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 and monocytes/macrophages are critical for host defense against invasive candidiasis, the most common deep-seated human mycosis and the fourth-leading cause of nosocomial bloodstream infection in the United States. Despite administration of antifungal therapy, mortality of patients who develop invasive Candida infection exceeds 40 percent. 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 percent 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 (vaginal candidiasis). Invasive aspergillosis, most often caused by the ubiquitous inhaled mold Aspergillus fumigatus, is a leading cause of infection-related mortality in cancer or hematopoietic stem cell transplant (HSCT) patients (mortality, >25-50%) and in patients with chronic granulomatous disease (CGD), who have a defective phagocyte oxidative burst. In all of these conditions, detailed knowledge of immunopathogenesis at the molecular and cellular levels is lacking and could inspire new treatment and prevention approaches. 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 candidiasis, invasive candidiasis and aspergillosis in clinically relevant animal models and to 2) better understand the genetic and immune defects that underlie inherited and acquired susceptibility to mucosal candidiasis, invasive candidiasis and aspergillosis 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 and Aspergillus 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 pulmonary aspergillosis, and clinical samples from targeted cohorts of patients with inherited or acquired susceptibility to mucosal and invasive candidiasis and aspergillosis to study host-fungal interactions by using a variety of immunological, biological, and imaging approaches. The first step in mounting any immune response is the effective recruitment and activation of immune cells at the site of infection. Yet, the molecular factors that mediate these processes in the setting of candidiasis are poorly defined. Hence, a major focus of the laboratory is to investigate the role of specific members of the chemoattractant system in mediating trafficking and effector function of specific resident and recruited immune cells in anti-Candida host defense in vivo. Characterization of the 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 candidiasis in patients. Further, an important event that determines the outcome of candidiasis is germination of Candida yeast into hyphae. Hence, Candida mutant strains that are unable to germinate are avirulent in vivo. We have previously demonstrated that in disseminated candidiasis, the innate antifungal immune response is highly idiosyncratic for each infected organ, associated with organ-specific differential ability of Candida to filament in these tissues. Thus, our laboratory is interested in delineating the host factors that govern antifungal resistance versus susceptibility at different anatomical sites. To that end, a major focus of our laboratory is the study of the immunological mechanisms that account for central nervous system (CNS)-targeted susceptibility to systemic candidiasis and other systemic fungal infections (including aspergillosis) in patients with CARD9 mutations. Hence, via an investigational review board (IRB)-approved clinical protocol, our lab is recruiting patients with biallelic CARD9 mutations to NIH to study them immunologically. In parallel, the cellular and molecular basis of enhanced susceptibility to CNS-targeted system fungal diseases in CARD9 deficiency is investigated in Card9-/- mice. 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 >90 percent of patients and is the only consistent infectious disease phenotype. Hence, our laboratory, via an investigational review board (IRB)-approved clinical protocol, has recruited >120 APECED patients to the National Institutes of Health 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 to investigating mechanisms of Aire-dependent mucosal antifungal host defense, our laboratory is interested in developing a better understanding of the clinical presentation, diagnostic criteria, genetics, and mechanisms of autoimmunity in AIRE deficiency with a goal to devise mechanism-based preventative and treatment strategies for affected patients, which are tested in clinical trials at the NIH Clinical Center. Beyond AIRE deficiency, the laboratory actively investigates the mechanisms of susceptibility to CMC in STAT1 gain-of-function mutations and DOCK8 deficiency using human and mouse studies. With regard to invasive aspergillosis, the laboratory studies novel genetic defects that cause susceptibility to pulmonary and/or extrapulmonary infection beyond CGD and investigates the mechanisms of Aspergillus susceptibility in the setting of iatrogenic inhibition of BTK (Brutons tyrosine kinase) in Btk-/- and Btk conditional knockout mice and in patients that are treated with the BTK inhibitors ibrutinib and acalabrutinib. Last, our lab is working with the NIAID Clinical Genomics Program with a goal to identify novel genetic variants that result in inherited susceptibility to fungal infections by Candida, Aspergillus, and other molds.

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8
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2019
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Cougnoux, Antony; Drummond, Rebecca A; Collar, Amanda L et al. (2018) Microglia activation in Niemann-Pick disease, type C1 is amendable to therapeutic intervention. Hum Mol Genet 27:2076-2089
Desai, Jigar V; van de Veerdonk, Frank L; Lionakis, Michail S (2018) Understanding the role of host immune responses in invasive candidiasis. Intensive Care Med 44:1310-1314
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

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