Post-doc fellow Harvard Medical School Newton, Massachusetts, United States
Introduction/Rationale: 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.
