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Hofbauer cells spread Listeria monocytogenes among placental cells and undergo pro-inflammatory reprogramming while retaining production of tolerogenic factors

ABSTRACT: Pregnant women are highly susceptible to infection by the bacterial pathogen Listeria monocytogenes leading to miscarriage, premature birth, and neonatal infection. It is thought that L. monocytogenes breaches the placental barrier by infecting trophoblasts at the maternal interface. However, the fate of L. monocytogenes within the chorionic villi and how infection reaches the fetus are unsettled. Hofbauer cells (HBCs) are fetal placental macrophages and the only leukocytes residing in healthy chorionic villi, forming a last immune barrier protecting fetal blood from infection. Little is known about HBCs’ antimicrobial responses to pathogens. Here, we present the first study of L. monocytogenes interactions with human HBCs isolated from healthy term placentas. Control untreated (5 h and 24 h) HBCs, 24 h LPS/IFNgamma-stimulated, and 5 h and 24 h L. monocytogenes-infected HBCs, were lysed with TRIzol. RNA was isolated followed by on-column DNase treatment and ribo-depletion. RNA-seq libraries were made, pooled, and sequenced on an Illumina NovaSeq SP flow cell in paired-end 150 bp format to a read yield between 70 – 80 million reads (equivalent to 35 – 40 million clusters). The RNA-seq data analysis showed that HBCs undergo pro-inflammatory reprogramming upon L. monocytogenes infection and following stimulation by the potent M1-polarizing agents LPS/IFNgamma. Of particular interest, infected HBCs also upregulated genes encoding numerous pro-inflammatory chemokines known to promote placental infiltration by maternal leukocytes. However, HBCs maintained expression of a collection of tolerogenic genes accompanied by secretion of tolerogenic cytokines, consistent with their tissue homeostatic role in prevention of fetal rejection.

ORGANISM(S): Homo sapiens

PROVIDER: GSE174689 | GEO | 2021/07/27

REPOSITORIES: GEO

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Project description:The bacterial pathogen Listeria monocytogenes breaches the placental barrier and infects the placental/fetal unit resulting in poor pregnancy outcomes. L. monocytogenes is thought to enter the placenta by infection of trophoblasts at the maternal/fetal interface. Trophoblasts are fetal epithelial cells that delineate the maternal/fetal interface and ensure critical functions by promoting all nutritional and waste exchanges between maternal and fetal bloods and by forming a protective immune barrier. In this work, we report the first transcriptomic analysis of L. monocytogenes-infected trophoblasts by RNA sequencing. Primary human trophoblasts (PHT) and BeWo (fused and non-fused) were infected for 5 h with WT L. monocytogenes and highly purified RNA was extracted from infected and control cells. A 200 ng total RNA sample was used for sequencing on Illumina NovaSeq SP flowcell in paired-end 150 bp format to a read yield between 70-80 million reads. Pathway analysis showed that infection upregulated TLR2-, NOD-like, and cytosolic DNA sensing pathways, as well as downstream pro-inflammatory circuitry (NF-KB, AP-1, IRF4, IRF7) leading to the production of mediators known to elicit the recruitment and activation of maternal leukocytes (IL8, IL6, TNFA, MIP-1). Signature genes associated with poor pregnancy outcomes were also upregulated upon infection. Measuring the release of 54 inflammatory mediators confirmed the transcriptomic data and revealed sustained production of tolerogenic factors (IL-27, IL-10, IL-1RA, TSLP) despite infection. Both the SYN and mononuclear trophoblasts produced cytokines, but surprisingly, some cytokines were predominantly produced by the SYN (IL-8, IL-6) or by non-fused trophoblasts (TNFA). Collectively, our data support that trophoblasts act as placental gatekeepers that limit and detect L. monocytogenes infection resulting in a pro-inflammatory response, which may contribute to the poor pregnancy outcomes if the pathogen persists.

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Hofbauer cells spread Listeria monocytogenes among placental cells and undergo pro-inflammatory reprogramming while retaining production of tolerogenic factors

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