David Nelson, Ph.D.
Summary of the focus of the research of Dr. Nelson
Chlamydial pathogenesis, microbiome pathogen interactions and pathogen discovery
Chlamydiae are obligate intracellular parasites that live inside eukaryotic cells. The human chlamydial disease burden is massive and increasing, and pathogens in the genus Chlamydia are the most common infectious agents of blindness and bacterial sexually transmitted infections. Reasons these infections are so common include that no anti-chlamydial vaccines have been developed and infection does not usually elicit lasting immunity. How these pathogens cause disease and evade immunity is poorly understood because chlamydiae were intractable to genetic manipulation until recently. However, the last few years have seen many firsts in chlamydial genetics including transformation, allelic exchange and mutagenesis; the pathogenesis of these organisms can now be investigated using classical bacterial genetic strategies. My lab is using these new tools, and developing improved tools (Kari et al. 2011, Brothwell et al., 2016, Muramatsu et al., 2016) to understand the molecular basis of how highly similar Chlamydia species infect different hosts and how the same Chlamydia isolates infect different tissues (eye, urogenital tract, GI tract, lungs). More recently, we began studying interactions of C. trachomatis with the urogenital and gastrointestinal microbiomes. This work revealed an unexpectedly diverse male urogenital tract microbiota (Nelson et al. 2010). We are now investigating if the composition of genital and gastrointestinal microbiomes is pertinent to C. trachomatis susceptibility and transmission in humans, and if some of the novel microorganisms we have recently identified are pathogens themselves, using a combination of metagenomic, immunological and epidemiological approaches.
Description and summary of your laboratory's research focus
Specific projects currently active in my laboratory include:
1. Identification of C. muridarum genes that dictate host tropism: We model human chlamydial in disease in mice using the mouse-adapted strain C. muridarum because the C. trachomatis strains that infect humans are quickly cleared in mice (McClarty et al., 2007, Nelson et al., 2005). A long-standing goal of the lab is to identify C. muridarum pathogenic determinants that that this pathogen uses to survive in mice and the cognate host immune defenses mechanisms these determinants counter (Rajaram 2015a, Rajaram 2015b). The longer goal of this work is develop better mouse models of human chlamydial infection and disease which we can use to evaluate new anti-chlamydial vaccines and therapeutics.
2. Identification of determinants of chlamydial pathogenesis. Most chlamydial genes are highly conserved, even in pathogenically distinct species. Core genes mediate shared aspects of chlamydial intracellular biology whereas species and strain specific-virulence factors may mediate niche specialization. We are using mutagenesis, forward genetic screens, and various reverse genetic approaches (Kari 2011, Rajaram 2015a, Muramatsu 2016, Brothwell 2016) to identify virulence factors that mediate chlamydial resistance to pro-apoptotic stimuli, cell-autonomous immunity and which help these pathogens invade different tissues. Separately, we are developing tools for manipulation of essential chlamydia genes that dictate broadly conserved aspects of chlamydial pathogenesis and intracellular biology (Brothwell 2016).
3. Microbiome of the human urogenital tract and pathogen discovery: The male urogenital tract has classically been thought to be sterile. Results from our and other groups challenge this idea (McClarty 2007, Nelson 2010, 2011, 2012) and suggest that uncharacterized microorganisms that colonize the urogenital and GI tracts and may be relevant to diseases of known (such as Chlamydia) and unknown etiologies. We are currently investigating the hypotheses that specific urethral microbiomes promote susceptibility to chlamydial infection and disease and that idiopathic urethritis is caused by novel urogenital microorganisms by comparing the microbiomes hundreds of men who do and do not have urethritis before and after antibiotic treatment. Separately, we are interested in how microbiomes of various body sites influence susceptibility to pathogens (Twigg 2016, van Rensberg 2015, Yanjiao 2013, Wolf 2012).
- Muramatsu MM, Brothwell JB, Stein B, Putman T, Rockey DD, Nelson DE. 2016. Beyond tryptophan synthase: identification of genes that contribute to Chlamydia trachomatis survival during IFN-γ induced persistence and reactivation. Infec Immun. Infect Immun. Jul 18. pii: IAI.00356-16.
- Brothwell JA, Muramatsu MK, Toh E, Rockey DD, Putman TE, Barta ML, Hefty PS, Suchland RJ, Nelson DE. 2016. Interrogating genes that mediate Chlamydia trachomatis survival in cell culture using conditional mutants and recombination. J. Bacteriology. 198(15):2131-9.
- Gehre L, Gorgette O, Perrinet S, Prevost MC, Ducatez M, Giebel AM, Nelson DE, Ball SG, Subtil A. 2016. Sequestration of host metabolism by an intracellular pathogen. Elife. 16;5. pii: e12552.
- Rajaram K, Giebel AM, Toh E, Hu S, Newman JH, Morrison SG, Kari L, Morrison RP, Nelson DE. 2015. Mutational Analysis of the Chlamydia muridarum Plasticity Zone. Infect Immun. 83(7):2870-81.
- Rajaram K, Nelson DE. 2015. Chlamydia muridarum infection of macrophages elicits bactericidal nitric oxide production via reactive oxygen species and cathepsin B. Infect Immun. 83(8):3164-75.
Microbiome in Infectious Disease
- Twigg Iii HL, Knox KS, Zhou J, Crothers KA, Nelson DE, Toh E, Day RB, Lin H, Gao X, Dong Q, Mi D, Katz BP, Sodergren E, Weinstock GM. 2016. Effect of Advanced HIV Infection on the Respiratory Microbiome. Am J Respir Crit Care Med. 194: 226-235.
- van Rensburg JJ, Lin H, Gao X, Toh E, Fortney KR, Ellinger S, Zwickl B, Janowicz DM, Katz BP, Nelson DE, Dong Q, Spinola SM. 2015. The Human Skin Microbiome Associates with the Outcome of and Is Influenced by Bacterial Infection. MBio. 15;6(5):e01315-15.
- Yanjiao Z, Gao H, Mihindukulasuriya K, Wylie K, Vishnivetskaya T, Podar M, Warner B, Tarr P, Nelson DE, Fortenberry DF, Burr S, Sodergren E and GM Weinstock. 2013. Biogeography of the ecosystems of the healthy human body. 2013. Genome Biology.14;14(1):R1.
- Wolfe AJ, Toh E, Shibata N, Rong R, Kenton K, Fitzgerald M, Mueller ER, Schreckenberger P, Dong Q, Nelson DE, Brubaker L. 2012. Evidence of Uncultivated Bacteria in the Adult Female Bladder. J. Clin Microbiology. 50(4):1376-83.
- Nelson DE, Van Der Pol B, Dong Q, Revanna KV, Fan B, Easwaran S, Sodergren E, Weinstock GM, Diao L, Fortenberry JD. 2010. Characteristic male urine microbiomes associate with asymptomatic sexually transmitted infection. PLoS One. 5(11):e14116.21.
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
Assistant Professor 2006-2012 Indiana University, Bloomington