Thomas E. Kehl-Fie
Assistant Professor of Microbiology
Host-Pathogen Interactions, Microbial Physiology, Protein Structure, Regulation of Gene Expression, Signal Transduction
B.S. (Microbiology and Biochemistry), University of Washington, 2001
Ph.D. (Microbial Pathogenesis and Molecular Microbiology), Washington University in St. Louis, 2002-2008
Postdoctoral Fellow (Pathology, Microbiology, and Immunology), Vanderbilt University, 2009-2013
Impact of host-imposed metal starvation on Staphylococcus aureus and bacterial mechanisms of resistance
Bacterial pathogens, such as Staphylococcus aureus, are a serious and growing threat to human health due to the continued emergence of antibiotic resistance. S. aureus is capable of infecting nearly every tissue in the body and is a leading cause of bone and joint infections, as well as skin and soft tissue infections. Staphylococcal infections are of particular concern due to the spread of antibiotic resistance from the hospital into the community. The continued emergence and spread of antibiotic resistance highlights the need for new therapeutics to treat bacterial infections.
During infection pathogens must acquire all of their nutrients from their host. To combat invading pathogens, the host takes advantage of this fact by restricting the availability of essential nutrients, a process known as “nutritional immunity”. One class of vital nutrients withheld by the host is metals. Transition metals such as manganese and zinc are essential for all forms of life and play critical roles in numerous cellular processes. Highlighting the importance of metals to life is the observation that 30% of all proteins are predicted to use a metal co-factor. The power of nutritional immunity is emphasized by the observation that loss of host-imposed metal limitation results in increased susceptibility to infection. Despite experiencing metal starvation during infection, S. aureus and other pathogens remain capable of causing devastating disease. The laboratory is interested in determining the bacterial processes that are disrupted by manganese and zinc starvation as well as the adaptations that allow successful pathogens to circumvent this host defense. Determining the impact of host-imposed metal starvation and the bacterial adaptations to this defense has the potential to identify new opportunities for therapeutic intervention.
Sites of staphylococcal infection are rendered virtually devoid of the essential nutrients manganese and zinc by the host. A critical component of this nutrient withholding response is the manganese and zinc binding protein calprotectin. During infection calprotectin concentrations can reach 1 mg/ml making it one of the most abundant proteins at sites of infection. Loss of calprotectin results in defects in host-mediated metal sequestration and increased susceptibility to infection with S. aureus and other pathogens. Our work has revealed thatmetal binding by calprotectin inhibits bacterial growth by starving invaders for these essential elements. By harnessing the metal binding properties of calprotectin, we have begun to elucidate the impact of host-imposed manganese and zinc starvation on invading pathogens using a biologically relevant chelator.
Our studies have revealed that calprotectin, a heterodimer comprised of S100A8 and S100A9, has two distinct transition metal binding sites, only one of which is capable of binding manganese. The manganese binding site utilizes a C-terminal extension, possessed by S100A9 but no other S100 protein, to form a previously unreported hexa-histidine binding site. Exploiting this observation, we have created calprotectin variants with altered metal binding properties that allow the individual effects of manganese and zinc starvation to be determined. Utilization of these reagents has revealed that the sequestration of both manganese and zinc contribute to the antimicrobial activity of calprotectin. Additionally, we have found that host-imposed manganese sequestration inhibits staphylococcal defenses against oxidative stress. This in turn renders S. aureus more sensitive to other innate immune effectors such as the oxidative burst of neutrophils. Ongoing studies continue to employ a multi-disciplinary approach in order to elucidate the effects of host-imposed nutrient metal starvation on invading pathogens and the adaptations that allow these invaders to overcome this defense and cause disease.
