Regularly Participating Groups

Web site: http://www.ucdmc.ucdavis.edu/medmicro/staff/baumler.html

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 (through Toll-like receptors) 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 Vi-capsular antigen, that reduces Toll-like receptor signaling 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.
A second 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 U.S. , 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.

Web Site: http://faculty.vetmed.ucdavis.edu/faculty/nbaumgarth/

The investigations in my lab are aimed at studying immune regulation in response to infections. The murine model of acute influenza virus infection is utilized for three of the projects. Those projects are involved in understanding the early (innate) regulation of antiviral B cell responses and the role of dendritic cells in regulating local respiratory tract immunity. Further studies are aimed at determining how the use of inactivated influenza virus (a prototype vaccine) and/or immunomodulatory CpG motives might affect the function of these cells. A different infectious disease mouse model, Borrelial burgdorferi infection, is being studied in collaboration with Dr. Stephen Barthold. The aim of this study is to understand the role of T cell-dependent and T-independent B cell responses in affecting this chronic infection. Finally, collaborative studies with investigators at the University of California, San Francisco are being conducted to determine how HIV-infection and highly antiretroviral therapy affect the immune status of the human oral mucosa and what effects this has on susceptibility to opportunistic infections.

Key References

• Coro ES, Chang WL, Baumgarth N  (2006) Type I IFN receptor signals directly stimulate local B cells early following influenza virus infection. J Immunol  2006 176:4343-51.
• Doucett VP, Gerhard W, Owler K, Curry D, Brown L, Baumgarth N (2005) Enumeration and characterization of virus-specific B cells by multicolor flow cytometry.  J Immunol Methods 303:40-52.
• Baumgarth N, Szubin R, Dolganov GM, Watnik MR, Greenspan D, Da Costa M, Palefsky JM, Jordan R, Roederer M, Greenspan JS (2004)  Highly tissue substructure-specific effects of human papilloma virus in mucosa of HIV-infected patients revealed by laser-dissection microscopy-assisted gene expression profiling.  Am J Pathol 165:707-18
  

Web Site: http://biosci.ucdavis.edu/FacultyProfiles/BMB_GG/DisplayFacultyProfile.cfm?ResearcherID=1875

Our laboratory is interested in innate immunity of mucosal tissues and we are focused on a newly discovered component of host defense: antimicrobial peptides.  Antimicrobial peptides are endogenous antibiotics, isolated from diverse species throughout the plant and animal kingdoms.  These peptides represent an evolutionary ancient mechanism of host defense, and they have a broad-spectrum of antimicrobial activity that includes bacteria, fungi and certain viruses.  Defensins are the major class of antimicrobial peptides in humans and other mammals.  Investigations from our laboratory, and others, have discovered that certain defensins are expressed in abundance by epithelial cells at wet mucosal surface where they contribute to innate immunity at these sites. The long-range goal of our research is to understand the specific role that these epithelial antimicrobial peptides play in mucosal host defense and to characterize the pathophysiology that characterizes altered expression of these peptides.  Our current studies include: (i) characterizing the primary structure and biological activity of the tissue forms defensins, (ii) defining the key regulatory steps for the expression of these molecules, (iii) examining expression of defensins in the gastrointestinal tract following acute infection and in states of chronic inflammation. The investigations include biochemical and molecular biological approaches and analysis of transgenic models.

Key references:

• Wehkamp, J, Salzman, NH, Porter, E, Weichenthal, M, Petras, RE, Shen, B, Schaeffeler, E, Schwab, M, Linzmeier, R, Feathers, RW, Chu, H, Lima, J, H., Fellermann, K, Ganz, T, Stange, EF, and Bevins, CL,  Reduced Paneth cell alpha-defensins in ileal Crohn's disease. Proc Natl Acad Sci U S A  102: 18129-18134, 2005.
• Salzman, NH, Ghosh, D, Huttner, KM, Paterson, Y, and Bevins, CL, Protection against enteric salmonellosis in transgenic mice expressing a human intestinal defensin. Nature 422: 522-526, 2003.
• Ghosh, D, Porter, EM, Shen, B, Lee, SK, Wilk, DJ, Crabb, JW, Drazba, J, Yadav, SY, Ganz, T, and Bevins, CL, Paneth cell trypsin is the processing enzyme for human defensin-5. Nat. Immunol. 3: 583-590, 2002.

