Nickerson, K.P.Senger, S.Zhang, Y.Lima, R.Patel, S.Ingano, L.Flavahan, W.A.Kumar, D.K.V.Fraser, C.M.Faherty, C.S.Sztein, M.B.Fiorentino, M.Fasano, A.2018-07-252018Nickerson, K., S. Senger, Y. Zhang, R. Lima, S. Patel, L. Ingano, W. Flavahan, et al. 2018. “Salmonella Typhi Colonization Provokes Extensive Transcriptional Changes Aimed at Evading Host Mucosal Immune Defense During Early Infection of Human Intestinal Tissue.” EBioMedicine 31 (1): 92-109. doi:10.1016/j.ebiom.2018.04.005. http://dx.doi.org/10.1016/j.ebiom.2018.04.005.http://nrs.harvard.edu/urn-3:HUL.InstRepos:37298408Commensal microorganisms influence a variety of host functions in the gut, including immune response, glucose homeostasis, metabolic pathways and oxidative stress, among others. This study describes how Salmonella Typhi, the pathogen responsible for typhoid fever, uses similar strategies to escape immune defense responses and survive within its human host. To elucidate the early mechanisms of typhoid fever, we performed studies using healthy human intestinal tissue samples and “mini-guts,” organoids grown from intestinal tissue taken from biopsy specimens. We analyzed gene expression changes in human intestinal specimens and bacterial cells both separately and after colonization. Our results showed mechanistic strategies that S. Typhi uses to rearrange the cellular machinery of the host cytoskeleton to successfully invade the intestinal epithelium, promote polarized cytokine release and evade immune system activation by downregulating genes involved in antigen sampling and presentation during infection. This work adds novel information regarding S. Typhi infection pathogenesis in humans, by replicating work shown in traditional cell models, and providing new data that can be applied to future vaccine development strategies.en-USSTY, Salmonella TyphiSTM,M cells, Microfold cellsCFU, colony forming unitsLB, Luria Burtoni brothDMEM, Dulbecco's Modified Eagle MediumPBS, phosphate buffered salineDTT, dithiothreitolEDTA, ethylenediaminetetraacetic acidISC, intestinal stem cellDAPT, N-[2S-(3,5-difluorophenyl)acetyl]-L-alanyl-2-phenyl-1,1-dimethylethyl ester-glycineqPCR, quantitative reverse transcriptase polymerase chain reactionFITC, fluorescein isothiocyanateTEER, trans-epithelial electrical resistanceRNA, ribonucleic acidLDH, lactate dehydrogenaseH&E, hematoxylin and eosinPAS, periodic acid SchiffTEM, transmission electron microscopyIL, interleukinTyphoid feverSnapwell™ systemHuman tissueTerminal ileumImmune systemInnate immunityImmune evasionHost-pathogen interactionVaccine developmentIntestinal organoidsOrganoid monolayerJournal Article2018-07-2510.1016/j.ebiom.2018.04.005