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A metabolite from commensal candida albicans enhances the bactericidal activity of macrophages and protects against sepsis

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Cellular & Molecular Immunology 2023年第10期20卷 1156-1170页

作者： Peng Gu Ruofan Liu Qin Yang Li Xie Rongjuan Wei Jiaxin Li Fengyi Mei Tao Chen Zhenhua Zeng Yan He Hongwei Zhou Hongjuan Peng Kutty Selva Nandakumar Huikuan Chu Yong Jiang Wei Gong Ye Chen Bernd Schnabl Peng Chen Department of Gastroenterology Shenzhen HospitalSouthern Medical UniversityShenzhenChina Department of Pathophysiology Guangdong Provincial Key Laboratory of ProteomicsSchool of Basic Medical SciencesSouthern Medical UniversityGuangzhouChina Department of Gastroenterology The Seventh Affiliated Hospital of Southern Medical UniversityFoshanChina Department of Critical Care Medicine Nanfang HospitalSouthern Medical UniversityGuangzhouChina Microbiome Medicine Center Zhujiang HospitalSouthern Medical UniversityGuangzhouChina Department of Pathogen Biology Guangdong Provincial Key Laboratory of Tropical Disease ResearchSchool of Public HealthSouthern Medical UniversityGuangzhouChina Department of Environment and Biosciences School of BusinessInnovation and SustainabilityHalmstad UniversityHalmstadSweden Division of Gastroenterology Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina Department of Medicine University of California San DiegoLa JollaCAUSA

The gut microbiome is recognized as a key modulator of sepsis ***,the contribution of the gut mycobiome to sepsis development is still not fully ***,we demonstrated that the level of candida albicans was markedly decreased in patients with bacterial sepsis,and the supernatant of candida albicans culture significantly decreased the bacterial load and improved sepsis symptoms in both cecum ligation and puncture(CLP)-challenged mice and Escherichia coli-challenged *** metabolomics and the genetic engineering of fungi revealed that candida albicans-derived phenylpyruvate(PPA)enhanced the bactericidal activity of macrophages and reduced organ damage during ***,PPA directly binds to sirtuin 2(SIRT2)and increases reactive oxygen species(ROS)production for eventual bacterial ***,PPA enhanced the bacterial clearance capacity of macrophages in sepsis patients and was inversely correlated with the severity of sepsis in *** findings highlight the crucial contribution of commensal fungi to bacterial disease modulation and expand our understanding of the host-mycobiome interaction during sepsis development.

关键词： candida albicans Phenylpyruvate Sepsis Macrophage Bacterial clearance

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Atmospheric humidity regulates same-sex mating in candida albicans through the trehalose and osmotic signaling pathways

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Science China(Life Sciences) 2023年第8期66卷 1915-1929页

作者： Chao Li Li Tao Guobo Guan Zhangyue Guan Austin M.Perry Tianren Hu Jian Bing Ming Xu Clarissa J.Nobile Guanghua Huang Department of Infectious Diseases Huashan HospitalShanghai Institute of Infectious Disease and Biosecurity and State Key Laboratory of Genetic EngineeringSchool of Life SciencesFudan UniversityShanghai 200438China State Key Laboratory of Mycology Institute of MicrobiologyChinese Academy of SciencesBeijing 100101China Department of Molecular and Cell Biology University of CaliforniaMercedMerced CA 95343USA Quantitative and Systems Biology Graduate Program University of CaliforniaMercedMerced CA 95343USA Health Sciences Research Institute University of CaliforniaMercedMerced CA 95343USA Shanghai Engineering Research Center of Industrial Microorganisms Shanghai 200438China Shanghai Huashen Institute of Microbes and Infections Shanghai 200052China

