Dataset Information

Salmonella Typhimurium Infection Leads to Colonization of the Mouse Brain and Is Not Completely Cured With Antibiotics.

ABSTRACT: Salmonella systemic infections claim thousands of lives worldwide even today. Certain cases lead to an infection in the brain culminating in meningitis and associated neurological abnormalities. Multiple reports have indicated neurological manifestations in patients suffering from typhoid fever during the course of infection and afterwards. While the meanderings of Salmonella systemic infections are fairly well studied, the flow of events in the brain is very poorly understood. We investigated the colonization of various brain parts by Salmonella in mice. It was observed that the bacterium is frequently able to invade various brain parts in mice. Selected mutants namely deletion mutants of key proteins encoded by the Salmonella pathogenicity islands (SPIs) 1 and 2 and ompA gene were also used to decipher the roles of specific genes in establishing an infection in the brain. Our results suggest roles for the Salmonella pathogenicity island (SPI) 1 and outer membrane protein A gene in enabling blood-brain barrier penetration by the pathogen. We further investigated behavioral abnormalities in infected mice and used an antibiotic treatment regime in an attempt to reverse the same. Results show some mice still display behavioral abnormalities and a high bacterial burden in brain despite clearance from spleen and liver. Overall, our study provides novel insights into S. Typhimurium's capacity to invade the mouse brain and the effectiveness of antibiotic treatment on behavioral manifestations due to infection. These observations could have important implications in understanding reported neurological manifestations in typhoid patients.

SUBMITTER: Chaudhuri D

PROVIDER: S-EPMC6058050 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Salmonella Typhimurium Infection Leads to Colonization of the Mouse Brain and Is Not Completely Cured With Antibiotics.

Chaudhuri Debalina D Roy Chowdhury Atish A Biswas Biswendu B Chakravortty Dipshikha D

Frontiers in microbiology 20180718

Salmonella systemic infections claim thousands of lives worldwide even today. Certain cases lead to an infection in the brain culminating in meningitis and associated neurological abnormalities. Multiple reports have indicated neurological manifestations in patients suffering from typhoid fever during the course of infection and afterwards. While the meanderings of Salmonella systemic infections are fairly well studied, the flow of events in the brain is very poorly understood. We ...[more]

PMID: 30072981

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Project description:BackgroundSalmonella are able to modulate host cell functions facilitating both uptake and resistance to cellular host defence mechanisms. While interactions between bacterial modulators and cellular proteins have been the main focus of Salmonella research, relatively little is known about mammalian gene regulation in response to Salmonella infection. A major class of mammalian gene modulators consists of microRNAs. For our study we examined interactions of microRNAs and regulated mRNAs in mammalian intestinal Salmonella infections using a piglet model.Methodology/principal findingsAfter performing microRNA as well as mRNA specific microarray analysis of ileal samples from Salmonella infected as well as control piglets, we integrated expression analysis with target prediction identifying microRNAs that mainly regulate focal adhesion as well as actin cytoskeleton pathways. Particular attention was given to miR-29a, which was involved in most interactions including Caveolin 2. RT-qPCR experiments verified up-regulation of miR-29a after infection while its predicted target Caveolin 2 was significantly down-regulated as examined by transcript and protein detection. Reporter gene assays as well as RNAi experiments confirmed Caveolin 2 to be a miR-29a target. Knock-down of Caveolin 2 in intestinal epithelial cells resulted in retarded proliferation as well as increased bacterial uptake. In addition, our experiments showed that Caveolin 2 regulates the activation of the small Rho GTPase CDC42 but apparently not RAC1 in human intestinal cells.Conclusions/significanceOur study outlines for the first time important regulation pathways in intestinal Salmonella infection pointing out that focal adhesion and organisation of actin cytoskeleton are regulated by microRNAs. Functional relevance is shown by miR-29a mediated Caveolin 2 regulation, modulating the activation state of CDC42. Further analysis of examined interactions may support the discovery of novel strategies impairing the uptake of intracellular pathogens.

Project description:Phage therapy is a promising alternative treatment of bacterial infections in human and animals. Nevertheless, despite the appearance of many bacterial strains resistant to antibiotics, these drugs still remain important therapeutics used in human and veterinary medicine. Although experimental phage therapy of infections caused by Salmonella enterica was described previously by many groups, those studies focused solely on effects caused by bacteriophages. Here, we compared the use of phage therapy (employing a cocktail composed of two previously isolated and characterized bacteriophages, vB_SenM-2 and vB_Sen-TO17) and antibiotics (enrofloxacin and colistin) in chickens infected experimentally with S. enterica serovar Typhimurium. We found that the efficacies of both types of therapies (i.e. the use of antibiotics and phage cocktail) were high and very similar to one another when the treatment was applied shortly (one day) after the infection. Under these conditions, S. Typhimurium was quickly eliminated from the gastrointestinal tract (GIT), to the amount not detectable by the used methods. However, later treatment (2 or 4 days after detection of S. Typhimurium in chicken feces) with the phage cocktail was significantly less effective. Bacteriophages remained in the GIT for up to 2-3 weeks, and then were absent in feces and cloaca swabs. Interestingly, both phages could be found in various organs of chickens though with a relatively low abundance. No development of resistance of S. Typhimurium to phages or antibiotics was detected during the experiment. Importantly, although antibiotics significantly changed the GIT microbiome of chickens in a long-term manner, analogous changes caused by phages were transient, and the microbiome normalized a few weeks after the treatment. In conclusion, phage therapy against S. Typhimurium infection in chickens appeared as effective as antibiotic therapy (with either enrofloxacin or colistin), and less invasive than the use the antibiotics as fewer changes in the microbiome were observed.

Dataset Information

Salmonella Typhimurium Infection Leads to Colonization of the Mouse Brain and Is Not Completely Cured With Antibiotics.

Publications

<i>Salmonella</i> Typhimurium Infection Leads to Colonization of the Mouse Brain and Is Not Completely Cured With Antibiotics.

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