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). In all of these conditions, detailed knowledge of immunopathogenesis at the molecular and cellular levels is lacking. Our laboratory research focuses on 1) cellular and molecular factors that regulate the immune response against mucosal and invasive candidiasis in clinically relevant animal models and on 2) better understanding the genetic and immune defects that underlie enhanced susceptibility to mucocutaneous and invasive fungal infections in humans. Our goal is to develop a detailed mechanistic understanding of the molecular and cellular basis of innate and adaptive immune responses against Candida with an aim to devise novel strategies to improve the diagnosis and augment or supplement the current antifungal drug treatment against candidiasis. To this end, we utilize in vitro cell culture systems and clinically relevant mouse models of mucosal and systemic Candida infections 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. 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.
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