Differential Response of Gestational Tissues to TLR3 Viral Priming Prior to Exposure to Bacterial TLR2 and TLR2/6 Agonists

Rasheed, Zahirrah B. M. and Lee, Yun S. and Kim, Sung H. and Rai, Ranjit K. and Ruano, Camino S. M. and Anucha, Eberechi and Sullivan, Mark H. F. and MacIntyre, David A. and Bennett, Phillip R. and Sykes, Lynne (2020) Differential Response of Gestational Tissues to TLR3 Viral Priming Prior to Exposure to Bacterial TLR2 and TLR2/6 Agonists. Frontiers In Immunology, 11. ISSN 16643224, DOI https://doi.org/10.3389/fimmu.2020.01899.

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Background:Infection/inflammation is an important causal factor in spontaneous preterm birth (sPTB). Most mechanistic studies have concentrated on the role of bacteria, with limited focus on the role of viruses in sPTB. Murine studies support a potential multi-pathogen aetiology in which a double or sequential hit of both viral and bacterial pathogens leads to a higher risk preterm labour. This study aimed to determine the effect of viral priming on bacterial induced inflammation in humanin vitromodels of ascending and haematogenous infection. Methods:Vaginal epithelial cells, and primary amnion epithelial cells and myocytes were used to represent cell targets of ascending infection while interactions between peripheral blood mononuclear cells (PBMCs) and placental explants were used to model systemic infection. To model the effect of viral priming upon the subsequent response to bacterial stimuli, each cell type was stimulated first with a TLR3 viral agonist, and then with either a TLR2 or TLR2/6 agonist, and responses compared to those of each agonist alone. Immunoblotting was used to detect cellular NF-kappa B, AP-1, and IRF-3 activation. Cellular TLR3, TLR2, and TLR6 mRNA was quantified by RT-qPCR. Immunoassays were used to measure supernatant cytokine, chemokine and PGE2 concentrations. Results:TLR3 (''viral'') priming prior to TLR2/6 agonist (''bacterial'') exposure augmented the pro-inflammatory, pro-labour response in VECs, AECs, myocytes and PBMCs when compared to the effects of agonists alone. In contrast, enhanced anti-inflammatory cytokine production (IL-10) was observed in placental explants. Culturing placental explants in conditioned media derived from PBMCs primed with a TLR3 agonist enhanced TLR2/6 agonist stimulated production of IL-6 and IL-8, suggesting a differential response by the placenta to systemic inflammation compared to direct infection as a result of haematogenous spread. TLR3 agonism generally caused increased mRNA expression of TLR3 and TLR2 but not TLR6. Conclusion:This study provides humanin vitroevidence that viral infection may increase the susceptibility of women to bacterial-induced sPTB. Improved understanding of interactions between viral and bacterial components of the maternal microbiome and host immune response may offer new therapeutic options, such as antivirals for the prevention of PTB.

Item Type: Article
Funders: Malaysian Government Agency, National Institute for Health Research Comprehensive Biomedical Research Centre at Imperial College Healthcare NHS Trust, March of Dimes Foundation, Medical Research Council (Grant No. MR/L009226/1), National Institute for Health Research, Imperial College London (Grant No. P45272), Imperial College Healthcare NHS Trust, Majlis Amanah Rakyat
Uncontrolled Keywords: toll like receptor; viral priming; preterm labour; pregnancy; inflammation
Subjects: R Medicine
Divisions: Faculty of Medicine > Obstetrics & Gynaecology Department
Depositing User: Ms Zaharah Ramly
Date Deposited: 30 Dec 2023 14:02
Last Modified: 30 Dec 2023 14:02
URI: http://eprints.um.edu.my/id/eprint/36476

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