Sex differences and immune correlates of Long COVID development, persistence, and resolution, 2024, Hamlin et al.

[SNT Gatchaman]

Sex differences and immune correlates of Long COVID development, persistence, and resolution
Rebecca E Hamlin; Shaun M Pienkos; Leslie Chan; Mikayla A Stabile; Kassandra Pinedo; Mallika Rao; Philip Grant; Hector Bonilla; Marisa Holubar; Upinder Singh; Karen B Jacobson; Prasanna Jagannathan; Yvonne Maldonado; Susan P Holmes; Aruna Subramanian; Catherine A Blish

Sex differences have been observed in acute COVID-19 and Long COVID (LC) outcomes, with greater disease severity and mortality during acute infection in males and a greater proportion of females developing LC. We hypothesized that sex-specific immune dysregulation contributes to the pathogenesis of LC.

To investigate the immunologic underpinnings of LC development and persistence, we used single-cell transcriptomics, single-cell proteomics, and plasma proteomics on blood samples obtained during acute SARS-CoV-2 infection and at 3 and 12 months post-infection in a cohort of 45 patients who either developed LC or recovered.

Several sex-specific immune pathways were associated with LC. Specifically, males who would develop LC at 3 months had widespread increases in TGF-β signaling during acute infection in proliferating NK cells. Females who would develop LC demonstrated increased expression of XIST, an RNA gene implicated in autoimmunity, and increased IL1 signaling in monocytes at 12 months post infection.

Several immune features of LC were also conserved across sexes. Both males and females with LC had reduced co-stimulatory signaling from monocytes and broad upregulation of NF-κB transcription factors. In both sexes, those with persistent LC demonstrated increased LAG3, a marker of T cell exhaustion, reduced ETS1 transcription factor expression across lymphocyte subsets, and elevated intracellular IL-4 levels in T cell subsets, suggesting that ETS1 alterations may drive an aberrantly elevated Th2-like response in LC.

Altogether, this study describes multiple innate and adaptive immune correlates of LC, some of which differ by sex, and offers insights toward the pursuit of tailored therapeutics.


Link | PDF (Preprint: BioRxiv) [Open Access]

 

[SNT Gatchaman]

ETS1 (GeneCards)

In both sexes, those with persistent LC demonstrated increased LAG3, a marker of T cell exhaustion, reduced ETS1 transcription factor expression across lymphocyte subsets, and elevated intracellular IL-4 levels in T cell subsets, suggesting that ETS1 alterations may drive an aberrantly elevated Th2-like response in LC.

In summary, this study utilizes multiple modalities to uncover patterns of immune dysregulation that correlate with LC development, persistence, and resolution. Our discovery of sex-specific differences in immune response suggests that future mechanistic and therapeutic studies should consider stratification by sex, as supported by disproportionate impacts of severe acute disease in males and LC in females. We have also found several potential targets for intervention, most notably downregulation of ETS1 transcription factor and increased expression of Th2 cytokines in those with LC.

Corroborated by Blood transcriptomic analyses reveal persistent SARS-CoV-2 RNA and candidate biomarkers in post-COVID-19 condition (2024, The Lancet Microbe) —

Transcript ID ETS1-mRNA
Log2 fold change -0.664
std error (log2) 0.164
Lower confidence limit (log2) -0.986
Upper confidence limit (log2) -0.342
Linear fold change 0.631
Lower confidence limit (linear) 0.505
Upper confidence limit (linear) 0.789
FDR <5% Yes
P value 0.000156
q value 0.012954
Gene.sets probe.ID Growth Factor Signaling NM_005238.3:1305

 

[Hutan]

Genecards mentioned a link with Lupus.
Googling ETS1 and Lupus:
The role of the transcription factor Ets1 in lupus and other autoimmune diseases, 2016

One of the important genetic contributions to SLE development is an alteration in the expression of the transcription factor Ets1, which regulates the functional differentiation of lymphocytes. Here we review the genetic, biochemical and immunological studies that have linked low levels of Ets1 to aberrant lymphocyte differentiation and to the pathogenesis of SLE.

 

[Hutan]

There's a lot in this study - it's a bit overwhelming in terms of sorting out what is going on and what is worth looking at .

NFKB1, which is a primary component of the canonical NF-κB signaling pathway and induces cell proliferation and immune response programs (151), was found to have higher expression during acute infection in those who will develop LC at 3 months, as well as higher expression at 3 and 12 months in those with LC persisting to 12 months (Fig 7D).

