3 results
403 Epithelial hypoxia maintains colonization resistance against Candida albicans
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- Derek J. Bays, Hannah P. Savage, Connor Tiffany, Mariela A. F. Gonzalez, Eli. J. Bejarano, Henry Nguyen, Hugo L. P. Masson, Thaynara P. Carvalho, Renato L. Santos, Andrew Tritt, Suzanne M. Noble, George R. Thompson, Andreas J. Bäumler
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- Journal:
- Journal of Clinical and Translational Science / Volume 8 / Issue s1 / April 2024
- Published online by Cambridge University Press:
- 03 April 2024, pp. 119-120
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OBJECTIVES/GOALS: Antibiotic treatment sets the stage for intestinal domination by Candida albicanswhich is necessary for development of invasive disease, but the resources driving this bloom remain poorly defined. We sought to determine these factors in order to design novel prophylaxis strategies for reducing gastrointestinal (GI) colonization. METHODS/STUDY POPULATION: We initially developed a generalizable framework, termed metabolic footprinting to determine the metabolites C. albicanspreferentially uses in the mouse GI tract. After identifying the metabolites C. albicansutilizes, we usedin vitro growth assays in the presence and absence of oxygen to validate out metabolomics findings. We next determined if a probiotic E. coli that utilizes oxygen would reduce C. albicanscolonization compared to a mutant E. coli that could not respire oxygen. Finding that oxygen was a necessary resource, we utilized germ-free mice to determine if Clostridiaspp. known to reduce GI oxygen would prevent C. albicanscolonization. Lastly, we sought to see if 5-aminosalicylic acid (5-ASA) could prevent C. albicanscolonization. RESULTS/ANTICIPATED RESULTS: We found that C. albicans preferentially utilizes simple carbohydrates including fructo-oligosaccharides (e.g., 1-kestose), disaccharides (e.g., β-gentiobiose), and alcoholic sugars (e.g., sorbitol) and is able to grow in vitro on minimal media supplemented with either of these nutrients. However, in the hypoxic environment that is found in the “healthy” colon, C. albicans cannot utilize these nutrients. We next found that pre-colonization in a mouse model with a probiotic E. coli significantly reduced C. albicanscolonization, but the mutant E. coli had no effect on colonization. We next showed that Clostridia supplementation restored GI hypoxia and reduced C. albicanscolonization. Remarkably, we found that 5-ASA significantly reduced GI colonization of C. albicans. DISCUSSION/SIGNIFICANCE: We have shown that C. albicans requires oxygen to colonize the GI tract. Importantly, we found that 5-ASA can prevent an antibiotic mediated bloom of C. albicans by restoring GI hypoxia, which warrants additional studies to determine if 5-ASA can be used as an adjunctive prophylactic treatment in high risk patients.
