Intrauterine growth restriction is a direct consequence of localized maternal uropathogenic Escherichia coli cystitis

Abstract

Despite the continually increasing rates of adverse perinatal outcomes across the globe, the molecular mechanisms that underlie adverse perinatal outcomes are not completely understood. Clinical studies report that 10% of pregnant women will experience a urinary tract infection (UTI) and there is an association of UTIs with adverse perinatal outcomes. We introduced bacterial cystitis into successfully outbred female mice at gestational day 14 to follow pregnancy outcomes and immunological responses to determine the mechanisms that underlie UTI-mediated adverse outcomes. Outbred fetuses from mothers experiencing localized cystitis displayed intrauterine growth restriction (20-80%) as early as 48 hours post-infection and throughout the remainder of normal gestation. Robust infiltration of cellular innate immune effectors was observed in the uteroplacental tissue following introduction of UTI despite absence of viable bacteria. The magnitude of serum proinflammatory cytokines is elevated in the maternal serum during UTI. This study demonstrates that a localized infection can dramatically impact the immunological status as well as the function of non-infected distal organs and tissues. This model can be used as a platform to determine the mechanism(s) by which proinflammatory changes occur between non-contiguous genitourinary organs.

Figure 1. Perinatal outcomes in the presence and absence of maternal UTI.

(A) Weight (grams) of each individual offspring from pregnant mice that received sham treatment (white) or experimental UTI (gray) at 48 h (10 mice each cohort), 96 h (10 mice each cohort), and delivery (8 mice each cohort). Box portion of the plot represents 95% of the samples with the range of samples indicated by the external bars; the horizontal bar within the box depicts the median and the mean values are indicated in the text. (B) The number of pups delivered for each mother is depicted. Statistical significance was determined using a two-tailed Mann-Whitney test for internal comparisons of each time point indicated in each panel.

Figure 2. PMN and macrophage infiltration in uteroplacental tissues.

The magnitude of the particular cell type of interest is reported as a percentage of live leukocytes within each individual organ indicated from pregnant mice that received sham infection (white) or experimental UTI (gray) at 48 h (10 mice each cohort), 96 h (10 mice each cohort), and delivery (8 mice each cohort). Abbreviations: PMN, polymorphonuclear neutrophil; Mac, macrophage. Bars indicate standard deviation. Statistical significance determined using a two-tailed Mann-Whitney for internal comparisons within each time point indicated in each panel.

Figure 3. Presence of dendritic cells in uteroplacental tissues.

The magnitude of the particular cell type of interest is reported as a percentage of live leukocytes within each individual organ indicated from pregnant mice that received sham infection (white) or experimental UTI (gray) at 48 h (10 mice each cohort), 96 h (10 mice each cohort), and delivery (8 mice each cohort. Statistical significance determined using a two-tailed Mann Whitney for internal comparisons within each time point, no significance observed. Abbreviations: mDC, mature dentritic cell; iDC, immature dendritic cell.

Figure 4. Serum cytokine profiles during pregnancy and UTI.

The magnitude of serum cytokines (pg/ml) of cytokines at 96 h (A) and delivery (B) of mothers that received sham infection (white) or experimental UTI (gray). The serum taken from each individual mouse is measured separately. The number of mice used in each cohort at 96 h and delivery were 10 and 8, respectively. Statistical significance was determined using two-tailed Mann-Whitney (**, p<0.04; ***, p<0.008; ****, p = 0.0003).