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

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]

 

ETS1 (GeneCards)

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

 

Also highlighting this passage —

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

 

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]