Andreas Bäumler, Ph.D.
Vice Chair of Research
GBSF Room 5513
- Ebehard-Karls Universität, Tübingen, Germany, Diplom (B.S.) Microbiology
- Ebehard-Karls Universität, Tübingen, Germany, Dr. rer. nat. (Ph.D.) Microbiology
- Oregon Health Sciences University, Portland, Oregon, Post-Doc Microbiology
Enteric Pathogens, the Host and its Gut Microbiota
Host responses during gastroenteritis. My laboratory has a long-standing history of pioneering new models and approaches to address key questions about the pathogenesis of gastroenteritis. When I started my faculty position in 1996, all major laboratories in the field studied Salmonella pathogenesis using the mouse model of typhoid fever. However, gastroenteritis, the disease S. Typhimurium causes in humans, was not being investigated at the molecular level. To fill this key gap in knowledge, we pioneered the use of a calf gastroenteritis model. Using this innovative approach, we identified the two type III secretion systems (T3SSs) of S. Typhimurium as the main virulence factors required for gastroenteritis. After moving my lab to UC Davis we collaborated with Dr. Dandekar’s lab to established a Rhesus macaque model to show that T helper 17 (TH17) responses during S. Typhimurium-induced gastroenteritis were blunted by infection with simian immunodeficiency virus (SIV). Further investigation of host responses induced by the TH17 cytokine interleukin (IL)-22 identified lipocalin-2 as an antimicrobial protein that places lipocalin-2 resistance mechanisms (i.e. salmochelin biosynthesis and uptake) under selection. In a collaboration with Dr. Bevins lab using a transgenic mouse model we identified human α-defensin (HD) 6, a major product of intestinal paneth cells, as an antimicrobial peptide that inhibits S. Typhimurium invasion by entrapping bacteria in nano-nets. Finally, we identified many of the innate immune pathways that become activated during S. Typhimurium infection using a mouse colitis model. A recent example for this type of work is the discovery that the T3SS effector protein SopE triggers inflammation by activating the NOD1 signaling pathway.
Typhoid fever pathogenesis. The pathogenesis of typhoid fever is incompletely understood due to the lack of suitable animal models for the strictly human-adapted S. enterica serovar Typhi (S. Typhi). S. Typhimurium infection of mice is commonly used to model the pathogenesis of S. Typhi infections in humans (mouse typhoid model). However, a limitation of this approach is that S. Typhimurium does not cause typhoid fever in humans, but rather causes a localized gastroenteritis. As a result, S. Typhi-specific virulence mechanisms that set typhoid fever apart from human gastroenteritis remain understudied. To address this knowledge gap, we investigated S. Typhi-specific virulence genes. This research identified the viaB locus, encoding the virulence-associated (Vi) capsular polysaccharide, as a S. Typhi-specific DNA region that enables the pathogen to evade innate immunity. We found that the viaB locus mediates innate immune evasion through two distinct mechanisms; one requires expression of the Vi capsular polysaccharide, and the other depends on TviA-mediated changes in virulence gene regulation. The drastic attenuation of host responses resulting from the viaB-mediated evasion of innate immune responses illuminates how S. Typhi disseminates from the intestinal mucosa into the bloodstream and helps explain why symptoms of acute gastroenteritis are typically absent during typhoid fever.
Interactions between Salmonella, the host and its microbiota. We were among the first to elucidate mechanisms explaining changes in the composition of gut-associated microbial communities during infection. This project emerged from our interest in the pathogenesis of gastroenteritis. The inflammatory response during gastroenteritis is accompanied by changes in the luminal environment, which tip the balance in the competition between S. Typhimurium and the resident microbiota in favor of the pathogen. The question of which mechanisms are responsible for these changes in the microbiota composition represents a high-impact topic that attracted our attention. Studies performed in collaboration with Dr. Roth’s lab revealed that inflammation provides a respiratory electron acceptor, tetrathionate, which boosts growth of S. Typhimurium in the gut. While tetrathionate had been used empirically in clinical laboratories since 1923 to enrich Salmonella serovars in samples containing competing microbes, our work suggested that this function is part of a “business plan” defining the genus Salmonella. We went on to show that tetrathionate respiration enables S. Typhimurium to use an abundant simple substrate, ethanolamine, which is provided by the host. Subsequently we discovered that energy taxis enables S. Typhimurium to seek out favorable spatial niches containing host-derived electron acceptors and that the host inflammatory response depletes butyrate-producing Clostridia, which in turn elevates epithelial oxygenation thereby driving an aerobic luminal pathogen expansion that ensures transmission.
