30 Viral and bacterial signatures impair trophoblast migration which is reversed by aspirin, aspirin-triggered-lipoxin and hydroxychloroquine

Abstract

While the etiology of preeclampsia remains elusive, an inflammatory response at the maternal-fetal interface is thought to play a role. Growing evidence suggests a relationship between maternal infection and risk of preeclampsia. Thus, infection may contribute to the pathogenesis by affecting trophoblast function. These cells express Toll-like receptors (TLRs) and Nod-like receptors (NLRs), which mediate infection-induced inflammation. We hypothesize that in addition to inducing inflammation via TLRs and NLRs, infections may limit trophoblast migration leading to a preeclampsia-like phenotype, and this may be reversed by potential therapeutics. A human first trimester trophoblast cell line (Sw.71) was treated with or without bacterial or viral signatures known to activate TLRs and NLRs (Table 1). For some experiments, cells were also treated with the therapeutics aspirin (ASA; 10ug/ml), aspirin-triggered lipoxin (ATL; 100nM), or hydroxychloroquine (HCQ; 1ug/ml). Cell viability was measured using the CellTiter assay. Cell migration was quantified using a two-chamber colorimetric assay. Cell viability was not altered by any infectious triggers with the exception of viral dsRNA which reduced viability by 50.4±4.7% (p<0.05). This was not tested further. Compared to media, viral ssRNA and bacterial CpG ODN significantly reduced trophoblast migration by 48.7±7.2% and 52.5±4.1%, respectively (p<0.05). Bacterial LPS, PGN, flagellin, iE-DAP and MDP did not alter cell migration. Compared to viral ssRNA alone, ASA, ATL and HCQ independently increased trophoblast migration by 1.6±0.3, 2.0±0.3 and 2.0±0.4-fold, respectively (p<0.05). Similarly, compared to CpG ODN alone, ASA, ATL and HCQ independently increased trophoblast migration by 1.6±0.1, 1.5±0.1 and 1.6±0.2-fold, respectively (p<0.05). Our findings suggest that viral ssRNA and bacterial CpG ODN may impair trophoblast migration leading to a preeclampsia-like phenotype. Further research is needed to understand the mechanisms by which ASA, ATL, and HCQ may reverse these effects and improve perinatal outcomes.