Hematogenously disseminated candidiasis is a major problem in hospitalized patients. Candida species are the third most commonly isolated organism from the bloodstream of these patients, and the attributable mortality of candidemia is 20% to 38%, despite currently available therapy. Candida albicans now causes less than 50% of cases of disseminated candidiasis, whereas the incidence of invasive infections caused by Candida glabrata is steadily increasing. The majority of C. glabrata isolates are fluconazole-resistant and a rising percentage are echinocandin-resistant. Therefore, new methods to prevent and treat disseminated candidiasis are urgently needed. During hematogenously disseminated candidiasis, blood-borne organisms must invade the endothelial cell lining of the vasculature to reach the target organs. Recently, we discovered that heat-labile serum proteins bind to the surface of yeast-phase C. albicans, C. glabrata, Candida parapsilosis, Candida tropicalis, and Candida krusei (collectively called Yeast-Phase Candida; YPC). Acting as bridging molecules, these serum proteins interact with receptors on the endothelial cell surface and induce endocytosis of the yeast. Based on these novel data, we hypothesize that the capacity of YPC to invade the endothelial cell lining of the vasculature is critical for the organism to escape from the bloodstream and establish a deep-seated infection. Our goal is to determine which endothelial cell receptors mediate the endocytosis of YPC, identify the serum proteins that act as bridging molecules and induce endocytosis, and define the fungal gene products that mediate binding to serum bridging molecules and serum-induced endocytosis. The experiments described in this proposal will identify and characterize a previously unexplored aspect of the host-pathogen interaction that plays a vital role in hematogenously disseminated infection by most medically important species of Candida. Utilizing this body of research, our ultimate goal is to develop new therapeutic strategies to block the escape of Candida spp. from the bloodstream. The use of bridging molecules to induce endothelial cell endocytosis is one of the first pathogenic mechanisms to be identified that is common to multiple species of Candida. Thus, interventions that inhibit this process hold promise to have broad therapeutic applicability.
Project Relevance / Narrative This research is highly relevant to public health because hematogenously disseminated candidiasis is common in hospitalized patients and still causes significant mortality, even with currently available treatment. Discovering the serum bridging molecules and their fungal ligands and host cell receptors that mediate endothelial cell invasion holds promise to provide new insight into the pathogenesis of disseminated candidiasis. Furthermore, this information may be used to develop new diagnostic or therapeutic strategies against this frequently fatal disease.
|Voltersen, Vera; Blango, Matthew G; Herrmann, Sahra et al. (2018) Proteome Analysis Reveals the Conidial Surface Protein CcpA Essential for Virulence of the Pathogenic Fungus Aspergillus fumigatus. MBio 9:|
|Uppuluri, Priya; Lin, Lin; Alqarihi, Abdullah et al. (2018) The Hyr1 protein from the fungus Candida albicans is a cross kingdom immunotherapeutic target for Acinetobacter bacterial infection. PLoS Pathog 14:e1007056|
|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|
|Guruceaga, Xabier; Ezpeleta, Guillermo; Mayayo, Emilio et al. (2018) A possible role for fumagillin in cellular damage during host infection by Aspergillus fumigatus. Virulence 9:1548-1561|
|Watkins, Tonya N; Gebremariam, Teclegiorgis; Swidergall, Marc et al. (2018) Inhibition of EGFR Signaling Protects from Mucormycosis. MBio 9:|
|Uppuluri, Priya; Singh, Shakti; Alqarihi, Abdullah et al. (2018) Human Anti-Als3p Antibodies Are Surrogate Markers of NDV-3A Vaccine Efficacy Against Recurrent Vulvovaginal Candidiasis. Front Immunol 9:1349|
|Solis, Norma V; Park, Yang-Nim; Swidergall, Marc et al. (2018) Candida albicans White-Opaque Switching Influences Virulence but Not Mating during Oropharyngeal Candidiasis. Infect Immun 86:|
|Labbaoui, Hayet; Bogliolo, Stéphanie; Ghugtyal, Vikram et al. (2017) Role of Arf GTPases in fungal morphogenesis and virulence. PLoS Pathog 13:e1006205|
|Jung, Sook-In; Rodriguez, Natalie; Irrizary, Jihyun et al. (2017) Yeast casein kinase 2 governs morphology, biofilm formation, cell wall integrity, and host cell damage of Candida albicans. PLoS One 12:e0187721|