Sex differences and immune correlates of Long Covid development, symptom persistence, and resolution

Nov 13, 2024Science translational medicine

How sex and immune factors relate to Long Covid development, lasting symptoms, and recovery

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Abstract

Acute COVID-19 leads to greater disease severity and mortality in males, while more females develop Long Covid.

Sex differences in immune response may contribute to varied outcomes in COVID-19 and Long Covid.
Males who later developed Long Covid showed increased transforming growth factor-β signaling during acute infection.
Females who developed Long Covid had reduced expression of TGF-β signaling during acute infection.
An RNA gene associated with autoimmunity was more highly expressed in females with Long Covid compared to those who recovered.
Common immune features of Long Covid included changes in the phenotype and activation state of monocytes across sexes.
There were up-regulations of nuclear factor κB transcription factors in various cell types during acute and convalescent phases.

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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 reducedexpression. Females who developed LC demonstrated increased expression of, 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 reducedexpression across lymphocyte subsets and elevated intracellular IL-4 in T cell subsets, suggesting thatalterations 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. TGFB1XIST ETS1ETS1

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Sex differences and immune correlates of Long Covid development, symptom persistence, and resolution

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