A synthetic system that senses Candida albicans and inhibits virulence factors

Abstract

19Due to a limited set of antifungals available and problems in early diagnosis invasive fungal 20 infections caused by Candida species are among the most common hospital-acquired 21 infections with staggering mortality rates. Here, we describe an engineered system able to 22 sense and respond to the fungal pathogen Candida albicans, the most common cause of 23 candidemia. In doing so, we identified hydroxyphenylacetic acid (HPA) as a novel molecule 24 secreted by C. albicans. Furthermore, we engineered E. coli to be able to sense HPA 25 produced by C. albicans. Finally, we constructed a sense-and-respond system by coupling 26 the C. albicans sensor to the production of an inhibitor of hypha formation thereby reducing 27 filamentation, virulence factor expression and fungal-induced epithelial damage. This system 28 could be used as a basis for the development of novel prophylactic approaches to prevent 29 fungal infections. 30 31 32 Introduction 33 Fungal pathogens cause diverse types of infections ranging from superficial to systemic and 34 claim about 1.5 million lives per year 1 . Candida species are among the most common 35 opportunistic fungal pathogens and represent the fourth-leading cause of hospital-acquired 36bloodstream infections with mortality rates of more than 40% in immunocompromised 37 patients 1-4 . 38Candida albicans represents the main cause of candidemia, being responsible for 39 more than 40% of all cases worldwide 2 . C. albicans is a commensal colonizing the 40 gastrointestinal and genitourinary tracts of healthy individuals 5 . However, under 41 immunocompromised conditions, C. albicans can penetrate epithelia and cause severe 42 systemic infections 6 . A key virulence factor of C. albicans is its morphologic plasticity; it can 43 reversibly switch between a yeast and a filamentous or true hyphal morphology depending on 44 the environmental conditions. On epithelial surfaces, initial adhesion and subsequent 45 filamentation are required for efficient epithelial penetration 7 . In addition, several virulence 46 factors such as Candidalysin, a peptide that damages epithelial cells, are produced 47 exclusively by the hyphal form 8 . 48Difficulties associated with rapid and reliable diagnosis as well as lack of specific 49 disease manifestations contribute to the high mortality rates of systemic fungal infections 9 . 50Antifungal prophylaxis is currently applied to high risk individuals. While effective in preventing 51 Candida infections 10,11 , prolonged prophylaxis can lead to the emergence of resistant strains 52 or to an increase of species, that are intrinsically resistant to the limited set of antifungals 53 available 10,12 . Development of novel antifungals with fungistatic or fungicidal activity is limited 54 by the relative dearth of specific targets in these eukaryotic pathogens. Thus, more recently 55 approaches targeting specific virulence factors have been gaining interest. This strategy can 56 increase the number of potential targets, that are specific to the pathogen, and will...

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“…This result corroborated with another, which identified E coli as capable of inhibiting effectively the formation of hypha by fungal cells ( C. albicans ) only when induced and modified by hydroxyphenylacetic acid (HPA). Bacterial cells that were not induced caused enormous filamentation of the fungus 35 …”

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