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Listeria monocytogenes is a Gram-positive facultative intracellular pathogen and the causative agent of listeriosis. The elderly, immunocompromised individuals, pregnant women, and neonates are at a higher risk of severe infection. Pregnancy-associated listeriosis can lead to miscarriage, premature birth, and neonatal infection. The placenta acts as an exchange platform for nutrients, gases, and waste products for the fetus. It also has the crucial role of protecting the fetus against invading pathogens. Among numerous human pathogens, only a small number are capable of invading the placenta and infecting the fetus. L. monocytogenes is among those pathogens and is used as a model organism to study the mechanisms of fetal/placental infection by intracellular pathogens. It is thought that L. monocytogenes breaches the placental barrier by infecting either the extravillous trophoblasts or the multinucleated syncytiotrophoblast both of which are in direct contact with maternal blood at the maternal/placental interface. However, the fate of L. monocytogenes within the chorionic villi and how infection reaches the fetus are unsettled. Hofbauer cells (HBCs) are fetal macrophages that play homeostatic anti-inflammatory functions in healthy placentas. HBCs are located in chorionic villi between the two cell barriers that protect the fetus from infection: trophoblast cells at the maternal interface (in contact with maternal blood), and fetal endothelial cells at the fetal interface (in contact with fetal blood). As the only leukocytes residing in chorionic villi, HBCs form a critical immune barrier protecting the fetus from infection. Little is known about HBCs' antimicrobial responses to pathogens. Here, we present the first study of L. monocytogenes interactions with HBCs. Remarkably, despite their M2 anti-inflammatory phenotype at basal state, HBCs control non-pathogenic bacteria such as L. innocua and display low susceptibility to infection by L. monocytogenes. However, L. monocytogenes can still multiply in the cytosol of HBCs and exploit these cells to spread to surrounding placental cells. Transcriptomic and cytokine analyses by RNA sequencing and cytokine arrays revealed that HBCs undergo pro-inflammatory reprogramming upon L. monocytogenes infection similar to macrophages stimulated by the potent M1-polarizing agents IFNg/LPS. Infected HBCs also express pro-inflammatory chemokines known to promote placental infiltration by maternal leukocytes. However, HBCs maintain expression of a collection of tolerogenic genes and secretion of tolerogenic cytokines, consistent with their tissue homeostatic role in prevention of fetal rejection. In conclusion, we propose a previously unrecognized model in which HBCs are permissive to L. monocytogenes placental propagation, spread the infection to other placental cells, and can repolarize towards a pro-inflammatory phenotype upon infection, likely to favor innate immune responses. However, consistent with their placental homeostatic functions, repolarized HBCs maintain expression of tolerogenic factors known to prevent the maternal anti-fetal adaptive immunity, at least at the early stages of infection. |
