Virology & Mycology Infectious Diseases
 
   Publications A-Z
A
»Accounting & Marketing
» Addiction Research & Therapy
» Advanced Chemical Engineering
»Advances in Automobile Engineering
»Advances in Crop Science and Technology
»Advances in Dairy Research
»Advancements in Genetic Engineering
»Advances in Pharmacoepidemiology & Drug Safety
»Advances in Robotics & Automation
»Advanced Techniques in Biology & Medicine
»Advance Research in Meteorological Sciences
»Aeronautics & Aerospace Engineering
»Aging Science
»Agrotechnology
»AIDS & Clinical Research
»Alcoholism and Drug Dependence
»Allergy & Therapy
»Alternative & Integrative Medicine
»Air & Water borne Diseases
»Alzheimers Disease & Parkinsonism
»Analytical & Bioanalytical Techniques
»Anaplastology
»Anatomy & Physiology
»Ancient Diseases & Preventive Remedies
»Andrology-Open Access
»Anesthesia & Clinical Research
»Angiology: Open Access
»Antivirals & Antiretrovirals
»Anthropology
»Applied & Computational Mathematics
»Applied Mechanical Engineering
»Aquaculture Research & Development
» Arabian Journal Business and Management Review
»Architectural Engineering Technology
»Arthritis
»Arts and Social Sciences Journal
» Astrobiology & Outreach
»Astrophysics & Aerospace technology
»Autacoids
»Automatic Control of Physiological State and Function
»Autism-Open Access
  
B
»Bacteriology & Parasitology
»Bioanalysis & Biomedicine
»Bioceramics Development and Applications
»Biochemistry and Analytical Biochemistry
»Biochemistry & Pharmacology: Open Access
»Biochips & Tissue Chips
»Biodiversity & Endangered Species
»Bioenergetics: Open Access
»Bioengineering & Biomedical Science
»Bioequivalence & Bioavailability
»Biosafety & Health Education
»Biofertilizers & Biopesticides
»Biometrics & Biostatistics
»Biomimetics Biomaterials and Tissue Engineering
»Biomolecular Research & Therapeutics
» Biomusical Engineering
»Biochemistry & Physiology: Open Access
»Biological Systems- Open Access
»Biology and Medicine
»Bioprocessing & Biotechniques
»Bioremediation & Biodegradation
»Biosafety
»Biosensors & Bioelectronics
» Biosensors Journal
»Biotechnology & Biomaterials
»Bioterrorism & Biodefense
»Blood Disorders & Transfusion
»Blood & Lymph
»Bone Marrow Research
»Brain Disorders & Therapy
»Business and Economics Journal
»Business and Financial Affairs
  
C
»Cancer Science & Therapy
»Climatology & Weather forecasting
»Carcinogenesis & Mutagenesis
»Cardiovascular Diseases & Diagnosis
»Cardiovascular Pharmacology: Open Access
»Cell & Developmental Biology
»Cell Science & Therapy
»Chemical Engineering & Process Technology
»Chemical Sciences Journal
»Chemotherapy: Open Access
»Child and Adolescent Behavior
»Chromatography & Separation Techniques
»Civil & Environmental Engineering
»Civil & Legal Sciences
»Clinical & Cellular Immunology
»Clinical Case Reports
»Clinical & Experimental Cardiology
»Clinical & Experimental Dermatology Research
»Clinical & Experimental Ophthalmology
»Clinical & Experimental Pathology
»Clinical & Experimental Pharmacology
»Clinical Microbiology: Open Access
»Clinical Pharmacology & Biopharmaceutics
»Clinical Research & Bioethics
»Clinical Research on Foot & Ankle
»Clinical Toxicology
»Clinical Trials
»Clinics in Mother and Child Health
»Cloning & Transgenesis
»Community Medicine & Health Education
»Communication Disorders, Deaf Studies & Hearing Aids
»Computer Science & Systems Biology
» Current Synthetic & Systems Biology
»Cytology & Histology
D
»Data Mining in Genomics & Proteomics
»Defense Management
»Dentistry
»Depression and Anxiety
»Developing Drugs
»Diabetes & Metabolism
»Drug Designing
»Drug Metabolism & Toxicology
  
E
»Earth Science & Climatic Change
»Ecosystem & Ecography
»Endocrinology & Metabolic Syndrome
»Entomology, Ornithology & Herpetology
»Environmental & Analytical Toxicology
»Epidemiology: Open Access
»Emergency Medicine
»Ergonomics
»Electrical & Electronics
»Enzyme Engineering
»Entrepreneurship & Organization Management
  
F
»Family Medicine & Medical Science Research
»Fermentation Technology
»Fertilization: In Vitro - IVF-Worldwide
»Fisheries and Aquaculture Journal
»Fisheries & Livestock Production
»Food Processing & Technology
»Forensic Biomechanics
»Forensic Research
»Forest Research: Open Access
»Fundamentals of Renewable Energy and Applications
»Fungal Genomics & Biology
  
