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. The mold Aspergillus is the most common cause of infectious mortality in recipients of allogeneic hematopoietic stem cell transplantation despite administration of antifungal therapy. Neutrophils and mononuclear phagocytes are critical for control of Aspergillus in the lung. 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 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 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. Beyond mucosal candidiasis, our research program performs the 1st prospective natural history study of APECED and has evaluated >80 patients with APECED with a multidisciplinary team of physician-scientists that spans 10 NIH institutes with a goal to develop knowledge to improve diagnosis and develop treatment and prevention strategies for the autoimmune manifestations of the syndrome. 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. 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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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
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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
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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
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