Web Site: http://www.ucdmc.ucdavis.edu/medmicro/staff/luckhart.html

Description:  The mosquitoes Anopheles stephensi and Anopheles gambiae respond to malaria parasite infection with inducible expression of nitric oxide synthase (NOS). Catalytic activity of mosquito NOS results in the synthesis of inflammatory levels of nitrogen oxides (NOx) that limit parasite development in the insect. Induction and activity of mosquito NOS are dependent on ingested midgut blood components including mammalian growth factors/cytokines that crosstalk with mosquito cells and blood proteins that function as substrates for NOx chemistry. Plasmodium falciparum glycosylphosphatidylinositols (PfGPIs), the "malaria toxin" in mammals, also drive biphasic induction of NOS in the mosquito, indicating that PfGPIs are critical inflammatory mediators in both mosquitoes and mammals. In addition to understanding parasite inducers like PfGPIs, we are also interested in how NO synthesis is controlled in the mosquito. In mammals, other studies have demonstrated that transforming growth factor (TGF)-beta1 maintains immunological balance during malaria parasite infection, primarily through an effect on inducible NOS. We have demonstrated that ingested mammalian TGF-beta1 dose-dependently regulates malaria parasite development in A. stephensi. Our observations indicated for the first time that TGF-beta-dependent Smad signaling regulates an important anti-parasite defense in the insect host. In mammals, TGF-beta1 regulates a myriad of genes that are associated with cell growth and death, differentiation, morphology, extracellular matrix synthesis and immunity which, in turn, influence the development and physiology of nearly every major tissue and organ system. The success of cytokine therapy for management of infectious disease in humans suggests that a similar strategy may be feasible in mosquitoes. As such, we are using genomics and proteomics approaches as well as overexpression and knockout strategies to understand the global effects of TGF-beta1, parasite signals like PfGPIs and other immunomodulatory factors on mosquito cells and innate immunity.

Key References:

• Lim J, Gowda DC, Krishnegowda G, Luckhart S Induction of nitric oxide synthase in Anopheles stephensi by Plasmodium falciparum: mechanism of signaling and the role of parasite glycosylphosphatidylinositols., Infection and Immunity, 73: 2778-89, 2005
• Vodovotz Y, Zamora R, Lieber MJ, Luckhart S, Cross-talk between nitric oxide and transforming growth factor-beta1 in malaria, Current Molecular Medicine, 4: 787-797, 2004
• Lieber MJ, Luckhart S, Transforming growth factor-betas and related gene products in mosquito vectors of human malaria parasites: signaling architecture for immunological crosstalk, Molecular Immunology, 41: 965-77, 2004

Web Site: http://www.ucdmc.ucdavis.edu/medmicro/staff/solnick.html

Our laboratory studies Helicobacter pylori, a common bacterial infection that causes peptic ulcer disease and gastric cancer, the second most common cause of cancer death worldwide.  Our research focuses on the following areas:

Gene expression during H. pylori-host interactions  Rapid progress in genomics and gene expression technologies makes it possible to use the macaque model to study the H. pylori host-pathogen interaction by in vivo analysis of gene expression. We are currently exploiting both DNA microarrays and real time RT-PCR to examine host and bacterial gene expression during experimental infection with genetically characterized H. pylori strains.  Parallel studies with naturally infected humans are also underway as part of an international collaboration in Mexico City.

Development of H. pylori genomic diversity  H. pylori is probably the most genetically diverse bacterium known: in effect, every strain isolated from an individual patient is unique. We are interested in understanding how this diversity develops during the often lifelong association of the bacterium with its host. Our recent studies suggest that H. pylori can modify expression of its outer membrane proteins after experimental infection, including one protein previously identified as an adhesin. Our working hypothesis is that these changes represent a dynamic response in the H. pylori outer membrane that is designed to adhere maximally to gastric epithelium and promote chronic infection.

