Studies On Molecular Mechanisms Of Key Factors Crucial For Candida Albicans Commensalism And Pathogenicity

In recent years,with the widely use of immunosuppressive agents and broadspectrum antibiotics,the development of technology such as catheterization,intubation and organ transplantation,as well as various diseases including AIDS,malignant tumors,hematological malignancies,diabetes and autoimmunity,the incidence of invasive fungal infections has risen sharply.Among them,80% is caused by Candida albicans.C.albicans is one of the most common opportunistic fungal pathogen in human.It colonizes on mucosal surfaces as a commensal in the healthy people.Commensalism of C.albicans is highly regulated mainly through host immune system and other flora,which helps the commensal fungi to better adapt to the mucosal surface while avoiding or overcoming the host’s defense mechanisms.However,when immune systems or microbiota are compromised,it will invade into the blood and internal organs causing life-threatening systemic candidiasis disease.Developing new preventive and therapeutic strategies are urgently needed for C.albicans infection,which requires better understanding the molecular mechanisms regulating the transition from being a commensal to being a pathogen of C.albicans.To discover mechanisms of commensalism and pathogenicity of C.albicans,this study focused on exploring the functional and molecular mechanisms of PHO84 and RBT4.In the first part of the research work,we mainly explore the important role of Pho84 in C.albicans commensalism.In this study,we analyzed the potential role of Pho84 in GI colonization using a mouse model of stable gastrointestinal candidiasis which keep the animals healthy,despite persistent infection with high titers of yeast cells.We found that Pho84 is indispensable for gastrointestinal colonization of C.albicans through both Pi transport and TORC1 activation.High Pi feeding or overexpression of GTR1 enhance the gastrointestinal colonization of pho84Δ/Δmutant when compared with WT.Further analysis show that the downstream commensalism-related gene expression are significantly upregulated.Interestingly,Pho84 was also found to promote C.albicans adherence to Caco-2 cells by adding Phosphate into culture medium or overexpression of GTR1.These results indicate that Pho84 promotes Candida abicans commensalism through interplay of phosphate transport and TOR.In the second part of the research work,we mainly explored the mechanism of secreted Rbt4 modulates host immunity to promote fungal infection.Our previous high-throughput genetic screen identified a novel secreted protein Rbt4 is required for C.albicans virulence.Rbt4 is highly O-mannosylated by O-mannosyltransferase Pmt1 and can be recognized by the pattern recognition receptor TLR4 and activates NF-κB and MAPK signaling pathways,promoting the expression of cytokines and chemokines(including IL-1β,IL-6,IL-12,m Cx CL1 and m Cx CL2),mediating excessive recruitment of neutrophils from the blood to the target organ,causing greater expression of kidney injury molecule-1(KIM-1)and increaseing mortality in invasive candidiasis.This study will shed a light on discovering new mechanisms of how secreted virulence factors promotes C.albicans infection,and will also support development of novel candidiasis vaccines and anti-fungal drugs.