Placental Viral Infection Sensitizes to Endotoxin-Induced Pre-Term Labor: A Double Hit Hypothesis

Abstract

Problem-Among pregnant women, acquired viral infections with a concurrent bacterial infection is a detrimental factor associated to poor prognosis. We evaluate the effect of a viral infection that does not lead to pre-term labor on the response to low doses of lipopolysaccharide (LPS). Our objectives were (i) to characterize the effect of a viral infection concurrent with exposure to microbial products on pregnancy outcome and (ii) to characterize the placental and fetal immune responses to the viral sensitization to LPS.Method-C57B/6 wild-type mice were injected with murine gammaherpesvirus 68 (MHV68) at E8.5. Either PBS or LPS was injected i.p. at E15.5. Pregnancy outcome and cytokine / chemokine profile from implantation sites were analyzed by multiplex.Results-LPS treatment of MHV-68-infected animals induced pre-term delivery and fetal death in 100% of the mice. Pre-term labor was characterized by a upregulation of pro-inflammatory cytokines and chemokines in both placenta and decidua. Similar profiles were observed from MHV-68-infected human primary trophoblast and trophoblast cell lines in response to LPS.Conclusion-We describe for the first time that a sub-clinical viral infection in pregnant mice might sensitize to a bacterial infection leading to pre-term delivery. We propose the 'Double Hit Hypothesis' where the presence of a viral infection enhances the effect of bacterial products during pregnancy leading not only to pre-term labor but likely larger adverse outcomes.

A clinicopathological study of episomal papillomavirus infection of the human placenta and pregnancy complications

“…7 Furthermore, cervical HPV infection impairs the physiological protective capacity of the uterine cervix. 30 Studies employing in situ hybridization have detected HPV DNA in non-neoplastic endometrium in 19.6 31 and 60% 32 of biopsies. It is possible that initial infection of the endometrium is facilitated by regular menstrual shedding (akin to wounding), whereas the lack of menstrual shedding, endometrial decidualisation, and immune suppression during pregnancy contributes to HPV persistence and growth.…”

Simple Plex™: A Novel Multi‐Analyte, Automated Microfluidic Immunoassay Platform for the Detection of Human and Mouse Cytokines and Chemokines

“…Assays were performed according to the manufacturer's instructions as previously described 12, 13, 14. Cartridges containing IL‐6, IP‐10, TNF‐α, and IL‐1β were run alongside the Luminex plates, and data were converted from relative units/RFU to concentration (pg/ml) to directly compare formats.…”

Risks associated with viral infections during pregnancy

“…The maternal immune response can be beneficially or detrimentally affected by pregnancy, depending on the enviare beginning to identify viral infections as potential risk factors for PTB (53,(56)(57)(58). For example, Zuo et al showed that cervical HPV infection was associated with PTB (56), while others determined that genital HSV was also associated with PTB (53,59).…”