Candidate. My career goal is to improve the health of people with infectious diseases through investigation of host-microbial interactions. My short-term objective is to refine and add to my skills as an independent investigator and begin my tenure-track appointment as a junior faculty member at the University of Wisconsin-Madison on an accelerated trajectory with the protected time and resources to fully develop my research program. The specific education linked to this proposal is in the area of immunology, which will enable me to complement my prior training in microbial pathogenesis and develop an innovative approach to study of the innate immune response to Candida biofilm infection. I will use this new knowledge, skill, and training to dissec numerous critical knowledge gaps impeding optimal therapy of infections. Research Project. Patients with indwelling medical devices, such as venous catheters, are at risk for invasive disease caused by Candida, one of the most common human fungal pathogens. In these patients, Candida sticks to the device surface and proliferates as a biofilm of resilient cells encased in an organism- derived extracellular matrix. As the host immune system and conventional antifungals are not capable of eradicating Candida biofilms, these infections can be devastating. The question of how transition to the biofilm lifestyle protects Candida from immune clearance remains a mystery, and the answer will have implications for patient care. When examining patient and animal models of Candida device-associated biofilm infection, I was struck by the lack of host immune cells, including neutrophils. My preliminary observations suggest these immune cells are both poorly recruited and lack effective killing activity against Candida biofilms. The extracellular biofilm matrix appears to be responsible for this phenomenon. The proposed experiments are designed to define the specific mechanism underpinning impaired neutrophil responses to Candida biofilm. Career Development Plan. My proposed mentoring and training activities will focus on (1) attaining expertise in immunology through mentoring, hands-on laboratory work, and coursework; (2) developing leadership skills to pursue investigations in an independent laboratory; (3) presenting and publishing data; and (4) continuing and expanding professional collaborations. My research will be closely coordinated with my training activities and will build toward a successful R01 application in the fourth year of this award. Research Environment. I will be well-supported within the Departments of Medicine and Medical Microbiology & Immunology at the University of Wisconsin. In addition, I will benefit from the outstanding collaborative biological sciences research infrastructure at our institution and state-of-the-art microscopy, biotechnology, and animal facilities.
Capable of proliferating as an adherent biofilm, Candida frequently causes devastating device-associated infections. These biofilms flourish in the face of a healthy host immune system and resist conventional antifungals. The purpose of this proposal is to define the molecular mechanism(s) underlying immune evasion of Candida biofilms.
|Hoyer, Amanda R; Johnson, Chad J; Hoyer, Matthew R et al. (2018) Echinocandin Treatment of Candida albicans Biofilms Enhances Neutrophil Extracellular Trap Formation. Antimicrob Agents Chemother 62:|
|Nett, Jeniel E (2018) Special Issue: Candida and Candidiasis. J Fungi (Basel) 4:|
|Urban, Constantin F; Nett, Jeniel E (2018) Neutrophil extracellular traps in fungal infection. Semin Cell Dev Biol :|
|Fites, J Scott; Gui, Michael; Kernien, John F et al. (2018) An unappreciated role for neutrophil-DC hybrids in immunity to invasive fungal infections. PLoS Pathog 14:e1007073|
|Johnson, Chad J; Davis, J Muse; Huttenlocher, Anna et al. (2018) Emerging Fungal Pathogen Candida auris Evades Neutrophil Attack. MBio 9:|
|Rossi, Diego C P; Gleason, Julie E; Sanchez, Hiram et al. (2017) Candida albicans FRE8 encodes a member of the NADPH oxidase family that produces a burst of ROS during fungal morphogenesis. PLoS Pathog 13:e1006763|
|Lorenzini, Jenna; Scott Fites, J; Nett, Jeniel et al. (2017) Blastomyces dermatitidis serine protease dipeptidyl peptidase IVA (DppIVA) cleaves ELR+ CXC chemokines altering their effects on neutrophils. Cell Microbiol 19:|
|Johnson, Chad J; Kernien, John F; Hoyer, Amanda R et al. (2017) Mechanisms involved in the triggering of neutrophil extracellular traps (NETs) by Candida glabrata during planktonic and biofilm growth. Sci Rep 7:13065|
|Bawadekar, Mandar; Shim, Daeun; Johnson, Chad J et al. (2017) Peptidylarginine deiminase 2 is required for tumor necrosis factor alpha-induced citrullination and arthritis, but not neutrophil extracellular trap formation. J Autoimmun 80:39-47|
|Kernien, John F; Snarr, Brendan D; Sheppard, Donald C et al. (2017) The Interface between Fungal Biofilms and Innate Immunity. Front Immunol 8:1968|
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