Since the 1990s, fungal infections have emerged as a major cause of morbidity and mortality in immunosuppressed and critically ill patients. The yeast Candida is the most common human fungal pathogen and is responsible for both invasive and mucosal infections. Neutrophils, monocytes, and macrophages are critical for host defense against invasive candidiasis, the most common deep-seated human mycosis in the US. Invasive candidiasis is the 3rd leading cause of nosocomial bloodstream infection in intensive care units (ICUs) with an estimated annual cost of >2 billion dollars. Vaccines are not available and despite antifungal therapy, mortality of patients who develop invasive candidiasis exceeds 40%. Hence, the estimated number of deaths associated with invasive candidiasis exceeds 15,000 per year in the US, comparable to or greater than the number of deaths caused by acquired immunodeficiency syndrome (AIDS) or staphylococcal infections. In stark contrast to the requirement of phagocytes for defense against invasive infection, mucosal candidiasis develops 1) in patients with impaired cellular immunity such as those with AIDS (more than 90% of whom develop oral thrush) or inborn errors of immunity leading to chronic mucocutaneous candidiasis (CMC) and 2) in the majority of healthy women, often associated with antibiotic use (vulvovaginal candidiasis VVC). Mucosal candidiasis, although not life-threatening, is associated with substantial global disease burden, morbidity and cost. As an example, VVC affects 75% of healthy women worldwide at some point during their childbearing years, of whom 50% will have at least one recurrence, and its estimated annual cost exceeds 2 billion dollars in the US alone. In all of these conditions, detailed knowledge of immunopathogenesis at the molecular and cellular levels is lacking. Research in our lab applies an integrated bench-to-bedside approach, which aims to 1) define the cellular and molecular factors that regulate the immune response against mucosal and invasive candidiasis in clinically relevant animal models and to 2) better understand the genetic and immune defects that underlie inherited and acquired susceptibility to mucosal and invasive candidiasis in humans. Our objective is to develop a detailed mechanistic understanding of the molecular and cellular basis of mammalian innate and adaptive immune responses against Candida with an aim to devise novel strategies to enhance the diagnosis, improve risk stratification and prognostication, and augment or supplement the current antifungal drug treatment against candidiasis. To this end, we utilize in vitro cell culture systems, clinically relevant mouse models of mucosal and invasive Candida infections, and clinical samples from targeted cohorts of patients with inherited or acquired susceptibility to mucosal and invasive candidiasis to study host-fungal interactions by using a variety of immunological, biological, and imaging approaches. A critical step in mounting any immune response is the effective recruitment and activation of immune cells at the site of infection. However, the molecular factors that mediate these processes during invasive candidiasis are poorly defined. Chemokines, the largest subgroup of structurally related cytokines, are 8-10kDa proteins that collectively coordinate leukocyte trafficking and activation in health and disease conditions such as infection, autoimmunity and cancer by binding to G-protein coupled chemokine receptors. There are 45 chemokines and 19 chemokine receptors in humans, as well as other chemoattractant receptors such as C5a, leukotriene B4, formyl-peptide and platelet-activating factor receptors. To date, detailed knowledge on the role of the chemoattractant system in host defense against invasive candidiasis is lacking. Hence, a major aim of this project is to investigate the role of specific members of the chemoattractant system in mediating trafficking and effector function of resident and recruited immune cells in anti-Candida host defense in vivo. Characterization of the mechanistic role of candidate chemotactic factors in antifungal host defense in mice is then followed by human immunogenomics studies, in which genetic polymorphisms in the identified chemotactic factor genes are tested for correlating effects on biological function and for associations with invasive candidiasis in patient cohorts from the US and Europe. With regard to mucosal candidiasis, the laboratory investigates the mechanisms of Candida susceptibility in inherited immunodeficiencies that lead to CMC and in healthy subjects following antibiotic use. Hence, the laboratory aims to define the immunological mechanisms that account for universal susceptibility to CMC in patients with the autosomal-recessive autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) syndrome. APECED, caused by mutations in autoimmune regulator (AIRE), is the only primary immunodeficiency in which CMC develops in 100 percent of patients and is the only infectious disease phenotype. Hence, our laboratory, via an investigational review board (IRB)-approved clinical protocol, is recruiting APECED patients to the National Institutes of Health (NIH) to study them immunologically. In parallel, the cellular and molecular basis of enhanced susceptibility to mucosal candidiasis in APECED is investigated in Aire-/- mice. In addition, antibiotic use is the most common controllable risk factor for development of vaginal candidiasis in health women. Hence, our laboratory aims to define the microbiomic and immunological perturbations that lead to vaginal candidiasis in antibiotic-treated healthy women. Better understanding of the antibiotic-induced alterations in the commensal flora and mucosal anti-Candida immune response that result in vaginal candidiasis could form the basis for development of targeted probiotic and/or immune-based strategies for the prevention and therapy of vaginal candidiasis in humans.
| Swidergall, Marc; Solis, Norma V; Lionakis, Michail S et al. (2018) EphA2 is an epithelial cell pattern recognition receptor for fungal ?-glucans. Nat Microbiol 3:53-61 |
| Drummond, Rebecca A; Zahra, Fatema Tuz; Natarajan, Mukil et al. (2018) GM-CSF Therapy in Human CARD9 Deficiency. J Allergy Clin Immunol : |
| Natarajan, Mukil; Hsu, Amy P; Weinreich, Michael A et al. (2018) Aspergillosis, eosinophilic esophagitis, and allergic rhinitis in signal transducer and activator of transcription 3 haploinsufficiency. J Allergy Clin Immunol 142:993-997.e3 |
| Swidergall, Marc; Solis, Norma V; Lionakis, Michail S et al. (2018) Publisher Correction: EphA2 is an epithelial cell pattern recognition receptor for fungal ?-glucans. Nat Microbiol 3:387 |
| Pappas, Peter G; Lionakis, Michail S; Arendrup, Maiken Cavling et al. (2018) Invasive candidiasis. Nat Rev Dis Primers 4:18026 |
| Lionakis, Michail S; Levitz, Stuart M (2018) Host Control of Fungal Infections: Lessons from Basic Studies and Human Cohorts. Annu Rev Immunol 36:157-191 |
| Break, Timothy J; Desai, Jigar V; Healey, Kelley R et al. (2018) VT-1598 inhibits the in vitro growth of mucosal Candida strains and protects against fluconazole-susceptible and -resistant oral candidiasis in IL-17 signalling-deficient mice. J Antimicrob Chemother 73:2089-2094 |
| Chamilos, Georgios; Lionakis, Michail S; Kontoyiannis, Dimitrios P (2018) Call for Action: Invasive Fungal Infections Associated With Ibrutinib and Other Small Molecule Kinase Inhibitors Targeting Immune Signaling Pathways. Clin Infect Dis 66:140-148 |
| Chamilos, Georgios; Lionakis, Michail S; Kontoyiannis, Dimitrios P (2018) Reply to Bazaz and Denning. Clin Infect Dis 67:157-159 |
| Collar, Amanda L; Swamydas, Muthulekha; O'Hayre, Morgan et al. (2018) The homozygous CX3CR1-M280 mutation impairs human monocyte survival. JCI Insight 3: |
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