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Faculty Research

Heather Conti

       

Heather Conti

Assistant Professor
Office:        WO 3235
Phone No:   419-530-7824
Email:         Heather.Conti@UToledo.edu

 

Research

Research Focus

What causes the fuzzy white patches commonly found on the tongues of babies? These patches are a fungal infection, commonly referred to as thrush, caused by the commensal fungus Candida albicans (C. albicans). We investigate the role of the oral mucosa and salivary gland in antifungal immunity to this opportunistic pathogen. Since C. albicans is a normal part of the oral flora it rarely causes disease, but can become pathogenic when the immune system is compromised. In addition to oral candidiasis (oropharyngeal or OPC), C. albicans causes different diseases including dermal, vaginal and disseminated candidiasis. OPC is common in infants, the elderly, denture wearers, patients on antibiotic treatments and those with various salivary defects. OPC is a serious complication for immunocompromised populations, including Sjögren’s Syndrome patients, cancer patients undergoing chemotherapy or head-neck irradiation, as well as individuals with HIV/AIDS. The other forms of candidiasis (vaginal, dermal and disseminated) are rarely diagnosed in HIV/AIDS+ or other immunodeficient patients. Thus, CD4+ T cells appear to play a dominant role in protecting against oral Candida infection, but not other forms of the disease. Individuals with rare genetic defects such as Hyper-IgE (HIES, Job’s) Syndrome have elucidated the crucial role of CD4+ Th17-associated cytokines IL-23 and IL-17 in protection to OPC. IL-17 upregulates neutrophil chemokines, antimicrobial proteins (AMPs) and pro-inflammatory cytokines such as IL-6. IL-17 binds to the IL-17R, composed of subunits IL-17RA and IL-17RC, which are highly expressed on epithelial and stromal cells, including oral tissue. We showed that both IL-17RA and IL-17RC are essential for immunity to OPC. While it is clear that the IL-17 signaling axis is vital for defense against OPC, the underlying mechanisms that provide immunity at the mucosal surface are not well defined

Immune Cells in the Oral Mucosa

We were the first group to link IL-17 and oral mucosal immunity, both in the context of OPC and periodontal disease. In addition to CD4+ Th17 cells, protection to OPC requires a potent innate response, mediated in part directly by the oral mucosa. The oral mucosal surface is unique as it facilitates the first interactions at the beginning of the GI tract between foreign pathogens, commensal microbiota and the host immune system. To date, the implications of these interactions in disease and immune homeostasis have been understudied in the oral cavity. The innate cells involved in protection to OPC are not well understood. We have recently defined ‘natural’ (n) Th17 cells as an important innate source of IL-17 during acute OPC. We will further investigate how these and other innate immune cells are regulated in the oral mucosa during Candida infection using techniques such as flow cytometry. Other projects include investigating the role of different AMPs in protection against candidiasis.

Salivary Components Involved in Antifungal Immunity

Saliva is often an underappreciated part of the immune response in the oral cavity. Saliva is an important immune component though, as patients with salivary defects are highly susceptible to OPC. We demonstrated that mouse and human salivary components, defensins and histatins, are essential in limiting Candida carriage and infection. Protection to OPC involves components derived from oral epithelium and salivary gland, but the underlying mechanisms of IL-17 anti-Candida host defense are largely undefined. We have projects aimed at investigating the specific role of IL-17 in the oral epithelium and the salivary gland using conditional knockout mouse systems.

Damage to the Oral Mucosa

The most common complications of non-surgical treatments for oral cancers are mucositis and xerostomia. All patients receiving targeted head-neck radiotherapy develop mucosal damage, known as oral mucositis (OM). The importance of an intact mucosal layer in defense against OPC is demonstrated by the high susceptibility of patients with OM to Candida infection. We investigate these processes using a mouse model of disease in order to examine the consequences of barrier destruction, the role of IL-17 in maintaining mucosal integrity and how OPC progresses during the stages of OM. We hope to make discoveries that lead to the development of improved therapeutics that promote oral health.

Current Students:

Undergraduates
Helena Harb
Bailey Slone
Cole White
Sam Meyers
Daniel O'Shea
Danielle Saevig
Grace Tieko

Master's Students
Joe Hunter
Bemnet Mengesha

Ph.D. student
Jackie Kratch

Publications

Peer-reviewed publications

Yu JJ, Ruddy MJ, Conti HR, Boonanantanasarn K, Gaffen SL. The IL-17 receptor plays a gender dependent role in host protection against P. gingivalis-induced periodontal bone loss. Infect Immun 2008; 76:4206-4213. 