Darker red means a stronger association between higher NFKB1 expression and Long covid at 12 months - for various cell types.
It's notable that there is no blue, which would indicate lower NFKB1 expression.
For males and females combined

 

[Hutan]

ETS1 - x axis has the scale, ETS1 is reduced in almost all cell types in people with Long covid at 12 months

 

[SNT Gatchaman]

Also highlighting this passage —

In this cohort, there were notable perturbations in innate and early adaptive immunity during acute infection that correlated with development of LC. Proliferating NK cells in males showed bidirectional TGF-β signaling, which would be expected to reduce NK cell cytotoxicity, as previously observed in severe COVID-19 (161), which may limit the efficacy of the initial antiviral response. Increased TGFβ1 expression was also found to be associated with LC development and persistence across many cell types, including naive and memory T cells, which may lead to reduced T helper 1 (Th1) differentiation (162) and impaired immunity against intracellular pathogens. Conversely, TGF-β signaling contributes to regulatory T cell differentiation, which may be important for avoiding self-reactivity (163). Interestingly, TGF-β has been previously suggested to play a role in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) (164) and was described to be increased in the plasma of males with LC in a pre-print study of a different LC patient cohort (165).

164 is Chronic fatigue syndrome and circulating cytokines: A systematic review (2015, Brain, Behavior, and Immunity) by a certain P.D. White, which stated —

The observations therefore seem to be consistent with a biologically significant elevation in the cytokine concentration in CFS. The clinical significance of a raised TGF-β is unclear in CFS, but its associations with clinical symptoms, severity and prognosis merits further evaluation.

 

[SNT Gatchaman]

Now published as —

Sex differences and immune correlates of Long Covid development, symptom persistence, and resolution
Rebecca E. Hamlin; Shaun M. Pienkos; Leslie Chan; Mikayla A. Stabile; Kassandra Pinedo; Mallika Rao; Philip Grant; Hector Bonilla; Marisa Holubar; Upinder Singh; Karen B. Jacobson; Prasanna Jagannathan; Yvonne Maldonado; Susan P. Holmes; Aruna Subramanian; Catherine A. Blish

Sex differences have been observed in acute coronavirus disease 2019 (COVID-19) and Long Covid (LC) outcomes, with greater disease severity and mortality during acute infection in males and greater proportions of females developing LC. We hypothesized that sex-specific immune dysregulation contributes to LC pathogenesis.

To investigate the immunologic underpinnings of LC development and symptom persistence, we performed multiomic analyses on blood samples obtained during acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and 3 and 12 months after infection in a cohort of 45 participants who either developed LC or recovered.

Several sex-specific immune pathways were associated with LC. Males who would later develop LC exhibited increases in transforming growth factor–β (TGF-β) signaling during acute infection, whereas females who would go on to develop LC had reduced TGFB1 expression. Females who developed LC demonstrated increased expression of XIST, an RNA gene implicated in autoimmunity, during acute infection compared with females who recovered. Many immune features of LC were also conserved across sexes, such as alterations in monocyte phenotype and activation state. Nuclear factor κB (NF-κB) transcription factors were up-regulated in many cell types at acute and convalescent time points. Those with ongoing LC demonstrated reduced ETS1 expression across lymphocyte subsets and elevated intracellular IL-4 in T cell subsets, suggesting that ETS1 alterations may drive aberrantly elevated T helper cell 2–like responses in LC.

Altogether, this study describes multiple innate and adaptive immune correlates of LC, some of which differ by sex, and offers insights toward the pursuit of tailored therapeutics.

Link | PDF (Science Translational Medicine) [Open Access]

 

[Hutan]

This is an interesting paper, especially with the corroboration of the reduced ETS1 finding.

Google AI said:

The transcription factor Ets1 is is highly expressed in B cells, particularly in naive B cells, and plays a key role in regulating B cell development and function:

Expression
Ets1 levels are high in naive B cells, but rapidly decrease after stimulation. This downregulation occurs within 2–4 hours of stimulation and remains low for at least 12 hours.

Function
Ets1 regulates B cell differentiation into plasma cells, and is necessary for maintaining B cells in a quiescent state. Ets1 also regulates antibody production and secretion.

Autoimmune diseases
Single-nucleotide polymorphisms (SNPs) in the human ETS1 gene have been linked to a variety of autoimmune diseases, including lupus.

Blimp1
Ets1 regulates B cell differentiation by interacting with the transcription factor Blimp1.Ets1 physically interacts with Blimp-1, blocking Blimp-1 DNA binding activity and reducing its ability to repress target genes.

Target genes
Ets1 regulates B cell differentiation through direct binding to target genes, including Pax5, which is crucial for maintaining mature B cell identity.

Ets1 is also expressed in T cells, and mice lacking Ets1 have excess B and T cell activation, leading to enhanced formation of Ab-secreting cells and high titers of autoantibodies.​

Ets-1 knockout mice develop increased numbers of IgM-secreting plasma cells.​

 

[wastwater]

Pax5 and B cells many articles out there on this

https://www.mypathologyreport.ca/pathology-dictionary/pax5/