SARS-CoV-2 niches in human placenta revealed by spatial transcriptomics

Barrozo, Enrico R.; Seferovic, Maxim D.; Castro, Eumenia; Major, Angela; Moorshead, David N.; Jochum, Michael D.; Rojas, Ricardo; Shope, Cynthia; Aagaard, Kjersti M.

doi:10.1016/j.medj.2023.06.003

Cited by 9 publications

(4 citation statements)

References 117 publications

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“…The maternal immune cells that populate the decidua include NK cells, macrophages, T cells, and dendritic cells [37], whereas the chorionic villous is composed of fetally-derived macrophages and invading maternal myeloid cells [38]. While abnormal placental pathologies, including inflammation and necrosis, are well documented [35,39], few studies have addressed how maternal SARS-CoV-2 impacts immunity in villous tissue within the fetal placental compartment [40][41][42][43]. In addition to placental inflammation, maternal SARS-CoV-2 infection is associated with altered cord blood immune cell composition including an increased frequency of memory T and B cells and nonclassical monocytes with maladaptive responses documented after immune stimulation [27].…”

Section: Discussionmentioning

confidence: 99%

“…In recent publications documenting the role of HBCs during maternal SARS-CoV-2 infection, expansion and activation of these cells was associated with elevated levels of myeloid cell recruiting chemokines [ 27 , 47 , 48 ]. Utilizing spatial transcriptomics, SARS-CoV-2 niches within the placenta have been described and shown to cause the depletion of M2 specific macrophages [ 43 ]. Our data may reflect HBC proliferation and hyperplasia, or specific HBC interactions with transplacental maternally-derived inflammatory proteins that have limited engagement with lining trophoblast cells.…”

Section: Discussionmentioning

confidence: 99%

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Maternal SARS-CoV-2 infection in pregnancy disrupts gene expression in Hofbauer cells with limited impact on cytotrophoblasts

Enninga,

Quach,

Jang

et al. 2024

PLoS Pathog

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Background Hofbauer cells (HBCs) and cytotrophoblasts (CTBs) are major cell populations in placenta. The indirect impact of maternal SARS-CoV-2 disease on these cells that are not directly infected has not been extensively studied. Herein, we profiled gene expression in HBCs and CTBs isolated from placentae of recovered pregnant subjects infected with SARS-CoV-2 during all trimesters of pregnancy, placentae from subjects with active infection, SARS-CoV-2 vaccinated subjects, and those who were unexposed to the virus. Methods Placentae were collected within 4 h post-delivery and membrane-free tissues were enzymatically digested for the isolation of HBCs and CTBs. RNA extracted from HBCs and CTBs were sequenced using 150bp paired-end reads. Differentially expressed genes (DEGs) were identified by DESeq2 package in R and enriched in GO Biological Processes, KEGG Pathway, Reactome Gene Sets, Hallmark Gene Sets, and Canonical Pathways. Protein-protein interactions among the DEGs were modelled using STRING and BioGrid. Results Pregnant subjects (n = 30) were recruited and categorized into six groups: infected with SARS-CoV-2 in i) the first (1T, n = 4), ii) second (2T, n = 5), iii) third (3T, n = 5) trimester, iv) tested positive at delivery (Delivery, n = 5), v) never infected (Control, n = 6), and vi) fully mRNA-vaccinated by delivery (Vaccinated, n = 5). Compared to the Control group, gene expression analysis showed that HBCs from infected subjects had significantly altered gene expression profiles, with the 2T group having the highest number of DEGs (1,696), followed by 3T and 1T groups (1,656 and 958 DEGs, respectively). These DEGs were enriched for pathways involved in immune regulation for host defense, including production of cytokines, chemokines, antimicrobial proteins, ribosomal assembly, neutrophil degranulation inflammation, morphogenesis, and cell migration/adhesion. Protein-protein interaction analysis mapped these DEGs with oxidative phosphorylation, translation, extracellular matrix organization, and type I interferon signaling. Only 95, 23, and 8 DEGs were identified in CTBs of 1T, 2T, and 3T groups, respectively. Similarly, 11 and 3 DEGs were identified in CTBs and HBCs of vaccinated subjects, respectively. Reassuringly, mRNA vaccination did not induce an inflammatory response in placental cells. Conclusions Our studies demonstrate a significant impact of indirect SARS-CoV-2 infection on gene expression of inner mesenchymal HBCs, with limited effect on lining CTB cells isolated from pregnant subjects infected and recovered from SARS-CoV-2. The pathways associated with these DEGs identify potential targets for therapeutic intervention.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Maternal SARS-CoV-2 infection in pregnancy disrupts gene expression in Hofbauer cells with limited impact on cytotrophoblasts