Changes in gut-associated microbial communities. Most recently we became interested in mechanisms that lower colonization resistance against Enterobacteriaceae. The human large intestine is host to a complex microbial community dominated by obligate anaerobic bacteria belonging to the phyla Bacteroidetes and Firmicutes. Antibiotic treatment or conditions of intestinal inflammation can lead to a microbial imbalance (dysbiosis) characterized by a marked decrease in the representation of obligate anaerobic bacteria and an increased relative abundance of facultative anaerobic bacteria, such as Enterobacteriaceae. We could demonstrate that antibiotic treatment and inflammatory host response selectively enhance growth of commensal Enterobacteriaceae through sugar oxidation and by generating respiratory electron acceptors. These findings have broad implications for understanding the mechanisms contributing to dysbiosis.
A full list of my published work can be found at: http://www.ncbi.nlm.nih.gov/pubmed/?term=baumler+aj
Faber, F., P. Thiennimitr, L. Spiga, M.X. Byndloss, Y. Litvak, S. Lawhon, H.L. Andrews-Polymenis, S.E. Winter and A.J. Bäumler. Respiration of microbiota-derived 1,2-propanediol drives Salmonella expansion during colitis. PLOS Pathogens. 2017 Jan 5;13(1):e1006129.
Lopez, C.A., B.M. Miller, F. Rivera-Chávez, E.M. Velazquez, M.X. Byndloss, A. Chávez-Arroyo, K.L. Lokken, R.M. Tsolis, S.E. Winter, A.J. Bäumler. Virulence factors enhance Citrobacter rodentium expansion through aerobic respiration. Science. 2016 Sep 16;353:1249-1253.
Rivera-Chávez, F., C.A. Lopez, L.F. Zhang, L. García-Pastor, A. Chávez-Arroyo, K.L Lokken, R.M. Tsolis, S.E. Winter and A.J. Bäumler. Energy taxis towards host-derived nitrate supports a Salmonella pathogenicity island 1-independent mechanism of invasion. mBIO. 2016 Jul 19;7(4). pii: e00960-16.
Faber, F., L. Tran, M.X. Byndloss, C.A. Lopez, E.M. Velazquez, T. Kerrinnes, S.-P. Nuccio, T. Wangdi, O. Fiehn, R.M. Tsolis and A.J. Bäumler. Host-mediated sugar oxidation promotes post-antibiotic pathogen expansion. Nature. 2016 Jun 30;534:697-699.
Bäumler, A.J. and V. Sperandio. Microbiota-bacterial pathogen interactions in the gut. Nature, 2016 Jul 7;535:85-93.
Rivera-Chávez, F., L.F. Zhang, F. Faber, C.A. Lopez, M.X. Byndloss, E.E. Olsan, G. Xu, E.M. Velazquez, C.B. Lebrilla, S.E. Winter and A.J. Bäumler. Depletion of butyrate-producing Clostridia from the gut microbiota drives an aerobic luminal expansion of Salmonella. Cell Host & Microbe. 2016 Apr 13;19:443-454.
Keestra-Gounder, A.M., M.X. Byndloss, N.B. Seyffert, B.M. Young, A. Chávez-Arroyo, A.Y. Tsai, S.A. Cevallos, M.G. Winter, O.H. Pham, C.R. Tiffany, M.F. de Jong, T. Kerrinnes, R. Ravindran, P.A. Luciw, S.J. McSorley, A.J. Bäumler and R.M. Tsolis. NOD1/NOD2 signaling links ER stress with inflammation. Nature. 2016 Apr 21;532:394-397.
