Ebehard-Karls Universität, Tübingen, Germany, B.S. Microbiology
Ebehard-Karls Universität, Tübingen, Germany, Ph.D. Microbiology
Oregon Health Sciences University, Portland, Oregon, Post-Doc Microbiology

Microbiology
http://microbiology.compmed.ucdavis.edu/microbiology/

Immunology
http://immunology.compmed.ucdavis.edu/

Molecular Mechanisms of Salmonella Interaction with the Intestinal Mucosa

The genus Salmonella contains a group of closely related organisms that are pathogenic for humans and other vertebrates. The human disease manifestations caused most frequently by Salmonella serotypes worldwide are typhoid fever and gastroenteritis. One focus of my lab is to understand why typhoid fever and gastroenteritis differ in the host response elicited at the site where both infections originate, the intestinal mucosa. Gastroenteritis, which is caused by non-typhoidal Salmonella serotypes (e.g. S. typhimurium), is a typical diarrheal disease characterized by a massive neutrophil influx in the terminal ileum and colon. In contrast, typhoid fever, which is caused by Salmonella typhi, is not a diarrheal disease and intestinal infiltrates are dominated by mononuclear cells (i.e. macrophages and dendritic cells). We have found that the neutrophil influx during gastroenteritis is caused by bacterial invasion (mediated by the invasion associated type III secretion system, T3SS-1), followed by innate immune recognition of S. typhimurium and survival in mononuclear cells (mediated by a second type III secretion system, T3SS-2). S. typhi is able to prevent neutrophil infiltration by expressing a virulence factor, the capsule encoding viaB locus, that reduces innate immune recognition in the intestinal mucosa. We are further studying the molecular mechanisms underlying the pathogenesis of gastroenteritis and typhoid fever using a variety of in vivo, ex vivo and tissue culture models.

More recently we have become interested in the fact that infection with human immune deficiency virus (HIV) alters the course of S. typhimurium infection in humans. Unlike immunocompetent individuals which develop gastroenteritis, S. typhimurium infection manifests as life threatening bacteremia in HIV patients. Due to the current HIV epidemic, infections with non-typhoidal Salmonella serotypes, such as S. typhimurium, have become leading causes of hospital admissions in Sub-Saharan Africa. In collaboration with Dr. Dandekar we have established a rhesus macaque model to study how infection with simian immunodeficiency virus (SIV) causes defects in mucosal barrier function that facilitate systemic dissemination of S. typhimurium. We are using immunological and genomic approaches to map the host response in this model.

Another focus of research in my lab is to understand the role of adhesins during S. typhimurium intestinal colonization and persistence. Intestinal persistence of Salmonella serotypes in apparently healthy livestock and domestic fowl leads to their subsequent introduction into the derived food products, thereby resulting in animal to human transmission. Although this route of infection is largely responsible for the estimated 1.4 million annual cases of Salmonella-induced enterocolitis in the US, the molecular mechanisms responsible for intestinal persistence in healthy food animals are unknown. Whole genome sequencing has revealed the presence of 13 operons containing fimbrial gene sequences and several genes encoding non-fimbrial adhesins in the S. typhimurium genome. We are currently studying the binding specificities of these adhesins using a variety of approaches, including tissue culture, animal models and glycomics.

2008. Winter, S.E., M. Raffatellu, R.P. Wilson, H. Rüssmann and A.J. Bäumler. The Salmonella enterica serotype Typhi regulator TviA reduces IL-8 production in intestinal epithelial cells by repressing flagellin secretion. Cell. Microbiol., 10:247-261.

2008. Chessa, D., C.W. Dorsey, Maria Winter, and A.J. Bäumler. Binding Specificity of Salmonella Plasmid-Encoded Fimbriae Assessed by Glycomics. J. Biol. Chem. 283:8118-8124.

2008. Briggs H.L., N. Pul, R. Seshadri, M.J. Wilson, C. Tersteeg, K.E. Russel-Lodrigue, M. Andoh, A.J. Bäumler and J.E. Samuel. A limited role for iron regulation in Coxiella burnetii pathogenesis. Infect. Immun. 76:2189-2201.

2008. Chessa, D., M. G. Winter, S.-P. Nuccio, Ç. Tükel and A.J. Bäumler. RosE represses Std fimbrial expression in Salmonella enterica serotype Typhimurium. Mol. Microbiol., 68:573-578.

2008. 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. 14:421-428.

2008. Wilson, R.P., M. Raffatellu, D. Chessa, S.E. Winter, Ç. Tükel, and A.J. Bäumler. The Vi capsule prevents Toll-Like Receptor 4 recognition of Salmonella. Cell. Microbiol., 10:876-890.

2008. Godinez, I., T. Haneda, M. Raffatellu, M.D. George, T.A. Paixão, H.G. Rolán, R.L. Santos, S. Dandekar, R.M. Tsolis and A.J. Bäumler. T cells help to amplify inflammatory responses induced by Salmonella enterica serotype Typhimurium in the intestinal mucosa. Infect. Immun. 76:2008-2017.

2008. Tsolis, R.M. G.M. Young, J.V. Solnick and A.J. Bäumler. From bench to bedside: stealth of enteroinvasive pathogens. Nature Rev. Microbiol. 6:883-892.

2008. Jakomin, M., D. Chessa, A.J. Bäumler, and J. Casadesus. Regulation of the Salmonella enterica std fimbrial operon by DNA adenine methylation, SeqA and HdfR. J. Bacteriol. 190:7406-7413.

