A Synthetic System That Senses Candida albicans and Inhibits Virulence Factors.

Due to a limited set of antifungals available and problems in early diagnosis, invasive fungal infections caused by Candida species are among the most common hospital-acquired infections with staggering mortality rates. Here, we describe an engineered system able to sense and respond to the fungal pathogen Candida albicans, the most common cause of candidemia. In doing so, we identified hydroxyphenylacetic acid (HPA) as a novel molecule secreted by C. albicans. Furthermore, we engineered E. coli to be able to sense HPA produced by C. albicans. Finally, we constructed a sense-and-respond system by coupling the C. albicans sensor to the production of an inhibitor of hypha formation, thereby reducing filamentation, virulence factor expression, and fungal-induced epithelial damage. This system could be used as a basis for the development of novel prophylactic approaches to prevent fungal infections.

[1]  Lian-Hui Zhang,et al.  Cis-2-dodecenoic acid signal modulates virulence of Pseudomonas aeruginosa through interference with quorum sensing systems and T3SS , 2013, BMC Microbiology.

[2]  E. Cota,et al.  Candidalysin is a fungal peptide toxin critical for mucosal infection , 2016, Nature.

[3]  R. Weinstein,et al.  Prophylactic antifungal therapy in the intensive care unit. , 2001, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[4]  A. von Haeseler,et al.  The Candida albicans Histone Acetyltransferase Hat1 Regulates Stress Resistance and Virulence via Distinct Chromatin Assembly Pathways , 2015, PLoS pathogens.

[5]  K. Kuchler,et al.  The histone acetyltransferase Hat1 facilitates DNA damage repair and morphogenesis in Candida albicans , 2012, Molecular microbiology.

[6]  D. Ingber,et al.  Human gut-on-a-chip inhabited by microbial flora that experiences intestinal peristalsis-like motions and flow. , 2012, Lab on a chip.

[7]  G. Fink,et al.  Tyrosol is a quorum-sensing molecule in Candida albicans. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[8]  A. Lemme,et al.  Streptococcus mutans Inhibits Candida albicans Hyphal Formation by the Fatty Acid Signaling Molecule trans‐2‐Decenoic Acid (SDSF) , 2010, Chembiochem : a European journal of chemical biology.

[9]  T. Calandra,et al.  Bench-to-bedside review: Candida infections in the intensive care unit , 2008, Critical care.

[10]  M. Chang,et al.  Designer probiotics for the prevention and treatment of human diseases. , 2017, Current opinion in chemical biology.

[11]  Tyler J. Ford,et al.  Synthetic biology expands chemical control of microorganisms. , 2015, Current opinion in chemical biology.

[12]  J. March,et al.  Engineered Commensal Bacteria Reprogram Intestinal Cells Into Glucose-Responsive Insulin-Secreting Cells for the Treatment of Diabetes , 2015, Diabetes.

[13]  J. Cronan,et al.  The Burkholderia cenocepacia BDSF quorum sensing fatty acid is synthesized by a bifunctional crotonase homologue having both dehydratase and thioesterase activities , 2012, Molecular microbiology.

[14]  J. Revelly,et al.  Preventing invasive candida infections. Where could we do better? , 2015, The Journal of hospital infection.

[15]  N. Bannert,et al.  Cellular interactions of Candida albicans with human oral epithelial cells and enterocytes , 2010, Cellular microbiology.

[16]  M. Schaller,et al.  Candida albicans-Epithelial Interactions: Dissecting the Roles of Active Penetration, Induced Endocytosis and Host Factors on the Infection Process , 2012, PloS one.

[17]  William E Bentley,et al.  Engineered probiotic Escherichia coli can eliminate and prevent Pseudomonas aeruginosa gut infection in animal models , 2017, Nature Communications.

[18]  D. Ho,et al.  Inhibition of HIV infectivity by a natural human isolate of Lactobacillus jensenii engineered to express functional two-domain CD4 , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[19]  Hongzhe Li,et al.  Archaea and Fungi of the Human Gut Microbiome: Correlations with Diet and Bacterial Residents , 2013, PloS one.

[20]  R. Kolter,et al.  A Pseudomonas aeruginosa quorum‐sensing molecule influences Candida albicans morphology , 2004, Molecular microbiology.

[21]  C. Lewis,et al.  Bacterial delivery of a novel cytolysin to hypoxic areas of solid tumors , 2009, Gene Therapy.

[22]  U. Alon,et al.  A comprehensive library of fluorescent transcriptional reporters for Escherichia coli , 2006, Nature Methods.

[23]  Michael Baym,et al.  Engineered bacteria can function in the mammalian gut long-term as live diagnostics of inflammation , 2017, Nature Biotechnology.

[24]  M. Castanheira,et al.  Nosocomial Candidiasis: Antifungal Stewardship and the Importance of Rapid Diagnosis. , 2015, Medical mycology.

[25]  Ron Weiss,et al.  Genetically programmable pathogen sense and destroy. , 2013, ACS synthetic biology.

[26]  I. Rowland,et al.  Profiling of phenols in human fecal water after raspberry supplementation. , 2010, Journal of agricultural and food chemistry.

[27]  M. A. Prieto,et al.  Identification of a novel positive regulator of the 4-hydroxyphenylacetate catabolic pathway of Escherichia coli. , 1997, Biochemical and biophysical research communications.

[28]  B. Hube,et al.  Systemic fungal infections caused by Candida species: epidemiology, infection process and virulence attributes. , 2005, Current drug targets.

[29]  Richard A Fekete,et al.  Toward a live microbial microbicide for HIV: commensal bacteria secreting an HIV fusion inhibitor peptide. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[30]  Xiaowei Zhan,et al.  Activation of HIF-1α and LL-37 by commensal bacteria inhibits Candida albicans colonization , 2015, Nature Medicine.

[31]  David W. Denning,et al.  Hidden Killers: Human Fungal Infections , 2012, Science Translational Medicine.

[32]  B. Halliwell,et al.  Human fecal water content of phenolics: the extent of colonic exposure to aromatic compounds. , 2005, Free radical biology & medicine.

[33]  S. Brunke,et al.  Candida albicans dimorphism as a therapeutic target , 2012, Expert review of anti-infective therapy.

[34]  V. Buchta,et al.  Ultra high performance liquid chromatography tandem mass spectrometry analysis of quorum-sensing molecules of Candida albicans. , 2010, Journal of pharmaceutical and biomedical analysis.

[35]  Deborah A. Hogan,et al.  Medically important bacterial–fungal interactions , 2010, Nature Reviews Microbiology.

[36]  James J Collins,et al.  Programmable bacteria detect and record an environmental signal in the mammalian gut , 2014, Proceedings of the National Academy of Sciences.

[37]  J. C. Junqueira,et al.  Clinical strains of Lactobacillus reduce the filamentation of Candida albicans and protect Galleria mellonella against experimental candidiasis , 2017, Folia Microbiologica.

[38]  Lian-Hui Zhang,et al.  A novel DSF-like signal from Burkholderia cenocepacia interferes with Candida albicans morphological transition , 2008, The ISME Journal.

[39]  Chueh Loo Poh,et al.  Engineering microbes to sense and eradicate Pseudomonas aeruginosa, a human pathogen , 2011, Molecular systems biology.

[40]  Jordi Rello,et al.  International study of the prevalence and outcomes of infection in intensive care units. , 2009, JAMA.

[41]  John C March,et al.  Engineered bacterial communication prevents Vibrio cholerae virulence in an infant mouse model , 2010, Proceedings of the National Academy of Sciences.