Oropharyngeal candidiasis (OPC) is an opportunistic fungal infection associated with immune deficiency, particularly in the T cell compartment. C. albicans is a commensal fungus that is the dominant causative species of OPC, and its key virulence trait is the ability to form invasive hyphae. This morphologic transition in the fungus triggers `danger' responses in oral epithelial cells (OECs), which are the first cell types to encounter this microbe. In 2009, we showed that an effective immune response to mucosal candidiasis in mice requires signaling by the cytokine IL-17 (IL-17A). The importance of IL-17 was subsequently confirmed in humans with IL-17R-deficiencies, who experience chronic mucosal candidiasis. Using mice as a model organism, we showed that in nave settings (i.e., innate responses), IL-17 is made by two innate lymphocyte cell subsets: ??-T and `natural' Th17 cells (nTh17). In recall (i.e., adaptive) responses, IL-17 is additionally made by conventional CD4+Th17 cells, which augment the innate response to accelerate fungal clearance. Collectively, IL-17+ cells comprise ?Type 17? immunity. Regardless of source, IL-17 signals through a ubiquitous receptor (a heterodimer of IL-17RA and IL-17RC). In the first funding period, we showed that OECs are the key IL-17-responsive cell type, which we achieved by creating a new Keratin- 13CRE transgenic mouse that deletes IL-17RA conditionally in OECs. The initiating event in OPC is exposure of OECs to C. albicans. However, it remains unclear how early epithelial recognition events lead to activation of Type 17 responses, and why these responses occur only in response to hyphae. In a landmark discovery recently reported in Nature, the co-I (Dr. Naglik) showed that the danger response in OECs is activated by a newly-discovered virulence factor, Candidalysin, the first pore- forming peptide toxin identified in any human fungal pathogen. Candidalysin is secreted specifically by hyphae and permeabilizes OEC membranes. Candidalysin triggers a MAPK-dependent pathway through c-fos, leading to upregulation of cytokines such as IL-1?, IL-6 and CCL20. Our new data reveal that (i) Candidalysin activates OEC responses via the epidermal growth factor receptor (EGFR), (ii) Candidalysin is required to induce IL-17 expression in innate lymphocytes in vivo, and (iii) Candidalysin and IL-17 signal cooperatively to enhance OEC activation. Given these exciting observations, our overarching goal is to understand the mechanisms by which host-and pathogen- derived factors coordinate effective Type 17 immunity against C. albicans. Our central hypothesis is that Candidalysin induces inflammatory mediators in OECs through an EGFR/c-fos danger response pathway, thereby triggering essential innate and adaptive Type 17 responses. In turn, IL-17 signals cooperatively with Candidalysin on OECs, which serves to amplify host defense in a feed-forward activation loop.

Public Health Relevance

Oral candidiasis, also known as oral thrush, is an AIDS-defining fungal infection of the oral mucosa. This disease also afflicts individuals on chemotherapy, transplant patients taking immunosuppressive drugs, asthma patients using inhaled corticosteroid drugs or others with compromised immune function such as infants and the elderly. The objective of this project is to understand interactions between Candida albicans and the host immune system. The long- term goal of this research is to develop better therapies or vaccines for mucosal disease of the oral cavity, and to understand the consequences of therapies that suppress specific immune events.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DE022550-07
Application #
9525937
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Chander, Preethi
Project Start
2012-04-01
Project End
2022-07-31
Budget Start
2018-08-01
Budget End
2019-07-31
Support Year
7
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Amatya, Nilesh; Childs, Erin E; Cruz, J Agustin et al. (2018) IL-17 integrates multiple self-reinforcing, feed-forward mechanisms through the RNA binding protein Arid5a. Sci Signal 11:
Verma, Akash H; Zafar, Hanna; Ponde, Nicole O et al. (2018) IL-36 and IL-1/IL-17 Drive Immunity to Oral Candidiasis via Parallel Mechanisms. J Immunol 201:627-634
Kasper, Lydia; König, Annika; Koenig, Paul-Albert et al. (2018) The fungal peptide toxin Candidalysin activates the NLRP3 inflammasome and causes cytolysis in mononuclear phagocytes. Nat Commun 9:4260
Richardson, Jonathan P; Naglik, Julian R (2018) Special Issue: Mucosal Fungal Infections. J Fungi (Basel) 4:
Bichele, Rudolf; Kärner, Jaanika; Truusalu, Kai et al. (2018) IL-22 neutralizing autoantibodies impair fungal clearance in murine oropharyngeal candidiasis model. Eur J Immunol 48:464-470
Richardson, Jonathan P; Mogavero, Selene; Moyes, David L et al. (2018) Processing ofCandida albicansEce1p Is Critical for Candidalysin Maturation and Fungal Virulence. MBio 9:
Allert, Stefanie; Förster, Toni M; Svensson, Carl-Magnus et al. (2018) Candida albicans-Induced Epithelial Damage Mediates Translocation through Intestinal Barriers. MBio 9:
Richardson, Jonathan P; Ho, Jemima; Naglik, Julian R (2018) Candida-Epithelial Interactions. J Fungi (Basel) 4:
Monin, Leticia; Gaffen, Sarah L (2018) Interleukin 17 Family Cytokines: Signaling Mechanisms, Biological Activities, and Therapeutic Implications. Cold Spring Harb Perspect Biol 10:
Monin, Leticia; Gudjonsson, Johann E; Childs, Erin E et al. (2017) MCPIP1/Regnase-1 Restricts IL-17A- and IL-17C-Dependent Skin Inflammation. J Immunol 198:767-775

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