Song, J., C.L.Wilhelm, T. Wangdi, T. Maira-Litran, S.-J. Lee, M. Raetz, C.R. Sturge, J. Mirpuri, J. Pei, N.V. Grishin, S.J. McSorley,. A.T. Gewirtz, A.J. Bäumler, G.B. Pier, J.E. Galán, and F. Yarovinsky. Absence of TLR11 in mice does not confer susceptibility to Salmonella Typhi. Cell 2016 Feb 25;164:827–828.
Nuccio, S.-P. and A.J. Bäumler. Reconstructing pathogen evolution from the ruins. Proc. Natl. Acad. Sci. USA. 2015 Jan 20;112:647-648.
Bevins. C.L. and A.J. Bäumler. What's one phosphate between friends (and foe)? Cell Host & Microbe. 2015 Jan 14;17:1-3.
Keestra-Gounder, A.M., R.M. Tsolis and A.J. Bäumler. Now you see me, now you don’t: The interaction of Salmonella serovars with pathogen recognition receptors. Nature Rev. Microbiol. 2015 Apr;13:206-216.
Lopez, C.A., D.D. Kingsbury, E.M. Velazquez and A.J. Bäumler. Collateral Damage: Microbiota-derived Metabolites and Immune Function in the Antibiotic Era. Cell Host & Microbe. 2014 Aug 13;16(2):156-163.
Hirao, L.A, I. Grishina, O. Bourry, W.K. Hu, M. Somrit, S. Sankaran-Walters, C.A. Gaulke, A.N. Fenton, J.A. Li, R.W. Crawford, F. Chuang, R. Tarara, M. Marco, A.J. Bäumler, H. Cheng and S. Dandekar. Early Mucosal Sensing of SIV Infection by Paneth Cells Induces IL-1β Production and Initiates Gut Epithelial Disruption. PLOS Pathogens. 2014 Aug 28;10: e1004311.
Winter, S.E., M.G. Winter, V. Poon, A.M. Keestra, T. Sterzenbach, F. Faber, and A.J. Bäumler. Salmonella enterica serovar Typhi conceals the invasion-associated type three secretion system from the innate immune system by gene regulation. PLOS Pathogens. 2014 Jul 3;10: e1004207.
Wangdi, T, C.-Y. Lee, A.M. Spees, C. Yu, D.D. Kingsbury, S.E. Winter, C.J. Hastey, R.P. Wilson, V. Heinrich and A.J. Bäumler. The Vi capsular polysaccharide enables Salmonella enterica serovar Typhi to evade microbe-guided neutrophil chemotaxis. PLOS Pathogens. 2014 Jul 3;10: e1004306.
Lokken, K.L., R.M. Tsolis and A.J. Bäumler. Hypoferremia of infection: a double-edged sword? Nature Medicine. 2014 Apr;20:335-337.
O’Donnell, H., O. Pham, L.-X. Li, S.-P. Nuccio, D. Monack, A.J. Bäumler, and S.J. McSorley. Innate bactericidal capacity of Th1 cells is tuned by TLR and inflammasome signaling. Immunity. 2014 Feb 20;40: 213–224.
Hirao, L.A, I. Grishina, O. Bourry, W.K. Hu, M. Somrit, S. Sankaran-Walters, C.A. Gaulke, A.N. Fenton, J.A. Li, R.W. Crawford, F. Chuang, R. Tarara, M. Marco, A.J. Bäumler, H. Cheng and S. Dandekar. Early Mucosal Sensing of SIV Infection by Paneth Cells Induces IL-1b Production and Initiates Gut Epithelial Disruption. PLOS Pathogens. 2014 Aug 28;10: e1004311.
Nuccio, S.-P. and A.J. Bäumler. Comparative analysis of Salmonella genomes identifies a metabolic network for escalating growth in the inflamed gut. mBIO. 2014 Mar 18;5: e00929-14.
