Herein we describe an association between activation of inflammatory pathways following transient hypoxia and the appearance of the multidrug resistant bacteria Staphylococcus simulans in the fetal brain. Reduction of maternal arterial oxygen tension by 50% over 30 min resulted in a subseiuent significant over-expression of genes associated with immune responses 24 h later in the fetal brain. The activated genes were consistent with stimulation by bacterial lipopolysaccharide; an influx of macrophages and appearance of live bacteria were found in these fetal brains. S. simulans was the predominant bacterial species in fetal brain after hypoxia, but was found in placenta of all animals. Strains of S. simulans from the placenta and fetal brain were equally highly resistant to multiple antibiotics including methicillin and had identical genome sequences. These results suggest that bacteria from the placenta invade the fetal brain after maternal hypoxia.
The fetus is thought to develop in a sterile environment in utero. Long standing dogma that “the uterus and the feto‐placental unit is “sterile” is based primarily on microbiological culture‐based techniques that were unsuccessful in growing “culture resistant” bacteria or intracellular bacteria. We have reported the presence of low numbers of bacteria in tissues from normal sheep fetuses in pregnancies not complicated by infection. The exposure of the fetus to bacteria might aid neonatal survival by informing fetal immune development. We propose that the fetus is not sterile and that bacteria or fragments of bacteria can be transferred from mother to fetus. We hypothesize that inoculation in the maternal mouth results in the appearance of bacteria in the fetus. We used S. aureus containing green (GFP), red (RFP), or far‐red (FRFP) fluorescent protein‐expressing plasmids to inoculate late‐gestation pregnant sheep (gestational age= 130–135 days, n=7) intravenously (GFP, 104 cfu), into maternal mouth (RFP, 104 cfu) and vagina (FRFP, 104 cfu). These were small doses of bacteria which did not cause physiological (no fever) or psychological (no anorexia) signs of infection. Five to seven days post maternal inoculation, animals were humanely sacrificed, and fetal tissues were collected, and DNA was extracted from placenta and fetal liver, spleen, and cerebral cortex. We probed for GFP plasmid using several primer pairs for endpoint PCR. While detection of whole‐length plasmids was not successful, PCR reactions probing for smaller fragments of plasmid were successful. We found GFP plasmid DNA in all tissues in 10/10 fetal livers and RFP in 10/10 livers. The appearance of GFP and RFP‐labelled bacteria in fetal liver (p=7.497e‐06) was statistically significant as tested by Chi‐Square analysis. We did not detect significant FRFP plasmid DNA in liver. Analysis of tissues by immunohistochemistry revealed GFP and RFP‐expressing bacteria in fetal tissues, although most appeared to be in aggregates. We conclude that S. aureus, introduced in small numbers in maternal mouth and bloodstream, appear in the fetus and placenta. We were unable to determine whether these bacteria were alive in the fetus. Support or Funding Information This work was supported by HD033053, AI120195, and HL083810 This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The oral cavity is often the first site where viruses interact with the human body. The oral epithelium is a major site of viral entry, replication and spread to other cell types, where chronic infection can be established. In addition, saliva has been shown as a primary route of person-to-person transmission for many viruses. From a clinical perspective, viral infection can lead to several oral manifestations, ranging from common intraoral lesions to tumors. Despite the clinical and biological relevance of initial oral infection, little is known about the mechanism of regulation of the viral life cycle in the oral cavity. Several viruses utilize host epigenetic machinery to promote their own life cycle. Importantly, viral hijacking of host chromatin-modifying enzymes can also lead to the dysregulation of host factors and in the case of oncogenic viruses may ultimately play a role in promoting tumorigenesis. Given the known roles of epigenetic regulation of viral infection, epigenetic-targeted antiviral therapy has been recently explored as a therapeutic option for chronic viral infection. In this review, we highlight three herpesviruses with known roles in oral infection, including herpes simplex virus type 1, Epstein–Barr virus and Kaposi’s sarcoma-associated herpesvirus. We focus on the respective oral clinical manifestations of these viruses and their epigenetic regulation, with a specific emphasis on the viral life cycle in the oral epithelium.
Recently, we identified in normally type 1 diabetes-prone NOD/LtJ mice a spontaneous new leptin receptor (LEPR) mutation (designated Lepr db-5J ) producing juvenile obesity, hyperglycemia, hyperinsulinemia, and hyperleptinemia. This early type 2 diabetes syndrome suppressed intraislet insulitis and permitted spontaneous diabetes remission. No significant differences in plasma corticosterone, splenic CD4؉ or CD8 ؉ T-cell percentages, or functions of CD3؉ T-cells in vitro distinguished NOD wild-type from mutant mice. Yet splenocytes from hyperglycemic mutant donors failed to transfer type 1 diabetes into NOD.Rag1 Ϫ/Ϫ recipients over a 13-week period, whereas wild-type donor cells did so. This correlated with significantly reduced (P < 0.01) frequencies of insulin and isletspecific glucose-6-phosphatase catalytic subunit-related protein-reactive CD8 ؉ T-effector clonotypes in mutant mice. Intra-islet insulitis was also significantly suppressed in lethally irradiated NOD-Lepr db-5J /Lt recipients reconstituted with wild-type bone marrow (P < 0.001). In contrast, type 1 diabetes eventually developed when mutant marrow was transplanted into irradiated wild-type recipients. Mitogen-induced T-cell blastogenesis was significantly suppressed when splenic T-cells from both NOD/Lt and NODLepr db-5J /Lt donors were incubated with irradiated mutant peritoneal exudate cells (P < 0.005). In conclusion, metabolic disturbances elicited by a type 2 diabetes syndrome (insulin and/or leptin resistance, but not hypercorticism) appear to suppress type 1 diabetes development in NODLepr db-5J /Lt by inhibiting activation of T-effector cells.
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