Sexual reproduction is prevalent in eukaryotic organisms and plays a critical role in the evolution of new traits and in the generation of genetic *** factors often have a direct impact on the occurrence and frequency of sexual reproduction in *** regulatory effects of atmospheric relative humidity(RH)on sexual reproduction and pathogenesis in plant fungal pathogens and in soil fungi have been extensively ***,the knowledge of how RH regulates the lifecycles of human fungal pathogens is *** this study,we report that low atmospheric RH promotes the development of mating projections and same-sex(homothallic)mating in the human fungal pathogen candida *** RH causes water loss in *** cells,which results in osmotic stress and the generation of intracellular reactive oxygen species(ROS)and *** water transporting aquaporin Aqy1,and the G-protein coupled receptor Gpr1 function as cell surface sensors of changes in atmospheric *** of the trehalose metabolic pathway by inactivating trehalose synthase or trehalase promotes same-sex mating in *** by increasing osmotic or ROS stresses,*** trehalose and ROS signal the Hog1-osmotic and Hsf1-Hsp90 signaling pathways to regulate the mating ***,therefore,propose that the cell surface sensors Aqy1 and Gpr1,intracellular trehalose and ROS,and the Hog1-osmotic and Hsf1-Hsp90 signaling pathways function coordinately to regulate sexual mating in response to low atmospheric RH conditions in ***.

关键词： atmospheric relative humidity sexual reproduction same-sex mating candida albicans trehalose metabolism osmotic stress

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Biofilm Alterations on the Stepwise Acquisition of Fluconazole-resistant candida albicans Isolates

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International Journal of Dermatology and Venereology 2022年第3期5卷 132-139页

作者： Na-Na Song Guan-Yu Qian Hai-Lin Zheng Xiao-Wei Zhou Huan Mei Dong-Mei Li Xiao-Fang Li Wei-Da Liu Department of Mycology Hospital for Skin Diseases(Institute of Dermatology)Chinese Academy of Medical Sciences and Peking Union Medical CollegeNanjingJiangsu 210042China Department of Dermatology Xuzhou Tumor HospitalXuzhouJiangsu 221000China Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs NanjingJiangsu 210042China Department of Microbiology&Immunology Georgetown University Medical CenterWashingtonDC 20057USA Center for Global Health School of Public HealthNanjing Medical UniversityNanjingJiangsu 211166China

Objectives:By assessing and comparing the phenotypic changes on the stepwise acquisition of fluconazole resistant candida albicans isolates,we could find and describe the relationship between drug resistance and biofilm formation ability in a series of clonal ***:We performed antifungal susceptibility of five drugs(fluconazole,itraconazole,voriconazole,caspofungin and amphotericin B)to further verify the antifungal activity of the six isolates in *** we combined hyphal formation assay,cell surface hydrophobicity test positively related to adherence ability,and biofilm assays in vitro to observe and compare the phenotypic characteristics of our six clonal ***:Biofilm capability is enhanced for four drug-intermediate strains,whereas the initial susceptible strain and the final resistant strain are both poor in adherence,hyphal growth and biofilm ***:It was suggested that the biofilm formation ability were not absolutely related to the degree of fluconazole resistance.

关键词： candida albicans stepwise acquired azole resistance in vivo adherence hyphal formation biofilm

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p62/SQSTM1 Participates in the Innate Immune Response of Macrophages Against candida albicans Infection

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International Journal of Dermatology and Venereology 2022年第2期5卷 75-81页

作者： Yan-Zhi He Zhi-Min Duan Xu Chen Min Li Center for Global Health School of Public HealthNanjing Medical UniversityNanjingJiangsu 211166China Department of Dermatology Hospital for Skin Diseases(Institute of Dermatology)Chinese Academy of Medical Sciences and Peking Union Medical CollegeNanjingJiangsu 210042China Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs Hospital for Skin Diseases(Institute of Dermatology)Chinese Academy of Medical Sciences and Peking Union Medical CollegeNanjingJiangsu 210042China.