Laughlin, R.C., L.A. Knodler, R. Barhoumi, H.R. Payne, J. Wu, G. Gomez, R. Pugh, S.D. Lawhon, A.J. Bäumler, O. Steele-Mortimer, L.G. Adams. Spatial segregation of virulence gene expression during acute enteric infection with Salmonella enterica serovar Typhimurium. mBIO. 2014 Feb 4;5: e00946-13.
Keestra, A.M., M.G. Winter, J.J. Auburger, S.P. Fräßle, M.N. Xavier, S.E. Winter, A. Kim, V. Poon, M.M. Ravesloot, J. Waldenmaier, R.M. Tsolis, R.A. Eigenheer and A.J. Bäumler. Manipulation of small Rho GTPases is a pathogen-induced process detected by Nod1. Nature. 2013 Apr 11;496:233-237.
Sterzenbach, T., K.T. Nguyen, S.-P. Nuccio, M.G. Winter, C. Vakulskas, S. Clegg, T. Romeo and A.J. Bäumler. A novel CsrA titration mechanism regulates fimbrial gene expression in Salmonella Typhimurium. EMBO J. 2013 Oct 30;32:2872-2883.
Xavier, M.N., M.G. Winter, A.M. Spees, K. Nguyen, V.L. Atluri, T.A.M. Silva, A.J. Bäumler, W. Müller3, R.L. Santos2, R.M.Tsolis. CD4+ T cell derived IL-10 promotes Brucella abortus persistence through modulation of macrophage function during early infection. PLOS Pathogens. 2013;9: e1003454.
Crawford, R.W., T. Wangdi, A.M. Spees, M.N. Xavier, R.M. Tsolis and A.J. Bäumler. Loss of very-long O-antigen chains optimizes capsule-mediated immune evasion by Salmonella enterica serovar Typhi. mBIO.2013 Jul 16; 4: e00232-13.
Spees, A.M., C.A. Lopez, D.D. Kingsbury, S.E. Winter and A.J. Bäumler. Colonization resistance: battle of the bugs or ménage à trois with the host? PLOS Pathogens. 2013;9: e1003730
Xavier, M.N., M.G. Winter, A.M. Spees, K. Nguyen, V.L. Atluri, A.B. den Hartigh, T.M. A. Silva, P.A. Luciw, D.M. Monack, A.J. Bäumler, R.L. Santos, R.M. Tsolis. A PPARg-mediated increase in glucose availability sustains chronic Brucella abortus infection in alternatively activated macrophages. Cell Host & Microbe. 2013 Aug 14;14:159-170.
Spees, A.M., T. Wangdi, C.A. Lopez, D.D. Kingsbury, M.N. Xavier, S.E. Winter, R.M. Tsolis and A.J. Bäumler. Streptomycin-induced inflammation enhances Escherichia coli gut colonization through nitrate respiration. mBIO. 2013 Jul 2;4: e00430-13.
Rivera-Chávez, F., S.E. Winter, C.A. Lopez, M.N. Xavier, M.G. Winter, J.M. Russell, R.C. Laughlin, S.D. Lawhon, T. Sterzenbach, C.L. Bevins, R.M. Tsolis, R. Harshey, L.G. Adams and A.J. Bäumler. Salmonella uses energy taxis to benefit from intestinal inflammation. PLOS Pathogens. 2013;9(4): e1003267
Winter, S.E., M.G. Winter, M.N. Xavier, P. Thiennimitr, V. Poon, A.M. Keestra, R. Laughlin, G. Gomez, J. Wu, S.D. Lawhon, I. Popova, S.J. Parikh, L.G. Adams, R.M. Tsolis, V.J. Stewart and A.J. Bäumler. Host-derived nitrate boosts growth of E. coli in the inflamed gut. Science. 2013 Feb 8;339:708-711.
Fang, F.C. and A.J. Bäumler. A Toll gate for typhoid. Cell. 2012 Oct 26;151:473-475.