2420: Loss of eptB decreases systemic inflammation during Salmonella infection and allows for evasion of the host immune response
- Lillian F. Zhang, Fabian Rivera-Chavez, Hirotaka Hiyoshi, Andreas J. Baumler
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- Journal:
- Journal of Clinical and Translational Science / Volume 1 / Issue S1 / September 2017
- Published online by Cambridge University Press:
- 10 May 2018, p. 9
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OBJECTIVES/SPECIFIC AIMS: Our long-term goal is to elucidate the molecular mechanisms and virulence factors that control the differential presentation of infection with Salmonella typhimurium and Salmonella typhi. The objectives of this study are to study the mechanisms that enable S. typhi to trigger a decreased inflammatory response in comparison with S. typhimurium and evade detection by the immune system, leading to the development of asymptomatic chronic carriage of S. typhi. METHODS/STUDY POPULATION: A loss of function eptB mutant S. typhimurium strain was generated. Lipopolysaccharide (LPS) was isolated from wild-type and eptB mutant S. typhimurium and wild-type S. typhi. Binding of LPS to recombinant intelectin was tested by dot blot and enzyme-linked immunosorbant assay (ELISA). C57BL/6 mice were infected with wild-type or eptB mutant S. typhimurium by oral gavage and inflammatory cytokines in the spleen, liver, and Peyer’s patches were measured by qPCR. RESULTS/ANTICIPATED RESULTS: LPS isolated from wild-type S. typhimurium is not bound by intelectin, a protein that has been proposed to function in innate immunity and that is known to be able to bind certain moieties within LPS. Conversely, LPS isolated from eptB mutant S. typhimurium and wild-type S. typhi, which lacks a functional eptB, is bound by intelectin. Mice infected with an eptB mutant S. typhimurium exhibit decreased expression of inflammatory cytokines in the spleen compared to mice infected with the wild type S. typhimurium, suggesting that loss of eptB function allows a nontyphoidal Salmonella serovar to mimic the stealth phenotype of typhoidal serovars. Together, these results suggest that loss of eptB function allows intelectin to bind to and detoxify Salmonella LPS, leading to decreased systemic inflammation during infection. DISCUSSION/SIGNIFICANCE OF IMPACT: These results have broad implications for how pathogens such as S. typhimurium induce systemic shock during infection and may also help to explain a mechanism for how S. typhi is able to evade immune detection and enhance dissemination to systemic sites, leading to development of the asymptomatic chronic carrier state. Further investigation of this novel virulence mechanism will mark a decisive step forward in understanding the mechanisms underlying the differential pathogenesis of S. typhimurium-induced gastroenteritis and S. typhi-induced typhoid fever. Additionally, these results contribute to our understanding of the interactions between host and pathogen in affecting disease presentation, which will have wide appeal among researchers interested in microbial pathogenesis and the contribution of host-pathogen interactions to health and disease.
7 - In vivo identification, expression and function of Salmonella virulence genes
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- By Helene Andrews-Polymenis, Department of Medical Microbiology & Immunology, 407 Reynolds Medical Building, Texas A&M University SHSC, College Station, TX 77843-1114, USA, Caleb W. Dorsey, Dept. Med. Microbiol. & Immunol., 407 Reynolds Medical Building, Texas A&M University SHSC, College Station, TX 77843-1114, USA, Manuela Raffatellu, Dept. Med. Microbiol. & Immonol., School of Medicine, University of California at Davis, One Shields Ave., Davis, CA 95616-8645, Andreas J. Bäumler, Department of Medical Microbiology & Immunology, School of Medicine, University of California at Davis, One Shields Ave., Davis, CA 95616-8645, USA
- Edited by Pietro Mastroeni, University of Cambridge
- Duncan Maskell, University of Cambridge
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- Book:
- Salmonella Infections
- Published online:
- 04 December 2009
- Print publication:
- 09 February 2006, pp 173-206
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Summary
INTRODUCTION
Any determinant that enables a Salmonella serotype to enter a host, to find a unique niche to multiply, to avoid or subvert the host defenses, to cause disease and to be transmitted to the next susceptible host may be considered a virulence determinant. Essential genes required for growth in standard laboratory medium are usually not included under this broad definition of virulence genes. The total number of virulence genes present in the Salmonella genome can be estimated by screening a bank of mutants generated by random transposon mutagenesis using an animal model of infection. The genome of Salmonella enterica serovar Typhimurium strain LT2 contains 4552 intact open reading frames (McClelland et al., 2001). Of these, approximately 490 genes are essential during growth in rich medium (Knuth et al., 2004). Thus, only the function of about 4062 genes is assessed when S. enterica serovar Typhimurium transposon mutants are generated and analyzed. Analysis of 197 randomly generated transposon mutants of S. enterica serovar Typhimurium for virulence in mice upon intra gastric infection identified 8 mutants that were more than 1000 fold attenuated (Bowe et al., 1998). Extrapolating to the actual number of intact genes present in the genome (4062 genes) this study suggests that mutations in approximately 165 S. enterica serovar Typhimurium genes result in attenuation of more than 1,000-fold in mice.