Klebsiella pneumoniae and antibiotic-resistant Enterobacteriaceae
Infections caused by Gram-negative bacteria belonging to the Enterobacteriaceae family are particularly problematic. This family includes organism such as Klebsiella pneumoniae, Escherichia coli, Enterobacter aerogenes and Enterobacter cloacae. The Enterobacteriaceae can inhabit the length of the gastrointestinal tract, from the oral cavity to the anaerobic colon but they rarely contribute more than a fraction of 1% to the colonic microbiota. Following antibiotic treatment, however, Enterobacteriaceae undergo marked expansion and, in some clinical settings, achieve over 90% occupancy of the lower GI tract. This scenario is increasingly common in clinical settings because E. coli and K. pneumoniae have acquired resistance against a wide range of antibiotics, in some circumstances all clinically available antibiotics.
One of the most important mechanisms of growth restriction of Enterobacteriaceae is mediated by short-chain fatty acids (SCFAs), such as acetate and butyrate. Our laboratory is identifying and isolating commensal bacterial species that acidify the lower intestinal tract and produce high concentrations of SCFAs. An important additional goal is to identify commensal bacteria that break down complex polysaccharides into simpler sugars, thereby enabling SCFA-producing strains to produce acetate, butyrate and propionate.
We also investigate mechanisms of K. pneumoniae persistence in the gastrointestinal tract and we study immune mechanisms of defense against pulmonary infections cause by K. pneumoniae. For these studies, we generated a transposon mutant library to identify genes that are essential for K. pneumoniae’s ability to colonize the mouse intestine and cause potentially lethal pneumonia.
Becattini S, Littmann ER, Seok R, Amoretti L, Fontana E, Wright R, Gjonbalaj M, Leiner IM, Plitas G, Hohl TM, Pamer EG. Enhancing mucosal immunity by transient microbiota depletion. Nat Commun. 2020 Sep 8;11(1):4475. doi: 10.1038/s41467-020-18248-4.
Sorbara MT, Littmann ER, Fontana E, Moody TU, Kohout CE, Gjonbalaj M, Eaton V, Seok R, Leiner IM, Pamer EG. Functional and Genomic Variation between Human-Derived Isolates of Lachnospiraceae Reveals Inter- and Intra-Species Diversity. Cell Host Microbe. 2020 Jul 8;28(1):134-146.e4. doi: 10.1016/j.chom.2020.05.005.
Gjonbalaj M, Keith JW, Do MH, Hohl TM, Pamer EG, Becattini S. Antibiotic Degradation by Commensal Microbes Shields Pathogens. Infect Immun. 2020 Mar 23;88(4):e00012-20. doi: 10.1128/IAI.00012-20.
Keith JW, Dong Q, Sorbara MT, Becattini S, Sia JK, Gjonbalaj M, Seok R, Leiner IM, Littmann ER, Pamer EG. Impact of Antibiotic-Resistant Bacteria on Immune Activation and Clostridioides difficile Infection in the Mouse Intestine. Immun. 2020 Mar 23;88(4):e00362-19. doi: 10.1128/IAI.00362-19. Print 2020 Mar 23.
Sorbara MT, Dubin K, Littmann ER, Moody TU, Fontana E, Seok R, Leiner IM, Taur Y, Peled JU, van den Brink MRM, Litvak Y, Bäumler AJ, Chaubard JL, Pickard AJ, Cross JR, Pamer EG. Inhibiting antibiotic-resistant Enterobacteriaceae by microbiota mediated intracellular acidification. Journal of Experimental Medicine. 2019; 216(1):84-98.
Jung HJ, Littmann ER, Seok R, Leiner IM, Taur Y, Peled J, van den Brink M, Ling L, Chen L, Kreiswirth BN, Goodman AL, Pamer EG. Genome-wide screening for enteric colonization factors in carbapenem resistant ST258 Klebsiella pneumoniae. MBio. 2019; 10(2). Pii: e02663-18.
Xiong H, Keith JW, Samilo DW, Carter RA, Leiner IM, Pamer EG. Innate lymphocyte/Ly6C(hi) monocyte crosstalk promotes Klebsiella pneumoniae clearance. Cell. 2016; 165(3):679-89.
Xiong H, Carter RA, Leiner IM, Tang YW, Chen L, Kreiswirth BN, Pamer EG. Distinct Contributions of neutrophils and CCR2+ monocytes to pulmonary clearance of different Klebsiella pneumoniae strains. Infection and Immunity. 2015; 83(9):3418-27.