Crawford, R.W., A.M. Keestra, S.E. Winter, M.N. Xavier, R.M. Tsolis, V. Tolstikov and A.J. Bäumler. Very long O-antigen chains enhance fitness during Salmonella-induced colitis by increasing bile resistance. PLOS Pathogens. 2012 Sep;8: e1002918. (PMID: 23028318)
Chu, H., M. Pazgier, G. Jung, S.-P. Nuccio, P.A. Castillo, M.F. de Jong, M.G. Winter, S.E. Winter, J. Wehkamp, B. Shen, N.H. Salzman, M.A. Underwood, R.M. Tsolis, G.M. Young, W. Lu, R.I. Lehrer, A.J. Bäumler, and C.L. Bevins. Human α-defensin 6 promotes mucosal innate immunity through self-assembled peptide nanonets. Science. 2012 Jul 27;337:477-481. (PMID: 22722251)
Lopez, C.A., S.E. Winter, F. Rivera-Chávez, M.N. Xavier, V. Poon, S.-P. Nuccio, R.M. Tsolis and A.J. Bäumler. Phage-mediated acquisition of a type III secreted effector protein boosts growth of Salmonella by nitrate respiration. mBIO. 2012 Jun 12;3:e00143-12. (PMID: 22691391)
Lee, S.-J., J.B McLachlan, J.R. Kurtz, D. Fan, S.E. Winter, A.J. Bäumler, M.K. Jenkins, and S.J. McSorley. Temporal expression of bacterial proteins instructs host CD4 T cell expansion and Th17 development. PLoS Pathogens. 2012 Jan;8(1):e1002499. (PMID: 22275869)
Keestra, A.M. and A.J. Bäumler. Host defenses trigger Salmonella’s arsenal. Cell Host & Microbe. 2011 Mar 17;9:167-168.
Keestra, A.M., M.G. Winter, D. Klein-Douwel, M.N. Xavier, S.E. Winter, A. Kim, R.M. Tsolis and A.J. Bäumler. A Salmonella virulence factor activates the Nod1/Nod2 Signaling Pathway. mBIO. 2011 Dec 20;2:e00266-11.
Thiennimitr, P., S.E. Winter, M.G. Winter, M.N. Xavier, V. Tolstikov, D.L. Huseby, T. Sterzenbach, R.M. Tsolis, J.R. Roth, A.J. Bäumler. Intestinal inflammation allows Salmonella to utilize ethanolamine to compete with the microbiota. Proc. Natl. Acad. Sci. USA. 2011 Oct 18;108:17480-17485.
Fookes, M., G.N. Schroeder, G. Langridge, C.J. Blondel, C. Mammina, G.S. Vernikos, K.S. Robinson, N.K. Petty, R.A. Kingsley, A.J. Bäumler, S.-P. Nuccio, I. Contreras, C.A. Santiviago, D. Maskell, P. Barrow, T. Humphrey, A. Nastasi, M. Roberts, G. Frankel, J. Parkhill, G. Dougan, N.R. Thomson. Salmonella bongori provides insights into the evolution of the salmonellae. PLOS Pathogens. 2011 Aug;7: e1002191.
Winter, S.E., A.M. Keestra, R.M. Tsolis and A.J. Bäumler. The blessings and curses of intestinal inflammation. Cell Host & Microbe 2010 Jul 22;8:36-43.
Winter S.E., P. Thiennimitr, M.G. Winter, B. Butler, D.L. Huseby, R.W. Crawford, J.M. Russell, C.L. Bevins, L.G. Adams, R.M. Tsolis, J.R. Roth and A.J. Bäumler. Gut inflammation provides a respiratory electron acceptor for Salmonella. Nature. 2010 Sep 23;467:426-429.
Winter, S.E., M.G. Winter, I. Godinez, H.-J. Yang, H. Rüssmann, H.L. Andrews-Polymenis, A.J. Bäumler. A rapid change in virulence gene expression during the transition from the intestinal lumen into tissue promotes systemic dissemination of Salmonella. PLOS Pathogens. 2010 Sep 23;6: e1001060.