Vaccine development   Growing antibiotic resistance has motivated development of a vaccine for prevention and therapy of H. pylori infection.  We are using the primate model to test a novel vaccine candidate together with a non-toxic adjuvant that is a derivative of cholera toxin.

Key References

• Solnick, JV, Hansen, LM, Salama, NR, Boonjakuakul, JK, and Syvanen, M.  Modification of Helicobacter pylori outer membrane protein expression during experimental infection of rhesus macaques.  Proc Natl Acad Sci USA, 101: 2106-2111, 2004.
• Boonjakuakul, JK, Syvanen, M, Suryaprasad, A, Bowlus, C, and Solnick, JV.  A transcription profile of Heliocbacter pylori in the human stomach reflects its physiology in vivo.  J Infect Dis, 190: 946-956, 2004.
• Huff JL, Hansen, LM, and Solnick, JV.  A gastric transcription  profile of Heliocbacter pylori infection in the rhesus macaque.   Infect Immun, 72: 5216-5226, 2004.

Web Site: http://www.ucdmc.ucdavis.edu/medmicro/staff/tsolis.html

Our laboratory is interested in how pathogens can evade innate and adaptive immune responses to cause persistent infection. To study this question, we are using species of the bacterial pathogen Brucella. The natural hosts of Brucella spp. are domesticated animals, such as cattle, goats and pigs. Wildlife species, including bison, elk and marine mammals, may also be infected in certain areas. Human infections with Brucella occur most frequently after consumption of unpasteurized dairy products. The bacteria invade through the epithelium of the digestive tract and spread to lymph nodes, spleen, liver and bone marrow, where they are thought to persist within macrophages. If a patient is not treated with the correct combination of antibiotics, the bacteria may persist in tissues for years.

A focus of our research is a set of virulence genes designated virB1-12, that are required for survival of Brucella in macrophages and for chronic infection. We are currently studying the function of the proteins encoded by the virB genes. Comparison to the genomes of other pathogenic bacteria suggests that these genes encode a Type IV secretion system (T4SS). T4SS have been shown to be important for infections with a variety of pathogens, including the gastric pathogen Helicobacter pylori and the respiratory pathogen Bordetella pertussis. While the proteins secreted by these two pathogens are known, no substrates secreted by the predicted Brucella T4SS have been identified yet. We are currently using bioinformatic and genetic approaches to determine whether Brucella also uses its T4SS to secrete proteins important for its intracellular survival.

We are also studying how these genes allow Brucella to persist in an animal model by studying the transcriptional response of the infected host. Interestingly, Brucella elicits a host response that is characteristic of viral infections, and includes induction of Type I interferon activated genes as well as interferon gamma. This response is dependent on expression of the virB genes, suggesting that the VirB proteins play a role in triggering a host response that contributes to persistence of the bacteria rather then resolution of the infection.

Publications:

Sun, Y.-H., Rolán, H.G., den Hartigh, A.B., Sondervan, D., and Tsolis, R.M. 2005. Brucella abortus VirB12 is expressed during infection but is not an essential component of the Type IV secretion system. Infect. Immun. 73: 6048-6054.

den Hartigh, A.B., Y.-H Sun, D. Sondervan, N. Heuvelmans, M. Reinders, T.A. Ficht and R.M. Tsolis.  2004.  Differential requirements for VirB1 and VirB2 during intracellular infection by Brucella abortus.  Infect. Immun. 72:5143-9. 

Sun, Y.-H., den Hartigh, A.B., Santos, R.L., Adams, L.G. and R.M. Tsolis. 2002. virB-mediated survival of B. abortus in mice and macrophages is independent of a functional inducible nitric oxide synthase or macrophage NADPH oxidase. Infect. Immun. 70(9), 4826-32. 

Tsolis, R. M. 2002. Comparative genome analysis of the alpha -proteobacteria: relationships between plant and animal pathogens and host specificity. Proc Natl Acad Sci U S A. 99(20):12503-5.

Hong, P.C., Tsolis, R.M., and T.A. Ficht. 2000. Identification of Brucella abortus genes required for chronic infection of mice. Infect. Immun.68:4102-4107.

