Preconceptual Priming Overrides Susceptibility to Escherichia coli Systemic Infection during Pregnancy

Abstract

Maternal sepsis is a leading cause of morbidity and mortality during pregnancy. Escherichia coli is a primary cause of bacteremia in women and occurs more frequently during pregnancy. Several key outstanding questions remain regarding how to identify women at highest infection risk and how to boost immunity against E. coli infection during pregnancy. Here, we show that pregnancy-induced susceptibility to E. coli systemic infection extends to rodents as a model of human infection. Mice infected during pregnancy contain >100-fold-more recoverable bacteria in target tissues than nonpregnant controls. Infection leads to near complete fetal wastage that parallels placental plus congenital fetal invasion. Susceptibility in maternal tissues positively correlates with the number of concepti, suggesting important contributions by expanded placental-fetal target tissue. Remarkably, these pregnancy-induced susceptibility phenotypes are also efficiently overturned in mice with resolved sublethal infection prior to pregnancy. Preconceptual infection primes the accumulation of E. coli-specific IgG and IgM antibodies, and adoptive transfer of serum containing these antibodies to naive recipient mice protects against fetal wastage. Together, these results suggest that the lack of E. coli immunity may help discriminate individuals at risk during pregnancy, and that overriding susceptibility to E. coli prenatal infection by preconceptual priming is a potential strategy for boosting immunity in this physiological window of vulnerability. IMPORTANCE Pregnancy makes women especially vulnerable to infection. The most common cause of bloodstream infection during pregnancy is by a bacterium called Escherichia coli. This bacterium is a very common cause of bloodstream infection, not just during pregnancy but in all individuals, from newborn babies to the elderly, probably because it is always present in our intestine and can intermittently invade through this mucosal barrier. We first show that pregnancy in animals also makes them more susceptible to E. coli bloodstream infection. This is important because many of the dominant factors likely to control differences in human infection susceptibility can be property controlled for only in animals. Despite this vulnerability induced by pregnancy, we also show that animals with resolved E. coli infection are protected against reinfection during pregnancy, including having resistance to most infection-induced pregnancy complications. Protection against reinfection is mediated by antibodies that can be measured in the blood. This information may help to explain why most women do not develop E. coli infection during pregnancy, enabling new approaches for identifying those at especially high risk of infection and strategies for preventing infection during pregnancy.

The induction of preterm labor in rhesus macaques is determined by the strength of immune response to intrauterine infection

“…E. coli is the leading cause of maternal sepsis during pregnancy [28], yet experimental models evaluating how E. coli prenatal infection impacts parturition timing remain limited. For example, while E. coli infection during pregnancy was recently shown to efficiently cause fetal wastage and congenital fetal invasion in mice, the effects on PTL were not reported, likely given the relatively short pregnancy duration in rodents compared with larger mammalian species [29]. We now report that IA injection of live E. coli causes IUI and PTL.…”

“…Although maternal bacteremia is not very common, E. coli infection is a leading cause when it occurs and can have devastating consequences both to the mother and the fetus [28]. In a mouse model, pregnancy was associated with higher susceptibility to E. coli infection compared to virgin mice [29]. To gain insights into the pathogenesis of PTL, we used nonhuman primate models of IUI with and without PTL (with or without E. coli infection) simulating human chorioamnionitis.…”

“…In a mouse model, pregnancy was associated with higher susceptibility to E . coli infection compared to virgin mice [ 29 ]. To gain insights into the pathogenesis of PTL, we used nonhuman primate models of IUI with and without PTL (with or without E .…”

“…For example, while E . coli infection during pregnancy was recently shown to efficiently cause fetal wastage and congenital fetal invasion in mice, the effects on PTL were not reported, likely given the relatively short pregnancy duration in rodents compared with larger mammalian species [ 29 ]. We now report that IA injection of live E .…”