Faculty

Samuel I. Miller, MD

• Professor of Medicine, Microbiology, and Genome Sciences
• University of Washington
• http://miller-lab.net/MillerLab/

The Miller laboratory is focused on defining the molecular basis of bacterial pathogenesis and interactions with eukaryotic cells. The laboratory has a particular interest in bacterial interactions with innate immunity. This work involves the use of animal and tissue culture (mice, macrophages, epithelial cells) models of infection. Research interests include Salmonellae-induced typhoid fever and gastroenteritis, bacterial dysentery caused by Shigella spp and E. coli O157, the chronic Pseudomonas airway disease of cystic fibrosis patients, and Gram-negative organisms important to biodefense, including Francisella tularensis, Burkholderia spp. and the plague bacillis Yersinia pestis.

The lab is organized into research groups focusing on the study of:

1. The effect of bacterial type III effector proteins on mammalian cells;
2. The assembly and regulation of the type III secretion system of Salmonella typhimurium, which translocates proteins into mammalian cells on contact;
3. The environmental remodeling of the gram-negative bacterial surface that occurs when bacteria infect host tissues;
4. The characterization of the phenotypic adaptation of Pseudomonas aeruginosa to the unique environmental niche of the CF airway;
5. Analysis of bacterial genes and proteins using bioinformatics;
6. Development of new antimicrobial compounds inhibiting pathogenic factors;
7. Understanding sensing and signaling by bacterial receptors, particularly the PhoQ protein of Salmonella; and
8. the development of methods to study the diversity of human susceptibility to bacterial infection.

Current projects organized by group include the study of:

1. Salmonellae translocated effectors (which are delivered across the phagosome membrane and recruited to the actin cytoskeleton, nucleus, and phagosome) and function as glycerol cholesterol transferases, guanine nucleotide exchange factors, and ubiquitin ligases;
2. Assembly and structure-function of the type III secretion system needle complex of S. typhimurium;
3. Analysis of bacterial membrane remodeling that occurs in environmental conditions typical of infection;
4. Analysis of Pseudomonas aeruginosa adaptation during CF with special attention to loss of regulatory genes that confer a metabolic advantage for growth;
5. Bioinformatic analysis, DNA sequencing and comparison of Gram-negative bacterial genomes of outbreak strains responsible for diarrheal disease;
6. Screening and characterization of specific molecules that target the secretin component of bacterial type II and type III secretion systems;
7. Using NMR and crystallography to define molecular mechanisms by which PhoQ responds to antimicrobial peptides and low pH; and
8. Development of in vitro assays as surrogates to measure human susceptibility to infection.

Selected Publications

Kulasekara BR, Jacobs M, Zhou Y, Wu Z, Sims E, Saenphimmachak C, Rohmer L, Ritchie JM, Radey M, McKevitt M, Freeman TL, Hayden H, Haugen E, Gillett W, Fong C, Chang J, Beskhlebnaya V, Waldor MK, Samadpour M, Whittam TS, Kaul R, Brittnacher M, Miller SI. Analysis of the genome of the Escherichia coli O157:H7 2006 spinach-associated outbreak isolate indicates candidate genes that may enhance virulence. Infect Immun. 2009 Sep;77(9):3713-21.
[ PubMed Abstract ]

Spreter T, Yip CK, Sanowar S, André I, Kimbrough TG, Vuckovic M, Pfuetzner RA, Deng W, Yu AC, Finlay BB, Baker D, Miller SI, Strynadka NC. A conserved structural motif mediates formation of the periplasmic rings in the type III secretion system. Nat Struct Mol Biol. 2009 May;16(5):468-76.
[ PubMed Abstract ]

Ohlson MB, Huang Z, Alto NM, Blanc MP, Dixon JE, Chai J, Miller SI. Structure and function of Salmonella SifA indicate that its interactions with SKIP, SseJ, and RhoA family GTPases induce endosomal tubulation. Cell Host Microbe. 2008 Nov 13;4(5):434-46.
[ PubMed Abstract ]

Ko DC, Shukla KP, Fong C, Wasnick M, Brittnacher MJ, Wurfel MM, Holden TD, O'Keefe GE, Van Yserloo B, Akey JM, Miller SI. A genome-wide in vitro bacterial-infection screen reveals human variation in the host response associated with inflammatory disease. Am J Hum Genet. 2009 Aug;85(2):214-27.
[ PubMed Abstract ]

Hoffman LR, Kulasekara HD, Emerson J, Houston LS, Burns JL, Ramsey BW, Miller SI. Pseudomonas aeruginosa lasR mutants are associated with cystic fibrosis lung disease progression. J Cyst Fibros. 2009 Jan;8(1):66-70. Epub 2008 Oct 29.
[ PubMed Abstract ]

Felise HB, Nguyen HV, Pfuetzner RA, Barry KC, Jackson SR, Blanc MP, Bronstein PA, Kline T, Miller SI. An inhibitor of gram-negative bacterial virulence protein secretion. Cell Host Microbe. 2008 Oct 16;4(4):325-36.
[ PubMed Abstract ]

Prost LR, Daley ME, Bader MW, Klevit RE, Miller SI. The PhoQ histidine kinases of Salmonella and Pseudomonas spp. are structurally and functionally different: evidence that pH and antimicrobial peptide sensing contribute to mammalian pathogenesis. Mol Microbiol. 2008 Jul;69(2):503-19.
[ PubMed Abstract ]

Ernst RK, Moskowitz SM, Emerson JC, Kraig GM, Adams KN, Harvey MD, Ramsey B, Speert DP, Burns JL, Miller SI. Unique lipid a modifications in Pseudomonas aeruginosa isolated from the airways of patients with cystic fibrosis. J Infect Dis. 2007 Oct 1;196(7):1088-92. Epub 2007 Aug 22.
[ PubMed Abstract ]

Haraga A, West TE, Brittnacher MJ, Skerrett SJ, Miller SI. Burkholderia thailandensis as a model system for the study of the virulence-associated type III secretion system of Burkholderia pseudomallei. Infect Immun. 2008 Nov;76(11):5402-11. Epub 2008 Sep 8.
[ PubMed Abstract ]

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