Enninga,

Quach,

Jang

et al. 2024

PLoS Pathog

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“…While several spatial transcriptomic analyses have been applied to study COVID-19 autopsy samples, they have focused on lung [69][70][71] , liver 72 , heart 73 , and placenta 74 . In this study, we used the GeoMx spatial transcriptomics and proteomics platform to comprehensively analyze changes in the immune cell composition and endocrine cell damage of COVID-19 pancreatic samples.…”

Section: Discussionmentioning

confidence: 99%

Human Vascularized Macrophage-Islet Organoids to Model Immune-Mediated Pancreatic β cell Pyroptosis upon Viral Infection

Yang,

Han,

Zhang

et al. 2024

Preprint

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SUMMARYThere is a paucity of human models to study immune-mediated host damage. Here, we utilized the GeoMx spatial multi-omics platform to analyze immune cell changes in COVID-19 pancreatic autopsy samples, revealing an accumulation of proinflammatory macrophages. Single cell RNA-seq analysis of human islets exposed to SARS-CoV-2 or Coxsackievirus B4 (CVB4) viruses identified activation of proinflammatory macrophages and β cell pyroptosis. To distinguish viral versus proinflammatory macrophage-mediated β cell pyroptosis, we developed human pluripotent stem cell (hPSC)-derived vascularized macrophage-islet (VMI) organoids. VMI organoids exhibited enhanced marker expression and function in both β cells and endothelial cells compared to separately cultured cells. Notably, proinflammatory macrophages within VMI organoids induced β cell pyroptosis. Mechanistic investigations highlighted TNFSF12-TNFRSF12A involvement in proinflammatory macrophage-mediated β cell pyroptosis. This study established hPSC- derived VMI organoids as a valuable tool for studying immune cell-mediated host damage and uncovered mechanism of β cell damage during viral exposure.

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“…Furthermore, while methods exist for identifying broad tissue regions using spatially aware clustering of gene expression profiles [5][6][7] , except for SPIAT 8 (which is written in R), we are not aware of any tools for the Python ecosystem that identify cellular niches as defined by cells that cluster according to the composition of the user-defined cell types in their spatial neighborhoods. Understanding the spatial cellular niches that comprise the tissue microenvironment is essential for understanding basic physiology [9][10][11] and disease [12][13][14] . Lastly, though some methods, such as squidpy 15 , stLearn 16 , Seurat 17 , Giotto 18 , and Voyager 7 provide broad functionality for analyzing spatial transcriptomics data, these methods are generalized to work on spatial data at both the spot-level and single-cell level but don't address the aforementioned challenges by specializing in the analysis of cellular niches in single-cell resolution spatial data.…”

Section: Introductionmentioning

confidence: 99%

Monkeybread: A Python toolkit for the analysis of cellular niches in single-cell resolution spatial transcriptomics data

Bernstein,

Scott,

Hession

et al. 2023

Preprint

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Spatial transcriptomics technologies enable the spatially resolved measurement of gene expression within a tissue specimen. With these technologies, researchers can investigate how cells organize into cellular niches which are defined as distinct regions in the tissue comprising a specific composition of cell types or phenotypes. While general-purpose software tools for the exploratory analysis of spatial transcriptomics data exist, there is a need for tools that specialize in the analysis of cellular organization into niches. This can further enhance the downstream application of these data towards drug target discovery, target validation, and biomarker development. We present Monkeybread: A Python toolkit for analyzing cellular organization and intercellular communication in single-cell resolution spatial transcriptomics data. We applied Monkeybread to a human melanoma sample to demonstrate its utility in identifying cellular niches with diverse immunogenic compositions in the tumor microenvironment. We found that these niches were differentially enriched for immunogenic and tolerogenic macrophage populations that could be correlated to T cell abundance. These findings highlight how Monkeybread can be used for revealing underlying biology of the tumor microenvironment, and in the future, for understanding the influence of these niches on response to available treatments and discovery of novel drug targets.

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SARS-CoV-2 niches in human placenta revealed by spatial transcriptomics

Cited by 9 publications

References 117 publications

Maternal SARS-CoV-2 infection in pregnancy disrupts gene expression in Hofbauer cells with limited impact on cytotrophoblasts

Maternal SARS-CoV-2 infection in pregnancy disrupts gene expression in Hofbauer cells with limited impact on cytotrophoblasts

Human Vascularized Macrophage-Islet Organoids to Model Immune-Mediated Pancreatic β cell Pyroptosis upon Viral Infection

Monkeybread: A Python toolkit for the analysis of cellular niches in single-cell resolution spatial transcriptomics data

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