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Review 2: "Single-cell RNA sequencing highlights a reduced function of natural killer and cytotoxic T cell in recovered COVID-19 pregnant women"

This study characterizes the immune landscape during active infection phase and recovery in pregnant females from COVID-19. Reviewers find the study potentially informative, with concerns over variability in gestation stage in different groups, and lack of functional follow-ups.

Published onSep 28, 2022
Review 2: "Single-cell RNA sequencing highlights a reduced function of natural killer and cytotoxic T cell in recovered COVID-19 pregnant women"
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Single-cell RNA sequencing highlights a reduced function of natural killer and cytotoxic T cell in recovered COVID-19 pregnant women

AbstractPregnancy is a complex phenomenon during which women undergo immense immunological change throughout this period. Having an infection with the SARS-CoV-2 virus leads to an additional burden on the highly stretched immune response. Some studies suggest that age-matched pregnant women are more prone to SARS-CoV-2 infection compared with normal healthy (non-pregnant) women, while alternative evidence proposed that pregnant women are neither susceptible nor develop severe symptoms. This discrepancy in different findings regarding the immune responses of pregnant women infected with SARS-CoV-2 virus is not well understood. In this study, we investigated how SARS-CoV-2 viral infection could modulate the immune landscape during the active infection phase and recovery in pregnant females. Using flow cytometry, we identified that intermediate effector CD8+ T cells were increased in pregnant women who had recovered from COVID-19 as opposed to those currently infected. Similarly, an increase in CD4+ T helper cells (early or late) during the recovered phase was observed during the recovery phase compared with infected pregnant women or healthy pregnant women, whilst infected pregnant women had a reduced number of late effector CD4+ T cells. CD3+CD4- CD8-NKT cells that diminished during active infection in contrast to healthy pregnant women were significant increase in recovered COVID-19 recovered pregnant women. Further, our single-cell RNA sequencing data revealed that infection of SARS-CoV-2 had changed the gene expression profile of monocytes, CD4+ effector cells and antibody producing B cells in convalescent as opposed to healthy pregnant women. Additionally, several genes with cytotoxic function, interferon signalling type I & II, and pro- and anti-inflammatory functions in natural killer cells and CD8+ cytotoxic T cells were compromised in recovered patients compared with healthy pregnant women. Overall, our study highlights that SARS-CoV-2 infection deranged the adaptive immune response in pregnant women and could be implicated in pregnancy complications in ongoing pregnancies.

RR:C19 Evidence Scale rating by reviewer:

  • Potentially informative. The main claims made are not strongly justified by the methods and data, but may yield some insight. The results and conclusions of the study may resemble those from the hypothetical ideal study, but there is substantial room for doubt. Decision-makers should consider this evidence only with a thorough understanding of its weaknesses, alongside other evidence and theory. Decision-makers should not consider this actionable, unless the weaknesses are clearly understood and there is other theory and evidence to further support it.



The manuscript titled ‘Single-cell RNA sequencing highlights a reduced function of one natural killer and cytotoxic T cell in recovered COVID-19 pregnant women’ by Abd Aziz et al., is potentially informative. The study profiled PBMC collected from pregnant women who are healthy, with acute SARS-CoV-2 infection, and convalescent expectant mothers. A number of findings reported here are in line with what is already known in the field— naïve CD4 lymphopenia, increase/loss of specific effector T cell subsets, and NK and myeloid cell activation—and add little to the current field.

Though the study uses a sample size of n=4 per group within infected/convalescent subjects, there is large variability in gestational age which could be the sole source of variability. For example, 2/4 of mothers in the acute infection group are at term, whereas 1/4 in the asymptomatic group are in their first trimester and 2/4 are in their second trimester. We know that the peripheral immune system changes significantly over the course of gestation—which the authors have highlighted as well—hence most of these findings are reliable if the sample cohort is larger and more homogeneous than the one presented.

Finally, while a large number of cells were profiled in the single-cell RNA-seq study, the analysis approach is not traditional or ideal. For example, the separation of T cell subsets is poor, and clustering as seen in the UMAP has not converged, hence identification of cell subsets is hard. Given these caveats, any reportage of scRNA-seq data is less reliable.

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