Objective: This study was designed to evaluate whether p62/SQSTM1 (hereafter referred to as p62) is involved in the immune response of macrophages against challenge bycandida albicans (C. albicans).Methods: We cultured bone marrow-derived macrophages (BMDMs) to investigate the immune response to challenge byC. albicans. The p62 gene was knocked down by transfection with p62 small interfering RNA (siRNA) in the p62 siRNA group. BMDMs transfected with nonsense siRNA served as the negative control (NC) group. These two groups of BMDMs were challenged withC. albicans in vitro. We detected p62 expression through quantitative reverse transcription PCR and western blotting. The phagocytosis ability of BMDMs was evaluated by flow cytometry and microscopic examination using an Olympus FV1000 laser scanning confocal microscope. Moreover, we determined the level of reactive oxygen species (ROS) in BMDMs. The mRNA levels of proinflammatory cytokines were determined by quantitative reverse transcription ***: After stimulation byC. albicans, the relative expression of p62 mRNA was increased in a dose-dependent manner, the relative expression of p62 and the ratio of BMDMs toC. albicans is 1.893 ± 0.2156 (1:1,P albicans, flow cytometry showed that the phagocytosis rates ofC. albicans by BMDMs were significantly lower in the p62 siRNA group than in the NC group (39.70 ± 1.69%vs. 55.23 ± 0.72%, 46.70 ± 0.89%vs. 60.80 ± 1.78%, 51.90 ± 0.98%vs. 64.43 ± 2.0%, respectively, allP < 0.05). Consistent results were seen in the production of ROS (4269 ± 392.6vs. 13426 ± 1859.7, 4967 ± 721.2vs. 13687 ± 2611.2, 7647 ± 1950.0vs. 17719 ± 1814.2, respectively, allP < 0.05). The ROS levels were higher in

关键词： p62/SQSTM1 candida albicans macrophage innate immune response phagocytosis

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Priming with FLO8-deficient candida albicans induces Th1-biased protective immunity against lethal polymicrobial sepsis

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Cellular & Molecular Immunology 2021年第8期18卷 2010-2023页

作者： Quan-Zhen Lv De-Dong Li Hua Han Yi-Heng Yang Jie-Lin Duan Hui-Hui Ma Yao Yu Jiang-Ye Chen Yuan-Ying Jiang Xin-Ming Jia Clinical Medicine Scientific and Technical Innovation Center Shanghai Tenth People’s HospitalTongji University School of MedicineShanghai200092China School of Pharmacy Second Military Medical UniversityShanghai200433China State Key Laboratory of Molecular Biology Shanghai Institutes for Biological SciencesChinese Academy of SciencesShanghai200031China

The morphological switch between yeast and hyphae of candida albicans is essential for its interaction with the host defense ***,the lack of understanding of host-pathogen interactions during *** infection greatly hampers the development of effective ***,we found that priming with the *** FLO8-deficient(flo8)mutant,locked in yeast form,protected mice from subsequent lethal *** *** of Dectin-2,a fungus-derivedα-mannan recognition receptor,completely blocked flo8 mutant-induced ***,the flo8 mutant-induced Dectin-2/CARD9-mediated IL-10 production in DCs and macrophages to block thymus atrophy by inhibiting the ***-induced apoptosis of thymic T cells,which facilitated the continuous output of naive T cells from the thymus to the *** recruitment of naive T cells to the spleen enhanced Th1-biased antifungal immune ***,depletion of CD4^(+)T cells or blockade of IL-10 receptor function using specific antibodies in mice completely blocked the protective effects of flo8 mutant priming against *** ***,mannans exposed on the surface of the flo8 mutant were responsible for eliciting protective immunity by inhibiting the ***-induced apoptosis of thymic T cells to sustain the number of naive T cells in the ***,priming with the flo8 mutant extensively protected mice from polymicrobial infection caused by cecal ligation and puncture(CLP)by enhancing Th1-biased immune ***,our findings imply that targeting FLO8 in *** elicits protective immune responses against polymicrobial infections and that mannans extracted from the flo8 mutant are potential immunotherapeutic candidate(s)for controlling infectious diseases.