Web Site: http://foodscience.ucdavis.edu/the_young_lab/

Yersinia enterocolitica is an invasive foodborne pathogen. This bacterium is closely related to Yersinia pestis, which is the pathogen that causes the plague. Strains of Yersinia enterocolitica can be devided into high-virulent and low-virulent groups. Our long-term goal is to understand the function of virulence factors that distinguish high-virulent from low-virulent strains. Low-virulent Y. enterocolitica generally cause a mild self-limiting gastrointestinal disease in humans and are generally not lethal to experimentally infected mice. By contrast, high-virulent Y. enterocolitica (restricted to serotypes O:4, O:8, O:13a,b, O:20 and O:21) are commonly associated with acute gastrointestinal syndromes in humans and are lethal to mice. High-virulent strains of Y. enterocolitica, but not low-virulent strains, harbor two candidate pathogenicity islands in the chromosome. One is called HPI (High Pathogenicity Island) and encodes an iron uptake system that has been extensively studied by others. The other is YSA and encodes a type III secretion system (TTSS) predicted to target virulence effectors into eukaryotic cells. It remains particularly under-studied and is the focus of our current work. The chromosomally encoded Ysa TTSS has been shown to secrete a set of proteins called Ysps. Its functions are independent of the plasmid-encoded Ysc TTSS, which is common to all pathogenic Yersinia species. Studies with both animal and cellular models of infection indicate the Ysa TTSS is important for pathogenesis.  Ysa TTSS mutants of Y. enterocolitica O:8 are less virulent for orally infected mice by LD50 analysis and exhibit a survival defect in competition assays with virulent Y. enterocolitica O:8. At the cellular level, macrophages are thought to play an important role in limiting Y. enterocolitica infections. My lab has shown that cultured macrophages respond differently to infection by Ysa TTSS mutants compared to wild type bacteria. Under conditions where the Ysa TTSS is functional, wild type Y. enterocolitica O:8 down-regulates the release of the pro-inflammatory cytokine TNF-alpha by macrophages and is cytotoxic to these cells. In contrast, Ysa TTSS mutants lack the ability to down-regulate the release of TNF-alpha and are not cytotoxic.

Key References:

• Matsumoto H. and G.M. Young. Proteomic and functional analysis of the suite of Ysp proteins exported by the Ysa type III secretion system of Yersinia enterocolitica Biovar 1B. Molecular Microbiology 59:689-706, 2006

Web Site: http://www.ucdmc.ucdavis.edu/medmicro/jeisen.html

Our group works on the mechanisms underlying the origin of novelty.  We are particularly interested in how novelty can be acquired from other organisms through lateral gene transfer or symbioses.  For our work on symboises, we study a range of systems, from single mutualistic symbionts living inside a host to communities of microbes in the gut of animals.  We are interested in the evolutionary origin of these symbioses and to study this we use genome sequencing, comparative genomic analyses, and experimental studies of microbial diversity.

Key References

• Wu D, Daugherty SC, van Aken S, Pai G, Watkins K, Khouri H, Tallon L, Zaborsky J, Dunbar H, Tran P, Moran NA, Eisen JA. Metabolic complementarity and genomics of the dual symbiosis of sharpshooters. PLoS Biol. 2006 Jun 6;4(6):e188
• Wu M, Sun L, Vamathevan J, Riegler M, Deboy R, Brownlie J, McGraw E, Mohamoud Y, Lee P, Berry K, Khouri HM, Paulsen IT, Nelson KE, Martin W, Esser C, Ahmadinejad N, Wiegand C, Durkin AS, Nelson WC, Beanan MJ, Brinkac LM, Daugherty SC, Dodson RJ, Gwinn M, Kolonay JF, Madupu R, Craven MB, Utterback T, Weidman J, Nierman WC, Aken SV, Tettelin H, O'Neill S, Eisen JA. 2004. Phylogenomics of the reproductive parasite Wolbachia pipientis wMel: a streamlined genome massively infected with mobile genetic elements.
• Eisen JA, Fraser CM. 2003. Phylogenomics: intersection of evolution and genomics. Science 300: 1706-1707.
• Salzberg SL, White O, Peterson J, Eisen JA. 2001. Microbial genes in the human genome: lateral transfer or gene loss? Science 292:1903-1906.