Conti HR, Shen F, Nayyar N, Stocum E, Sun JN, Lindemann MJ, Ho AW, Hai JH, Yu JJ, Jung JW, Filler SG, Masso-Welch P, Edgerton M, Gaffen SL. Th17 cells and IL-17 receptor signaling are essential for mucosal host defense against oral candidiasis. J Exp Med 2009 Feb 16; 206(2):299-311.

Ho AW, Shen F, Conti HR, Patel N, Childs EE, Peterson AC, Hernandez-Santos N, Kolls JK, Kane LP, Ouyang W, Gaffen SL. IL-17RC is required for immune signaling via an extended SEF/IL-17R signaling domain in the cytoplasmic tail. The Journal of Immunology 2010 Jul 15;(185)2:1063-70.

Pandiyan P, Conti HR, Zheng L, Peterson AC, Mathern DR, Hernandez-Santos N, Edgerton M, Gaffen SL, Lenardo MJ. CD4+CD25+Foxp3+ regulatory T cells promote Th17 cells in vitro and enhance host resistance in mouse Candida albicans Th17 infection model.  Immunity 2011 Mar 25;34(3):422-34.

Conti HR, Baker O, Freeman AF, Jang WS, Holland SM, Li RA, Edgerton M, Gaffen SL. New mechanism of oral immunity to mucosal candidiasis in hyper-IgE syndrome. Mucosal Immunology 2011 Jul; 4(4):448-55.

Kumar R, Chadha S, Saraswat D, Bajwa JS, Li RA, Conti HR, Edgerton M. Histatin 5 uptake by Candida albicans utilizes the polyamine transporters Dur3 and Dur31 proteins. Journal of Biological Chemistry 2011 Dec 23;286(51):43748-58.

Puri S, Kumar R, Chadha S, Tati S, Conti HR, Hube B, Cullen PJ, Edgerton M. Secreted aspartic protease cleavage of Candida albicans Msb2 activates Cek1 MAPK signaling affecting biofilm formation and oropharyngeal candidiasis. PLoS One 2012;7(11).

Bishu S, Hernandez-Santos N, Simpson-Abelson MR, Huppler AR, Conti HR, Ghilardi N, Mamo AJ, Gaffen SL. The adaptor CARD9 is required for adaptive but not innate immunity to oral mucosal Candida albicans infections. Infect Immun, 2014 Mar;82(3):1173-80.

Huppler AR, Conti HR, Hernandez-Santos N, Biswas P, Darville T, Gaffen SL. Role of neutrophils in IL-17-dependent immunity to mucosal candidiasis. J Immunol, 2014 Feb 15;192(4):1745-52.

Conti HR, Peterson AC, Brane L, Huppler AR, Hernandez-Santos N, Whibley N, Garg AV, Simpson-Abelson M, Gibson G, Mamo AJ, Osborne L, Bishu S, Ghilardi N, Siebenlist U, Watkins SL, Artis D, McGeachy MJ, Gaffen SL. Oral-resident ‘natural’ Th17 cells  and γδT cells control opportunistic Candida albicans infections. J Exp Med, 2014 Sep 22:211(10):2075-84.

Conti HR, Whibley N, Coleman BM, Garg AV, Jaycox J, Gaffen SL, Signaling through the IL-17C/IL-17RE axis is dispensable for immunity to systemic, oral and cutaneous candidiasis. PLoS One 2015 Apr 7;10(4).

Garg AV, Chen K, Cruz JA, Whibley N, Conti HR, Hernandez Mir G, Amatya N, Sirakova T, Childs EC, Biswas PS, Kolls JK, McGeachy MJ, Kolattukudy PE, Gaffen SL. MCPIP1/Regnase-1 is a negative feedback inhibitor of IL-17-mediated signaling and inflammation. Immunity, 2015 Sep 15;43(3):475-87.

Huppler AR, Verma AH, Conti HR, Gaffen SL, Neutrophils do not express IL-17A in the context of acute oropharyngeal candidiasis. Infection and Immunity 2015 Jul 24;4(3)559-72.

Simpson-Abelson MR, Childs EE, Ferreira MC, Bishu S, Conti HR, Gaffen SL, C/EBPβ promotes immunity to oral candidiasis through regulation of β-defensins. PLoS One 2015 Aug 28;10(8)

Book Chapters and Reviews:

Conti HR and Gaffen SL. Host responses to Candida albicans: Th17 cells and mucosal candidiasis. Microbes and Infection 2010 Jul; (12)7:518-27. 

Conti HR*, Huppler AR, Whibley N, Gaffen SL. Animal models for candidiasis. Curr Protoc Immunol, 2014 Apr 2;105:19.6.1-19.6.17 *Corresponding author

Conti HR and Gaffen SL. IL-17-mediated immunity to the opportunistic fungal pathogen Candida albicans. Brief Review for The Journal of Immunology. 2015 Aug 1;195(3):780-8.

Last Updated: 6/16/16