• 2018-07
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  • 2019-04
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  • 2019-10
  • Our experiments demonstrate that serotonin activates the las


    Our experiments demonstrate that serotonin activates the las quorum sensing pathway, which leads to greater infectivity of P. aeruginosa, however continued experimentation with Pseudomonas infection and serotonin can help to fully elucidate this complex interplay. Our mouse model was limited due to its focus on three day old mouse pups based upon their natural susceptibility to Pseudomonas infection, however, it may be possible to exploit serotonin\'s enhancement of Pseudomonas virulence to investigate Pseudomonas infections in adult mice. Additionally, there are limitations to current biochemical assays for QSMs, such as a lack of a full crystal structure for LasR. Advancements in this field will allow for binding studies of serotonin with LasR, which would further enhance our findings. While it is uncertain why Pseudomonas utilizes another organism\'s molecules to enhance their QS networks, it is not a novel phenomenon. Social cheating by bacteria, where the bacteria exploit sensing molecules produced by other organisms in their vicinity to activate their QS systems, has been observed in many circumstances. Thus serotonin may be a way the opportunistic bacteria P. aeruginosa participates in social cheating to enhance its virulence. While our knowledge of the human microbiome is in its nascent stage, the observed Janus-type behavior of serotonin, acting as both mammalian neurotransmitter and bacterial communication molecule, undoubtedly will contribute to further our knowledge of the complex relationship between the host and its\' microbiome. Specifically, these findings could lead to a better understanding of the host regulation of the microbiome, especially during infection, potentially leading to a paradigm shift in the management of intestinal bacterial-related illnesses or disorders of the ceramidase that are triggered by bacteria.
    Conflict of Interest
    Author Contributions L.D.K. assisted in the study design, collected in vitro and in vivo experimental data, and wrote the initial draft of the manuscript. G.O. assisted in the experimental design, collected data in the in vivo experiment, and assisted in finalizing the manuscript. R.M. designed and performed the in vivo studies, and facilitated SEM imaging. X.L., P.D., P.P, S.K.D, and S.D. collaborated in the design of the study and analyzed the data. SD postulated the hypothesis of the work, was the initial creator of the study, edited, and finalized the manuscript. All authors discussed the results and had input on the manuscript writing process.
    Acknowledgments S.D. would like to thank the National Science Foundation (ECC-08017788 and CHE-1506740), the Department of Defense Peer Reviewed Medical Research Program (PRMRP) Discover Award (W1XWH-13-1-0343) and the National Institutes of Health (R01GM047915) for funding this work. S.D. thanks the Miller School of Medicine of the University of Miami for the Lucille P. Markey Chair in Biochemistry and Molecular Biology. L.D.K. would like to thank the National Science Foundation Integrative Graduate Education Research Traineeship (DGE-0653710). The research work in Dr. Liu\'s laboratory is supported by the National Institutes of Health grants R01DC005575, R01DC012546, and R01DC012115. We would like to thank Dr. Pascal J. Goldschmidt and Dr. Michal Toborek for stimulating and helpful discussions as well as Dr. Patricia Blackwelder for helping in scanning electron microscopy experiments. The authors thank Dr. Peter Greenberg for supplying the E. coli strain harboring plasmids pJN105Q and pJL101 and Dr. Johanna Schwingel for providing P. aeruginosa strains PAO1 and JP2.
    Introduction Approximately one third of the global population is infected with Mycobacterium tuberculosis (M. tuberculosis), the etiologic agent responsible for tuberculosis (TB). While many individuals who harbour M. ceramidase tuberculosis never develop active disease, TB is often lethal and is estimated to have been responsible for 1.5 million deaths in the year 2013 (WHO, 2014). Multidrug-resistant (MDR) TB, which is defined as in vitro resistance to both rifampin and isoniazid, is a public health problem of increasing importance, with an estimated 480,000 incident cases in 2013 (WHO, 2014). Treatment of drug-resistant TB is more complex, lengthy, costly, toxic, and ultimately less successful at eradicating M. tuberculosis infection. With few novel antitubercular antibiotics in development, the emergence of extensively drug-resistant (XDR) M. tuberculosis strains (defined as MDR with additional resistance to both quinolones and second-line injectable agents) and the lack of effective treatment regimens have highlighted the potential to repurpose existing antibiotics in innovative ways (Wong et al., 2013).