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Host susceptibility to recurrent cystitis is shaped by bladder TNF-alpha signaling dynamics

ABSTRACT: Urinary tract infections (UTI) are common and recurrent. Both host genetics and UTI history impact susceptibility to recurrent UTI (rUTI) in women and in animal models. To identify shared patterns of host response that correlate with susceptibility, we investigated bladder inflammatory and transcriptional kinetics in acute and rUTI models. We found that TNFɑ signaling kinetics differed with mouse strain and infection history. Mice resistant to severe UTI/rUTI displayed a robust TNFɑ-dependent inflammation during the first 6 hours of acute cystitis, which waned by 24 hours; mice that are susceptible varied in their early responses but were prone to severe inflammation at 24 hours post-infection. Depletion of TNFɑ in an rUTI model revealed that early TNFɑ signaling promoted colonization resistance via exfoliation of infected bladder cells, but prolonged TNFɑ signaling exacerbated inflammation, thereby worsening infection. Host genetics and disease history impacts susceptibility by regulating the kinetics of a common TNFɑ pathway.

ORGANISM(S): Mus musculus

PROVIDER: GSE117532 | GEO | 2019/07/21

REPOSITORIES: GEO

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Project description:Background: Staphylococcus aureus is a major pathogen of humans and animals and rapidly emerging antibiotic-resistant strains have further increased the severity of this health issue. Host genetics influence susceptibility to S. aureus infections, and genes determining infection outcome should be identified to analyze immune-based therapies as an alternative to antibiotics. Here, we used outbred animals from a divergent selection on susceptibility towards Staphylococcus infection to explore host immunogenetics. Methodology/Principal Findings: We investigated how dendritic cells respond to heat-inactivated S. aureus and whether dendritic cells from animals with different degree of susceptibility have distinct gene expression profiles. We measured expression levels of 15K probes from in vitro S. aureus-stimulated bone marrow-derived dendritic cells at three different time points (0, 3 and 8 hours) by using Agilent microarrays. Furthermore, a selected number of genes were confirmed by RT-qPCR. Gene signatures of stimulated DCs were obtained and genes involved in inflammatory process and T helper cell polarization were highly up regulated upon stimulation. Moreover, a set of 204 genes were statistically different between susceptible and resistant animals, and grouped them according to their predisposition to staphylococcal infection. Interestingly, a role of classical pathway of Complement and early regulation of inflammation is observed in the resistant line through over expression of C1q and Ido1 genes respectively. On the opposite, over expression of genes in the IL1R pathway in the susceptible animals was noticed. Furthermore, leucocyte extravasation pathway was also found dominant in the susceptible line. Conclusion/Significance: we successfully obtained Staphylococcus aureus associated gene expression of ovine BM-DC in 8 hour kinetics experiment. Distinct transcriptional profiles of dendritic cells obtained from resistant and susceptible lines may explain susceptibility towards S. aureus infections in a broad context. Keywords: Staphylococcus aureus, dendritic cells, mammalian, transcriptome, immunity, mastitis 44 sample records; two-colour dye-swap experimental design

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Host susceptibility to recurrent cystitis is shaped by bladder TNF-alpha signaling dynamics

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