Pregnancy-Associated Immune Features in COVID-19 Link Fetal Protection to Heightened Maternal Viral Risk 2334492

Introduction Pregnancy is a risk factor for increased severity of SARS-CoV-2 and other respiratory infections. The mechanisms underlying this risk have not been well-established, partly due to a limited understanding of how pregnancy shapes immune responses. Methods We assessed the differences between immune responses to SARS-CoV-2 in pregnant women and non-pregnant women, including the effects of disease severity, phase of illness (acute versus convalescent), and obesity. Using flow cytometry, single-cell multiomics, ex vivo immune cell stimulation, and unbiased immune correlative analyses. Results We found that CD8+ T cells in pregnant patients with severe/critical COVID-19 expressed elevated T cell exhaustion markers, such as PD-1 and T cell immunoglobulin and Tim-3. Further, we observed significantly down-regulated interferon-stimulated gene (ISG) responses in pregnant individuals with COVID-19 compared to non-pregnant COVID-19 counterparts. We identified altered T cell clonal expansion in pregnant patients with COVID-19, suggesting altered virus-mediated T cell responses in pregnancy. Relative to pregnant controls, COVID-19 infection in pregnancy was associated with suppressed monocyte function such as diminished cytokine and chemokine production. We also demonstrate that CD4+ and CD8+ T cells from obese pregnant women with COVID-19 produced increased inflammatory cytokine levels. Intriguingly, we found pregnancy was associated with a significantly increased level of circulating IL-27, a cytokine involved in T cell exhaustion. Using preclinical models, we demonstrated that augmented IL-27 resulted in more severe lung damage and increased mortality upon induction of respiratory viral infection, while protecting fetuses from maternal inflammation during pregnancy. Conclusion Our findings highlight mechanisms by which pregnancy influences maternal immune responses against viral infection. Funding Source Dongsun Oh was supported by a postdoctoral fellowship program (Nurturing Next-generation Researchers) through the National Research Foundation of Korea (2021R1A6A3A14044062)