Uterine infection alters the transcriptome of the bovine reproductive tract three months later

in Reproduction

Correspondence should be addressed to I M Sheldon; Email: i.m.sheldon@swansea.ac.uk
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Infection of the postpartum uterus with pathogenic bacteria is associated with infertility months later in dairy cattle. However, it is unclear whether these bacterial infections lead to long-term changes in the reproductive tract that might help explain this infertility. Here we tested the hypothesis that infusion of pathogenic bacteria into the uterus leads to changes in the transcriptome of the reproductive tract 3 months later. We used virgin Holstein heifers to avoid potential confounding effects of periparturient problems, lactation, and negative energy balance. Animals were infused intrauterine with endometrial pathogenic bacteria Escherichia coli and Trueperella pyogenes (n = 4) and compared with control animals (n = 6). Three months after infusion, caruncular and intercaruncular endometrium, isthmus and ampulla of the oviduct, and granulosa cells from ovarian follicles >8 mm diameter were profiled by RNA sequencing. Bacterial infusion altered the transcriptome of all the tissues when compared with control. Most differentially expressed genes were tissue specific, with 109 differentially expressed genes unique to caruncular endometrium, 57 in intercaruncular endometrium, 65 in isthmus, 298 in ampulla, and 83 in granulosa cells. Surprisingly, despite infusing bacteria into the uterus, granulosa cells had more predicted upstream regulators of differentially expressed genes than all the other tissues combined. In conclusion, there were changes in the transcriptome of the endometrium, oviduct and even granulosa cells, 3 months after intrauterine infusion of pathogenic bacteria. These findings imply that long-term changes throughout the reproductive tract could contribute to infertility after bacterial infections of the uterus.

Supplementary Materials

    • Supplemental Figure 1. Gene expression comparison. In tissues collected from animals 3 onths after intrauterine infusion of either control medium or pathogenic bacteria, gene expression determined y RNAseq was confirmed by real time RT-PCR. Gene expression of CD38 in granulosa cells (A), NXPE3 n isthmus tissue (B) and CTTN in ampulla tissue (C) was evaluated by real time RT-PCR (●) and compared to expression patterns obtained by RNAseq (○). Pearson correlations between relative fold change from real time RT-PCR and read number obtained by RNAseq is presented for CD38 (D), NXPE3 (E), and CTTN (F).
    • Supplemental Table 1. Read mapping summary. The read mapping summary from the RNAseq data in tissues from control (orange) and bacteria-infused (purple) animals.
    • Supplemental Table 2. DEGs. Differentially expressed genes (DEGs) are provided for the top five up and down DEGs, and DEGs of interest, in the tissues of bacteria-infused compared with control animals. Base mean values determined by RNAseq read number.
    • Supplemental Table 3. Gene networks. Gene networks enriched by differentially expressed genes in tissues from bacteria-infused compared with control animals. Genes are indicated in bold. Enriched gene networks determined by Ingenuity Pathway analysis using significantly differentiated expressed genes only. Network score is derived from P value and indicates the likelihood of the genes in a given network being found together due to random chance alone. A network score of 2 or higher gives a 99% confidence the network and genes not being generated by random chance alone.

 

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