Innate immunity is an ancient system that prevents microbial infection in all animals, from worms to humans. In the face of daily exposure to potential pathogens, vertebrates use this system to prevent opportunistic infections such as invasive candidiasis through coordinated activities of barrier tissues and professional innate immune phagocytes. Deficiencies in neutrophils or barrier breaches predispose for lethal invasive candidiasis, the fourth most common nosocomial infection. Thus, understanding of Candida interaction with these host cells at mucosal surfaces promises to elucidate aspects of mucosal candidiasis and may reveal how this non-lethal disease progresses to invasive candidiasis. While simplified in vitro studies have revealed how C. albicans can interact with epithelial cells and phagocytes, these in vitro interactions result in epithelial destruction rather than the containment usually seen in vivo. Thus, it is important to study C. albicans-barrier interactions in vivo to understand how phagocytes normally collaborate with the epithelium to prevent invasive candidiasis in vivo. The transparent zebrafish infection models we have developed enable us to study these events at high resolution within the complex natural environment of the intact host. Our objective here is to use intravital imaging to determine how innate and epithelial immune response in vivo impacts epithelial invasion, a key aspect of C. albicans pathogenesis. We propose to test the hypothesis that phagocyte recruitment and epithelial barrier integrity block invasive hyphal growth of C. albicans. Our own preliminary data, combined with work from others, implicate neutrophils in blocking filamentous growth and mucosal tissue invasion.
In Aim 1, we will capitalize on these preliminary results to discover how neutrophils directly target C. albicans, how their activity is modulated by chemokine signaling, and examine how other immune responses are altered in their absence. Published work implicates active epithelial responses in barrier protection, and our preliminary data has identified an epithelial receptor required for protection.
In Aim 2, we will focus on this receptor to determine how epithelial signaling assists in immunity, examining its roles in immune response and epithelial organization during infection. The long-term rationale for the proposed research is that intravital imaging of host-C. albicans dynamics in vivo will generate more complete models for fungal-innate immune dynamics during infection that may lead to more rational therapeutic approaches. The transparent zebrafish model of mucosal candidiasis offers a unique opportunity to characterize complex dialog that coordinates anti-fungal defense at this barrier. The proposed experiments are expected to reveal how neutrophil attack (Aim 1) and epithelial signaling (Aim 2) prevent C. albicans invasion of the mucosal epithelium, a crucial event in its pathogenesis.
Infectious diseases affect humans worldwide and cause significant mortality and morbidity in the United States. Current methods to control fungal disease are inadequate, especially in the immunocompromised patient population, so it is critical to investigate alternative treatments. A long-term goal of this investigation involves leveraging basic information about host-pathogen interaction to develop therapeutics to treat fungal disease.
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