关键词： Fungi infection candida albicans Protective immunity Thymus atrophy Apoptosis

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cDNA Array Analysis of the Differential Expression Change in Virulence-related Genes During the Development of Resistance in candida albicans

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Acta Biochimica et Biophysica Sinica 2005年第7期37卷 463-472页

作者： Zheng XU Yong-Bing CAO~1 Jun-Dong ZHANG~1 Ying-Ying CAO~1 Ping-Hui GAO~1 De-Jun WANG~1 Xu-Ping FU~2 Kang YING~2 Wan-Sheng CHEN~1 Yuan-Ying JIANG~1 1 Department of Pharmacology,School of Pharmacy,Second Military Medical University,Shanghai 200433,China 2 State Key Laboratory of Genetic Engineering,Institute of Genetics.School of Life Science,Fudan University,Shanghai 200433,China Department of Pharmacology School of Pharmacy Second Military Medical UniversityShanghai 200433 China State Key Laboratory of Genetic Engineering Institute of Genetics School of Life Science Fudan UniversityShanghai 200433 China

candida albicans is the most frequently isolated fungus in immunocompromised patientsassociated with mucosal and deep-tissue *** investigate the correlation between virulence andresistance on a gene expression profile in ***,we examined the changes in virulence-related genesduring the development of resistance in *** from bone marrow transplant patients using a constructedcDNA array representing 3096 *** addition to the genes known to be associated with azole resistance,16 virulence-related genes were identified,whose differential expressions were newly found to be associatedwith the resistant *** expressions for these genes were confirmed by ***,the up-regulation of EFG1,CPH2,TEC1,CDC24,SAP10,ALS9,SNF1,SPO72and BDF1,and the down-regulation of RAD32,IPF3636 and UBI4 resulted in stronger virulence andinvasiveness in the resistant isolates compared with susceptible *** findings provide a link betweenthe expression of virulence genes and development of resistance during *** infection in bone marrowtransplant (BMT) patients,where *** induces hyphal formation and expression change in multiplevirulence factors.

关键词： candida albicans cDNA array resistance virulence

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Berberine reverses multidrug resistance in candida albicans by hijacking the drug efflux pump Mdr1p

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Science Bulletin 2021年第18期66卷 1895-1905,M0004页

作者： Yaojun Tong Jingyu Zhang Nuo Sun Xiang-Ming Wang Qi Wei Yu Zhang Ren Huang Yingying Pu Huanqin Dai Biao Ren Gang Pei Fuhang Song Guoliang Zhu Xinye Wang Xuekui Xia Xiangyin Chen Lan Jiang Shenlin Wang Liming Ouyang Ning Xie Buchang Zhang Yuanying Jiang Xueting Liu Richard Calderone Fan Bai Lixin Zhang Gil Alterovitzk State Key Laboratory of Bioreactor Engineering and School of Biotechnology East China University of Science and TechnologyShanghai 200237China Chinese Academy of Sciences Key Laboratory of Pathogenic Microbiology and Immunology Institute of MicrobiologyChinese Academy of SciencesBeijing 100190China Biomedical Pioneering Innovation Center(BIOPIC) School of Life SciencesPeking UniversityBeijing J00871China Georgetown University Medical Center Department of Microbiology&Immunology.Washington DC 20057USA Institute of Health Sciences School of Life SciencesAnhui UniversityHefei 230601China Guangdong Provincial Key Laboratory of Laboratory Animals Guangdong Laboratory Animals Monitoring InstituteGuangzhou 510663China Department of Pharmacology Second Military Medical UniversityShanghai 200433China State Key Laboratory of Mycology Institute of MicrobiologyChinese Academy of SciencesBeijing 100101China The Novo Nordisk Foundation Center for Biosustainability Technical University of Denmark2800 Kgs.LyngbyDenmark Key Biosensor Laboratory of Shandong Province Biology InstituteQilu University of Technology(Shandong Academy of Sciences)Jinan 250013China Brigham and Women's Hospital Boston MA 02115USA National Artificial Intelligence Institute US.Department of Veterans AffairsWashington DC 20420USA