Kehl-Fie TE, Zhang Y, Moore JL, Farrand AJ, Hood MI, Rathi S, Chazin WJ, Caprioli RM, Skaar EP. MntABC and MntH contribute to systemic Staphylococcus aureus infection by competing with calprotectin for nutrient manganese. Infect Immun 2013; 81:3395-405. Link
Lee K, Boyd KL, Parekh DV, Kehl-Fie TE, Baldwin HS, Brakebusch C, Skaar EP, Boothby M, Zent R. Cdc42 promotes host defenses against fatal infection. Infect Immun 2013; 81:2714-23. Link
Mike LA, Dutter BF, Stauff DL, Moore JL, Vitko NP, Aranmolate O, Kehl-Fie TE, Sullivan S, Reid PR, Dubois JL, Richardson AR, Caprioli RM, Sulikowski GA, Skaar EP. A small molecule that stimulates endogenous heme biosynthesis is toxic to fermenting Staphylococcus aureus. Proc Natl Acad Sci USA 2013; 110:8206-11. Link
*Damo SM, *Kehl-Fie TE, Sugitani N, Holt ME, Rathi S, Murphy WJ, Zhang Y, Betz C, Hench L, Fritz, G Skaar EP, Chazin WJ. Molecular basis for manganese sequestration by calprotectin and roles in the innate immune response to invading bacterial pathogens. Proc Natl Acad Sci USA 2013; 110:3841-6. Link
*These authors contributed equally to this work
Hood MI, Mortensen BL, Moore JL, Zhang Y, Kehl-Fie TE, Sugitani N, Chazin WJ, Caprioli RM, Skaar EP. Identification of an Acinetobacter baumannii zinc acquisition system that facilitates resistance to calprotectin-mediated zinc sequestration. PloS Pathogens 2012; 8:e1003068. Link
Porsch EP, Kehl-Fie TE, St. Geme JW, III. Modulation of Kingella kingae adherence to respiratory epithelial cells by type IV pili, capsule, and a novel trimeric autotransporter. mBio 2012; 3:e00372-12. Link
*Liu JZ, Jellbauer S, Poe AJ, Ton V, Pesciaroli M, Kehl-Fie TE, Restrepo NA, Hosking MP, Edwards RA, Battistoni A, Pasquali P, Lane TE, Chazin WJ, Vogl T, Roth J, Skaar EP, Raffatellu M. Zinc sequestration by the neutrophil protein calprotectin enhances Salmonella growth in the inflamed gut. Cell Host and Microbe 2012; 11:227-39. Link
*Featured in Nature Reviews Microbiology, Nat Rev Microbiology 2012; 10:309.
Damo S, Chazin WJ, Skaar EP, Kehl-Fie TE. Inhibition of bacterial superoxide defense: A new front in the struggle between host and pathogen. Virulence 2012; 3:3. Link
*Kehl-Fie TE, Chitayat S, Hood MI, Damo S, Restrepo N, Garcia C, Munro KA, Chazin WJ, Skaar EP. Nutritional metal sequestration by calprotectin enhances neutrophil killing of Staphylococcus aureus through inhibition of superoxide defense. Cell Host and Microbe 2011; 10:158-64. Link
*Featured in Nature Reviews Microbiology, Nat Rev Microbiology 2011; 9:700.
*Grossoehme N, *Kehl-Fie TE, Ma Z, Adams KW, Cowart DM, Scott RA, Skaar EP, Giedroc DP. Control of copper resistance and inorganic sulfur metabolism by paralogous regulators in Staphylococcus aureus. J Biol Chem 2011; 15:13522-31. Link
*These authors contributed equally to this work.
Kehl-Fie TE, Porsch EA, Yagupsky P, Grass EA, Olbert C, Benjamin D, St. Geme JW, III. Examination of type IV pilus expression and pilus associated phenotypes in K. kingae clinical isolates. Infect Immun, 2010; 78:1692-9. Link
Kehl-Fie TE, Skaar EP. Nutritional immunity beyond iron: A role for manganese and zinc. Curr Opin Chem Biol. 2010; 14:218-24. Link
Kehl-Fie TE, Porsch EA, Miller SA, St Geme JW, III. Expression of Kingella kingae type IV pili is regulated by σ54, PilS, and PilR. J Bacteriol, 2009; 15:4976-86. Link
Kehl-Fie TE, Miller SA, St Geme JW, III. Kingella kingae expresses type IV pili that mediate adherence to respiratory epithelial and synovial cells. J Bacteriol 2008; 21:7157-7163. Link
Kehl-Fie TE, St Geme JW, III. Identification and characterization of an RTX toxin in the emerging pathogen Kingella kingae. J Bacteriol 2007; 189:430-436. Link
Surana NK, Buscher AZ, Hardy GG, Grass S, Kehl-Fie T, St Geme JW, III. Translocator proteins in the two-partner secretion family have multiple domains. J Biol Chem 2006; 281:18051-18058. Link
Interthal H, Chen HJ, Kehl-Fie TE, Zotzmann J, Leppard JB, Champoux JJ. SCAN1 mutant Tdpl accumulates the enzyme-DNA intermediate and causes camptothecin hypersensitivity. EMBO J 2005; 24:2224-2233. Link
Sexton JA, Miller JL, Yoneda A, Kehl-Fie TE, Vogel JP. Legionella pneumophila DotU and IcmF are required for stability of the Dot/Icm complex. Infect Immun 2004; 72:5983-5992. Link