2008. Bogomolnaya, L.M., C. Santiviago, H.-J. Yang, A.J. Bäumler and H.L. Andrews-Polymenis. ‘Form Variation’ of the O12 Antigen is Critical for Persistence of Salmonella Typhimurium in the Murine Intestine. Mol. Microbiol. 10:1105-1119.

2009. Godinez, I., M. Raffatellu, T.A. Paixão, T. Haneda, R.L. Santos, R.M. Tsolis and A.J. Bäumler. IL-23 orchestrates mucosal responses to Salmonella enterica serotype Typhimurium in the intestine. Infect. Immun. 77:387-398.

2009. Chessa, D., M.G. Winter, M. Jakomin, and A.J. Bäumler. Salmonella enterica serotype Typhimurium Std fimbriae bind terminal a(1,2)fucose residues in the cecal mucosa. Mol. Microbiol. 71:864-875.

2009. Figueiredo J.F., S.D. Lawhon, K. Gokulan, S. Khare, M. Raffatellu, R.C. Burghardt, R.M. Tsolis, A.J. Bäumler, B. McCormick, L.G. Adams. Salmonella Typhimurium SipA induces CXC-chemokine expression through p38MAPK and JUN pathways. Microb. Infect. 11:302-310.

2009. Winter, S.E., P. Thiennimitr, S.-P. Nuccio, T. Haneda, M.G. Winter, R.P. Wilson, J.M. Russell, T. Henry, Q.N. Tran, S.D. Lawhon, G. Gomez, C.L. Bevins, H. Ruessmann, D. Monack, L.G. Adams, A.J. Bäumler. Contribution of flagellin pattern recognition to intestinal inflammation during Salmonella enterica serotype Typhimurium infection. Infect. Immun. 77:1904-1916.

2009. 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. 5:476-486.

2009. Haneda, T., S.E. Winter, B.P. Butler, R.P. Wilson, Ç. Tükel, M.G. Winter, I. Godinez, R.M. Tsolis and A.J. Bäumler. The capsule-encoding viaB locus reduces intestinal inflammation by a Salmonella Pathogenicity Island 1-independent mechanism. Infect. Immun. 77:2932-2942.

2009. 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. 6:45-53.

2009. Figueiredo J.F., R. Barhoumi, M. Raffatellu, S.D. Lawhon, L. Rousseau, R.C. Burghardt, R.M. Tsolis, A.J. Bäumler, L.G. Adams. Salmonella enterica serovar Typhimurium-induced internalization and IL-8 expression in HeLa cells does not have a direct relationship with intracellular Ca2+ levels. Microb. Infect. 11:850-858.

2009. Winter, S.E., M.G. Winter, P. Thiennimitr, V.A. Gerriets, S.-P. Nuccio, H. Rüssmann, A.J. Bäumler. The TviA auxiliary protein renders the Salmonella enterica serotype Typhi RcsB regulon responsive to changes in osmolarity. Mol. Microbiol. 74:175-193.

2009. Santos, R.L., M. Raffatellu, C.L. Bevins, L.G. Adams, Ç. Tükel, R.M. Tsolis and A.J. Bäumler. Life in the inflamed intestine, Salmonella style. Trends Microbiol. 17:498-506.

2010. Tran, Q.T., G. Gomez, S. Khare, S.D. Lawhon, M. Raffatellu, A.J. Bäumler, and L.G. Adams. The Salmonella enterica serotype Typhi Vi capsular antigen is expressed after entering the ileal mucosa. Infect. Immun. 78:527-535.

2010. Raffatellu, M. and A.J. Bäumler. Salmonella’s iron armor for battling the host and its microbiota. Gut Microbes. 1:24-26.

Former Ph.D. students
Tracy L. Nicholson (Currently Microbiologist at USDA, Ames, Iowa)
http://www.ars.usda.gov/pandp/people/people.htm?personid=35723

Stacy M. Townsend (Currently Sen. Research Microbiologist, BioSTAR West, Claremont, CA)
http://www.biostarwest.com/team.swf

Andrea D. Humphries

Former Postdocs and Visiting Professors
Robert A. Kingsley, Ph.D. (Currently Deputy Head, Team 15, Sanger Centre, UK)
http://www.sanger.ac.uk/Teams/Team15/

Helene Andrews-Polymenis, DVM Ph.D. (Currently Assist. Professor at Texas A&M Univ.)
http://medicine.tamhsc.edu/basic-sciences/mmp/faculty/helene-andrews.html

Manuela Raffatellu, MD (Currently Assist. Professor at the Univ. of California, Irvine)
http://www.immunology.uci.edu/investigators_detail.cfm?UID=231672106568

Caleb Dorsey, Ph.D. (Currently Research Associate, ConjuGon, Madison, WI)

Mustafa Akçelik, Ph.D. (Currently Associate Professor, University of Ankara, Turkey)
http://www.science.ankara.edu.tr/eng/index.php?link=3021

Renato de Lima Santos, DVM Ph.D. (Currently Professor Adjunto, UFMG, Brasil)
http://buscatextual.cnpq.br/buscatextual/visualizacv.jsp?id=K4728429H9

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)

Technicians
Maria G Winter (Lab Manager)
Kim Nguyen
Jessalyn Nishimori

PhD students
R. Paul Wilson
Ivan Godinez
Sean-Paul Nuccio
Parameth Thiennimitr, MD
Alanna O’Leary

Postdocs
Sebastian E. Winter, Ph.D.
Marijke Keestra, Ph.D.
Torsten Sterzenbach, Ph.D.
Robert Crawford, Ph.D.