Raffatellu, M., M.D. George, Y. Akiyama, M.J. Hornsby, S.-P. Nuccio, T.A. Paixao, B.P. Butler, H. Chu, R.L. Santos, T. Berger, T.W. Mak, R.M. Tsolis, C.L. Bevins, J.V. Solnick, S. Dandekar and A.J. Bäumler. Lipocalin-2 resistance confers an advantage to Salmonella enterica serotype Typhimurium for growth and survival in the inflamed intestine. Cell Host Microbe. 2009 May 8;5:476-486.
Tükel, Ç., R.P. Wilson, M. Pezeshki, B.A. Chromy and A.J. Bäumler. Responses to amyloids of microbial and host origin are mediated through Toll-like receptor 2. Cell Host Microbe. 2009 Jul 23;6:45-53
Tsolis, R.M., G.M. Young, J.V. Solnick and A.J. Bäumler. From bench to bedside: stealth of enteroinvasive pathogens. Nature Rev. Microbiol. 2008 Dec;6:883-892.
M. Raffatellu, R.L .Santos, D. Verhoeven, M.D. George, R.P. Wilson, S.E. Winter, I. Godinez, S. Sankaran, T.A. Paixao, M.A. Gordon, J.K. Kolls, S. Dandekar, and A.J. Bäumler. Simian immunodeficiency virus–induced mucosal IL–17 deficiency promotes Salmonella dissemination from the gut. Nature Medicine. 2008 Apr;14:421-428.
- Briana Young (Lab Manager)
- Connor Tiffany
- Henry Nguyen
- Eric Velazquez
- Lillian Zhang
- Stephanie Cevallos
- Brittany Miller
- Megan Liou
- Franziska Faber, Ph.D.
- Mariana Xavier, DVM, Ph.D.
- Erin Olsen, Ph.D.
- Denise Bronner, Ph.D.
Assistant Project Scientists
- Hirotaka Hiyoshi, Ph.D.
- Yael Litvak, Ph.D.
- Tamding Wangdi, Ph.D.
Former Ph.D. students
- Tracy L. Nicholson (Currently Microbiologist at USDA, Ames, Iowa)
- Stacy M. Townsend (Currently Sen. Research Microbiologist, BioSTAR West, Claremont, CA)
- Andrea D. Humphries
- R. Paul Wilson (Currently Investigator at GlaxoSmithKline, Philadelphia, PA)
- Ivan Godinez (Illumina)
- Alanna Spees
- Parameth Thiennimitr, MD (Currently Assistant Professor at Chiang Mai University, Thailand)
- Sean-Paul Nuccio (Currently postdoc at UC Irvine)
- Dawn Kingsbury
- Fabian Rivera (Currently postdoc at Harvard Medical School, Boston, MA)
- Christopher Lopez (Currently postdoc at Vanderbilt University, Nashville, TN)
Former Postdocs and Visiting Professors
- Robert A. Kingsley, Ph.D. (Research Leader, Institute of food research, UK)
- Helene Andrews-Polymenis, DVM Ph.D. (Currently Associate. Professor at Texas A&M Univ.)
- Manuela Raffatellu, MD (Currently Associate Professor at the Univ. of California, Irvine)
- Caleb Dorsey, Ph.D. (Currently Research Associate, ConjuGon, Madison, WI)
- Mustafa Akçelik, Ph.D. (Currently Associate Professor, University of Ankara, Turkey)
- Renato de Lima Santos, DVM Ph.D. (Currently Professor, UFMG, Brasil)
- Daniela Chessa, Ph.D. (Currently Research Associate, Univ. Sassari, Italy)
- Takeshi Haneda, Ph.D. (Currently Assist. Professor, Kitasato Univ., Japan)
- Çagla Tükel, Ph.D. (Currently Assist. Professor at Temple University, Philadelphia, PA)
- Robert Crawford, Ph.D. (Currently Assistant Professor at California State University, Sacramento)
- Torsten Sterzenbach, Ph.D. (Currently Group Leader at the Universität Osnarbrück, Germany)
- Sebastian E. Winter, Ph.D. (Currently Assist. Professor at the University of Texas Southwestern Medical Center, Dallas, TX)
- Marijke Keestra, Ph.D. (Currently Assist. Professor at the University of Colorado Health Sciences Center, Denver, CO)