Thomas E. Kehl-Fie
Assistant Professor of Microbiology
Host-Pathogen Interactions, Microbial Physiology, Molecular Evolution, 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.
Párraga Solórzano PK, Yao J, Rock CO, Kehl-Fie TE. Disruption of glycolysis by nutritional immunity activates a two-component system that coordinates a metabolic and anti-host response by Staphylococcus aureus . mBio. 2019; 10:4 e01321-19. Link
Radin JN, Kelliher JL, Párraga Solórzano PK, Grim KP, Ramezanifard R, Slauch JM, Kehl-Fie TE. Metal-independent variants of phosphoglycerate mutase promote resistance to nutritional immunity and retention of glycolysis during infection. PloS Pathog. 2019; 15:7 :e1007971. Link
Radin JN, Zhu J, Brazel E, McDevitt CA, Kehl-Fie TE. Synergy between nutritional immunity and independent host defenses contributes to the importance of the MntABC manganese transporter during Staphylococcus aureus infection. Infect Immun 2018; 87:1 e00642-18. Link
Kelliher JL, Radin JN, Kehl-Fie TE. PhoPR contributes to Staphylococcus aureus growth during phosphate starvation and pathogenesis in an environment specific manner. Infect Immun 2018; 86:10 e00371-18. Link
Besold AN, Gilston BA, Radin JN, Ramsoomair C, Li CX, Cormack BP, Chazin WJ, Kehl-Fie TE, Culotta VC. The role of calprotectin in withholding zinc and copper from Candida albicans. Infect Immun 2018; 86:2 e00779-17. Link
Grim KP, San Francisco B, Radin JN, Brazel EB, Kelliher JL, Párraga Solórzano PK, Kim PC, McDevitt CA, Kehl-Fie TE. The metallophore staphylopine enables Staphylococcus aureus to compete with the host for zinc and overcome nutritional immunity. mBio 2017; 5:e01281-17. Link
Kelliher JL, Radin JN, Grim KP, Párraga Solórzano PK, Degnan PH, Kehl-Fie TE. Acquisition of the phosphate transporter NptA enhances Staphylococcus aureus pathogenesis by improving phosphate uptake in divergent environments. Infect Immun. 2018; 86:1 e00631-17. Link
Garcia YM, Barwinska-Sendra A, Tarrant E, Skaar EP, *Waldron KJ, *Kehl-Fie TE. A superoxide dismutase capable of functioning with iron or manganese promotes the resistance of Staphylococcus aureus to calprotectin and nutritional immunity. PLoS Pathogens 2017; 13:e1006125. Link
Radin JN, Kelliher JL, Parraga Solorzano PK, Kehl-Fie TE. The two-component system ArlRS and alterations in metabolism enable Staphylococcus aureus to resist calprotectin-induced manganese starvation. PLoS Pathogens 2016; 12:e1006040. 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