Clinical use of antimicrobials faces great challenges from the emergence of multidrug-resistant pathogens. The overexpression of drug efflux pumps is one of the major contributors to multidrug resistance(MDR). Reversing the function of drug efflux pumps is a promising approach to overcome MDR. In the life-threatening fungal pathogen candida albicans, the major facilitator superfamily(MFS) transporter Mdr1p can excrete many structurally unrelated antifungals, leading to MDR. Here we report a counterintuitive case of reversing MDR in C. albicans by using a natural product berberine to hijack the overexpressed Mdr1p for its own importation. Moreover, we illustrate that the imported berberine accumulates in mitochondria and compromises the mitochondrial function by impairing mitochondrial membrane potential and mitochondrial Complex I. This results in the selective elimination of Mdr1 p overexpressed C. albicans cells. Furthermore, we show that berberine treatment can prolong the mean survival time of mice with blood-borne dissemination of Mdr1p overexpressed multidrug-resistant candidiasis. This study provides a potential direction of novel anti-MDR drug discovery by screening for multidrug efflux pump converters.

关键词： candida albicans Berberine Multidrug-resistance Drug excretion transporter Mitochondria

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White-opaque Switching in Different Mating Type-like Locus Gene Types of Clinical candida albicans Isolates

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Chinese Medical Journal 2016年第22期129卷 2725-2732页

作者： Hou-Min Li Yumi Shimizu-Imanishi Reiko Tanaka Ruo-Yu Li Takashi Yaguchi Department of Dermatology Peking University People's Hospital Beijing 100044 China Medical Mycology Research Center Chiba University Chiba 260-8673 Japan Department of Dermatology Peking University First Hospital Beijing 100034 China

Background：candida albicans （***） can become a pathogen causing superficial as well as life-threatening systemic infections,especially in immunocompromised *** phenotypic attributes contribute to its capacity to colonize human *** our study,93 *** isolates from patients of various candidiasis in a hospital of China were *** aimed to investigate the white-opaque （WO） switching competence,drug sensitivity,and virulence of mating type-like （MTL） a/α ***：Internal transcribed spacer （ITS） gene and the MTL configuration were detected in all the isolates by reverse transcription-polymerase chain ***/opaque phenotype and doubling time of cell growth were *** minimum inhibitory concentrations of antifungal agent were measured using broth microdilution ***：Sixty-four isolates （69.6%） were classified to serotype A,19 （20.6%） to serotype B,and 9 （9.8%） to serotype ***,phylogenetic analysis showed that these isolates were divided into four different subgroups of ITS *** of our clinical isolates were MTLa/α type,while 6.8% remained MTLa or MTLα *** frequency of opaque phenotype was 71.0% （66 isolates）.Following the guidelines of Clinical and Laboratory Standards Institute M27-A3,all isolates were susceptible to caspofungin and a few （0.6-3.2%） of them showed resistance against amphotericin B,flucytosine,fluconazole,itraconazole,and ***：From these analyses,there were comparatively more *** strains classified into serotype B,and the frequency of opaque phase strains was significant in the clinical isolates from ***,phenotypic,or drug susceptibility patterns were not significantly different from previous ***/α isolates could also undergo WO switching which facilitates their survival.

关键词： candida albicans Drug Susceptibility Genotype Mating Type-like White-opaque

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Lactobacillus crispatus Modulates Vaginal Epithelial Cell Innate Response to candida albicans

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Chinese Medical Journal 2017年第3期130卷 273-279页

作者： Xiao-Xi Niu Ting Li Xu Zhang Su-Xia Wang Zhao-Hui Liu Department of Obstetrics and Gynecology Peking University First Hospital Beijing 100034 China Laboratory of Electron Microscopy Ultrastructural Pathology Center Peking University First Hospital Beijing 100034 China

