Department of Biology

Program

Microbiology

Research Areas

• Genomics and Bioinformatics
• Microbial Cell Biology and Environmental Responses
• Microbial Interactions and Pathogenesis

Education

Ph.D., 2001 University of North Dakota School of Medicine
Postdoctoral Fellow 2001-2002 IUPUI, Indianapolis
Postdoctoral Fellow 2002-2006 Rocky Mountain Labs, NIH/NIAID

Awards

2009 Trustees Teaching Award

 

 

Research Description

Chlamydial pathogenesis and pathogen discovery

Chlamydiae are obligatory intracellular parasites that grow inside eukaryotic cells. These bacteria are ubiquitous pathogens of mammals and cause serious human diseases, including blinding trachoma (the leading cause of preventable blindness), sexually transmitted infections (estimated at 4 million new cases in the US alone in 2005), pneumonia, and may contribute to chronic diseases such as arthritis and atherosclerosis.

The short term goal of our research is to characterize virulence factors that dictate chlamydial host ranges and tissue tropisms in vivo. Long term, we will apply these findings towards rational vaccine design and improved animal models of human chlamydial infection. Recently, we have become involved in multiple NIH Human Microbiome Projects. We are especially interested in how urogenital tract microbiomes impact chlamydial infection, and the discovery of novel pathogens that cause diseases of unknown etiology.

Specific projects include:

1. Characterization of chlamydial pathogenicity factors
The genomes of different disease-causing C. trachomatis strains share more than 99% sequence identity. Genetic variations among these strains primarily map to a short region of their genomes termed the plasticity zone (PZ). Two strain-variable PZ gene families, the chlamydial cytotoxins and phospholipase D homologs, share homology with well-characterized virulence factors of other pathogens. We are attempting to identify the targets of these proteins using genetic, biochemical and in vivo approaches.

2. Development of genetic approaches for analysis of chlamydial-host interactions
Most C. trachomatis genes are highly conserved, suggesting these "core component" genes perform critical functions. In contrast, variability in pathogenicity factors in the PZ among different C. trachomatis strains suggests these genes may be amenable to manipulation. We are developing techniques to generate pools of mutant and recombinant chlamydiae. We will screen these pools and identify mutants that lack specific virulence phenotypes, then identify mutations responsible for these phenotypes using high throughput DNA sequencing.

In parallel, we are developing methods to characterize host factors that modulate chlamydial infection. Recently we developed a trans-dominant peptide genetic approach for dissecting pathogen-host interactions, with Dr. Jim Drummond's group in Biochemistry, which allows us to rapidly screen millions of rationally designed anti-chlamydial peptide aptamers.

3. Microbiome of the human urogenital tract and pathogen discovery
The male urogenital tract has classically been viewed as sterile outside cases of infection with known pathogens. Recent studies from our group challenge this idea and suggest that microbes in the urogenital tract are relevant to diseases of known (such as Chlamydia) and unknown etiologies. We are using state-of-the-art sequencing and bioinformatic approaches to characterize urogenital microbes in adolescents and in men at high risk for STI. The long term goals of these projects are to identify, cultivate and study novel urogenital microorganisms which are relevant to disease.

Selected publications.

Raff EC, Schollaert KL, Nelson DE, Donoghue PC, Thomas CW, Turner FR, Stein BD, Dong X, Bengtson S, Huldtgren T, Stampanoni M, Chongyu Y and RA RAff. Embryo fossilization is a biological process mediated by microbial biofilms. 2008. Proc. Natl. Acad. Sci, USA. 105(49):19360-5.

Ghosh AS, Chowdhury C and DE Nelson. 2008. Physiological functions of D-alanine carboxypeptidases in Escherichia coli. Trends Microbiol. 16(7):309-17.

Kari L, Whitmire WM, Carlson JH, Crane DD, Reveneau N, Nelson DE, Mabey DC, Bailey RL, Holland MJ, McClarty G and HD Caldwell. 2008. Pathogenic diversity among Chlamydia trachomatis ocular strains in non human primates is affected by subtle genomic variations. J. Infect Dis. 197(3):449-56.

Nelson DE, Taylor LD, Shannon, JG, Whitmire WM, Crane DD, McClarty G, Su H, Kari L and HD Caldwell. 2007. Phenotypic rescue of Chlamydia trachomatis growth in IFN-g treated mouse cells by irradiated Chlamydia muridarum. Cellular Microbiology. 9:2289-98.

McClarty G, Caldwell HD and DE Nelson. 2007. Chlamydial interferon gamma immune evasion influences infection tropism. Current Opinion in Microbiology. 10:1-5.

Nelson DE, Crane DD, Taylor LD, Dorward DW, Goheen MM and HD Caldwell. 2006. Inhibition of Chlamydiae by primary alcohols correlates with the strain-specific complement of plasticity zone phospholipase D genes. Infection and Immunity. 74(1):73-80.12.

Nelson DE, Virok DP, Wood H, Roshick C, Johnson RM, Whitmire WM, Crane DD , Steele-Mortimer O, Kari L, McClarty G and HD Caldwell. 2005 Chlamydial Interferon Gamma Immune Evasion is Linked to Host Infection Tropism. Proc. Natl. Acad. Sci, USA. 102(30):10658-63.

Virok DP, Nelson DE, Whitmire WM, Crane DD, Goheen MM and HD Caldwell. 2005. Chlamydial infection induces pathobiotype-specific protein tyrosine phosphorylation in epithelial cells. Infection and Immunity. 73(4):1939-46.

Belland RJ, Nelson DE, Crane DD, Hogan D, Sturdevant D, Beatty WL and HD
Caldwell. 2003. Transcriptome Analysis of Chlamydial Growth During IFN-gamma Mediated Persistence and Reactivation. Proc. Natl. Acad. Sci, USA . 100(26):15971-6.