erythropoiesis contribute to fatigue and tissue damage in LCF. Cytokine profiling indicates a stronger pro-inflammatory response in LCF compared to males (LCM), along with markers of gut barrier dysfunction.
Hormonal analysis shows reduced testosterone in LCF and estradiol in LCM. Transcriptomic data reveal neuroinflammatory signatures in LCF, potentially explaining cognitive symptoms.
We also identify biomarkers that distinguish LCF from LCM and correlate with sex-specific clinical symptoms.

Overall, LC with ME/CFS is characterized by sex-specific immune, hormonal, and transcriptional alterations, with females exhibiting more severe inflammation. These insights underscore the need for sex-tailored interventions, including consideration of hormone replacement therapy.

Graphical abstract​

 

[Chandelier]

Women are three times more likely than men to get severe long COVID: Here’s why

U of A research published in Cell Reports Medicine reveals the underlying mechanisms that explain why women are three times more likely than men to have severe long COVID.

www.ualberta.ca

 

[Eleanor]

Importantly, most of the upregulated genes were associated with neuronal injury response and cognitive dysfunction. The most upregulated gene in LCF was the zinc-finger-containing gene (ZNF469; >6.7-fold), which is involved in neuronal differentiation34,35(Figure S6). Another significant upregulated gene, bone morphogenetic protein and retinoic acid (RA) inducible neural-specific protein 2 (BRINP2, >5.8-fold) (Figure S6), is associated with neurological development and disorders.36 The third most highly upregulated gene, forebrain embryonic zinc finger (FEZF2, >5.5-fold), is essential for deep-layer neuron development and function.

HOXC12, another upregulated gene (>5.1-fold), is involved in hematopoietic stem cell (HSC) and hematopoietic stem and progenitor cell (HSPC) renewal and differentiation.39,40 Similarly, zinc-finger homeobox 3 (ZFHX3; >4.8-fold), which is involved in neuronal differentiation34,35 and extracellular matrix (ECM) remodeling,41 was upregulated in LCFs (Figure S6). Reln (>4-fold), an extracellular matrix protein (Reelin) influencing synaptic plasticity and cognitive function,42,43 which has been reported to be elevated at the gene and protein levels in LC patients,17 was upregulated in LCFs

None of the top 20 genes in LCF overlapped with the top 20 genes in LCM. Notably, our comparative RNA-seq analysis revealed that the top 20 upregulated genes in LCM were enriched for pathways related to persistent innate immune activation, interferon signaling, mitochondrial stress, and inflammation. In contrast, the top 20 upregulated genes in LCF were associated with neuroinflammation and cognitive dysfunction, suggesting both qualitative and quantitative differences in transcriptomic activation between the sexes.

 

[forestglip]

Previous paper from many of the same authors has a very large overlap in upregulated genes.

From thread paper:

The most upregulated gene in LCF was the zinc-finger-containing gene (ZNF469; >6.7-fold), which is involved in neuronal differentiation34,35(Figure S6). Another significant upregulated gene, bone morphogenetic protein and retinoic acid (RA) inducible neural-specific protein 2 (BRINP2, >5.8-fold) (Figure S6), is associated with neurological development and disorders.36 The third most highly upregulated gene, forebrain embryonic zinc finger (FEZF2, >5.5-fold), is essential for deep-layer neuron development and function.37,38 HOXC12, another upregulated gene (>5.1-fold), is involved in hematopoietic stem cell (HSC) and hematopoietic stem and progenitor cell (HSPC) renewal and differentiation.39,40 Similarly, zinc-finger homeobox 3 (ZFHX3; >4.8-fold), which is involved in neuronal differentiation34,35 and extracellular matrix (ECM) remodeling,41 was upregulated in LCFs (Figure S6). Reln (>4-fold), an extracellular matrix protein (Reelin) influencing synaptic plasticity and cognitive function,42,43 which has been reported to be elevated at the gene and protein levels in LC patients,17 was upregulated in LCFs (Figures 6I and S6A).

Other upregulated genes include Ski family transcriptional corepressor 2 (SKOR2; >3.7-fold), linked to cerebellar Purkinje cells (PCs)44,45; RPL17-C18orf32 (>3.4-fold), a ribosomal protein associated with Alzheimer disease46; and Meis homeobox 2 (MEIS2; >3.2-fold), associated with neuronal dysfunction and intellectual impairment,47,48,49 which were also highly upregulated in LCFs versus RFs (Figure 6I).

Upregulation of olfactory receptors and neuronal-associated genes highlights complex immune and neuronal dysregulation in Long COVID patients, 2025, Shahbaz et al

Key findings include the upregulation of genes involved in immune dysregulation and neuronal development, such as Fezf2, BRINP2, HOXC12, MEIS2, ZFHX3, and RELN.

Similarly, Zinc-finger homeobox 3 (ZFHX3; > 4.5fold) and Zin-finger containing gene (ZFN469; > 4 fold), [...] were upregulated in LC patients (Fig. 3A).