Background： Vulvovaginal candidiasis is caused by candida albicans. The vaginal epithelium, as the first site of the initial stage of infection by pathogens, plays an important role in resisting genital tract infections. Moreover, lactobacilli are predominant members of the vaginal microbiota that help to maintain a normal vaginal microenvironment. Therefore, Lactobacillus crispatus was explored for its capacity to intervene in the immune response of vaginal epithelial cells VK2/E6E7 to C. albicans. Methods： We examined the interleukin-2 （IL-2）, 4, 6, 8, and 17 produced by VK2/E6E7 cells infected with C. albicans and treated with L. crispatus in vitro. The capacity ofL. crispatus to adhere to VK2/E6E7 and inhibit C. albicans growth was also tested by scanning electron microscopy （SEM） and adhesion experiments. Results： Compared with group VK2/E6E7 with C. albicans, when treated with L. crispatus, the adhesion of C. albicans to VK2/E6E7 cells decreased significantly by 52.87 ± 1.22%, 47.03 ± 1.35%, and 42.20 ± 1.55% under competition, exclusion, and displacement conditions, respectively. SEM revealed that the invasion of C. albicans into VK2/E6E7 cells was caused by induced endocytosis and active penetration. L. crispatus could effectively protect the cells from the virulence ofhyphae and spores of C. albicans and enhance the local immune function of the VK2/E6E7 cells. The concentrations of IL-2, 6, and 17 were upregulated significantly （P 〈 0.0 1） and that of IL-8 were downregulated significantly （P 〈 0.0 1） in infected VK2/E6E7 cells treated with L. crispatus. The concentration of IL-4 was similar to that of the group VK2/ E6E7 with C. albicans （24.10 ± 0.97 vs. 23.12 ±0.76 pg/ml, P= 0.221）. Conclusions： L. crispatus can attenuate the virulence of C. albicans, modulate the secretion of cytokines and chemokines, and enhance the immune response of VK2/E6E7 cells in vitro. The vaginal mucosa has a potential function in the local immune responses against pathogens tha

关键词： candida albicans Cytokines Immunity Lactobacillus crispatus Scanning Electron Microscope Vaginal Epithelial Cells

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Antimicrobial effect of sodium houttuyfonate on Staphylococcus epidermidis and candida albicans biofilms

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Journal of Traditional Chinese Medicine 2013年第6期33卷 798-803页

作者： Jing Shao Huijuan Cheng Daqiang Wu Changzhong Wang Lingling Zhu Zhenxin Sun Qiangjun Duan Weifeng Huang Jinliang Huang Laboratory of Microbiology and Immunology School of Chinese and Western Integrative Medicine Anhui University of Chinese Medicine

OBJECTIVE： To study antimicrobial effect of Sodi- um houttuyfonate （SH） on Staphylococcus epider- midis （SE） and candida albicans （CA）. METHODS： The prepared strain broths （OD600=0.05） containing SE and CA were firstly used to test the minimal inhibitory concentrations （MICs） of SH, azithromycin （AZM） and fluconazole （FLU） by mi- cro-dilution method. Then the biofilms of SE and CA were matured in 96-well plates, and co-cultured with SH, AZM and FLU for 1, 2 and 3 days to assess the antibiofilm efficacies of the agents with differ- ent concentrations by crystal violet staining meth- od. At last, the treated biofilms of SE and CA by 2× MIC agents were observed by scanning electronic microscope. RESULTS： The MlCs of SE and CA were 256 and 1024 μg/mL, respectively. After the 1st, 2nd and3rd day of medications, the suppressions of biofilm were about 60% （P〈0.01）, 76% （P=0.000） and 75% （P=0.000） by 2×MIC SH, the suppressions of biofilm were about 90% （P=0.000）, 88% （P=0.000） and 90% （P=0.000） by 2×MIC SH, which could be testified by scanning electron microscope results. However, the inhibitions of biofilm attachment had no significant difference for SE by SH and azithromycin and CA by SH and fluconazole. CONCLUSION： SH had widely anti-pathogenic ef- fect on pathogenic biofilm formation of either bac- teria or fungus, had more influence on enclosed cells of SE and CA than the traditional antibiotics, revealing its target might be the extracellular poly- meric substances, and was more active to inhibit the growth of CA than SE.

关键词： Biofilms candida albicans Drugs, Chi-nese herbal Sodium houttuyfonate Staphylococ-cus epidermidis

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