G
»Gastrointestinal & Digestive System
»Genetic Syndromes & Gene Therapy
»Gene Technology
»Generalized Lie Theory and Applications
»Glycobiology
»Glycomics & Lipidomics
»Gynecology& Obstetrics
»General Medicine
»General Practice
»Geography & Natural Disasters
»Geology & Geosciences
»Geophysics & Remote Sensing
»Gerontology & Geriatric Research
»Global Economics
»Global Journal of Technology and Optimization
  
H
»Hair : Therapy & Transplantation
»Hematology & Thromboembolic Diseases
»Health Care : Current Reviews
»Health & Medical Informatics
»Hereditary Genetics
»Homeopathy & Ayurvedic Medicine
»Horticulture
»Hotel & Business Management
»Human Genetics & Embryology
»Hydrology: Current Research
»Hypertension- Open Access
  
I
»Industrial Engineering & Management
»Irrigation and Drainage Systems Engineering
»Infectious Diseases and Therapy
»Information Technology & Software Engineering
»Intellectual Property Rights: Open Access
»Integrative Oncology
»Internal Medicine
»International Journal of Accounting Research
»International Journal of Advanced Innovations, Thoughts & Ideas
»International Journal of Biomedical Data Mining
»International Journal of Economics and Management Science
»International Journal of Sensor Networks and Data Communications
»International Journal of Swarm Intelligence and Evolutionary Computation
»International Journal of waste resources
»International Journal of Genomic Medicine
»International Journal of Physical Medicine & Rehabilitation
»Innovative Energy Policies
»Immunome Research
  
J
»JBR Journal of Interdisciplinary Medicine and Dental Science
»JBR Journal of Clinical Diagnosis and Research
»JBR Journal of Young Scientist
  
L
»Liver
» Leukemia
» Lovotics
  
M
»Marine Science: Research & Development
»Malaria Chemotherapy, Control & Elimination
»Mass Communication & Journalism
»Material Sciences & Engineering
»Medicinal Chemistry
»Medicinal & Aromatic Plants
»Medical Diagnostic Methods
»Medical Microbiology & Diagnosis
»Medical & Surgical Urology
»Membrane Science & Technology
»Metabolic Syndrome
»Metabolomics:Open Access
»Microbial & Biochemical Technology
»Modern Chemistry & Applications
»Molecular Biology
»Molecular Biomarkers & Diagnosis
»Molecular and Genetic Medicine
»Molecular Imaging & Dynamics
»Molecular Pharmaceutics & Organic Process Research
»Mycobacterial Diseases
N
»Natural Products Chemistry & Research
»Nanomedicine & Biotherapeutic Discovery
»Nanomedicine & Nanotechnology
»Neonatal Biology
»Nephrology & Therapeutics
»Neurology & Neurophysiology
»Neuroinfectious Diseases
»Neurological Disorders
»Novel Physiotherapies
»Nuclear Medicine & Radiation Therapy
»Nutrition & Food Sciences
»Nutritional Disorders & Therapy
»Nursing & Care
  
O
»Obesity & Weight Loss Therapy
»Oceanography-Open Access
»Occupational Medicine & Health Affairs
»OMICS Journal of Radiology
»Osteoporosis and Physical Activity
»Oral Health and Dental Management
»Oral Hygiene & Health
»Organic Chemistry: Current Research
»Orthopedic & Muscular System: Current Research
»Otolaryngology
  
P
»Pain & Relief
»Palliative Care & Medicine
»Pancreatic Disorders & Therapy
»Pediatrics & Therapeutics
»Petroleum & Environmental Biotechnology
»Pharmaceutica Analytica Acta
»Pharmaceutical Regulatory Affairs: Open Access
»Pharmacogenomics & Pharmacoproteomics
»Pharmacovigilance
»Physical Chemistry & Biophysics
»Physical Mathematics
»Plant Pathology & Microbiology
»Plant Biochemistry & Physiology
»Pollution Effects & Control
»political Sciences & public affairs
»Poultry, Fisheries & Wildlife Sciences
»Powder Metallurgy & Mining
»Primatology
»Primary Health Care: Open Access
»Probiotics & Health
» Phylogenetics & Evolutionary Biology
»Proteomics & Bioinformatics
»Phylogenetics & Evolutionary Biology
»Psychology & Psychotherapy
»Psychological Abnormalities in Children
»Pulmonary & Respiratory Medicine
  
R
»Reproductive System & Sexual Disorders
»Research and Development
»Review of Public Adminstration and Management
»Rheumatology: Current Research
»Rice Research: Open Access
  
S
» Single Cell Biology
»Sleep Disorders & Therapy
»Socialomics
»Sociology and Criminology-Open Access
»Sports Medicine & Doping Studies
»Spine
»Stem Cell Research & Therapy
»Steroids & Hormonal Science
»Stock & Forex Trading
»Surgery: Current Research
  
T
»Telecommunications System & Management
»Textile Science & Engineering
»Theoretical and Computational Chemistry:Open Access
»Thermodynamics & Catalysis
»Thyroid Disorders & Therapy
»Tissue Science & Engineering
»Translational Medicine
»Transplantation Technologies & Research
»Transcriptomics: Open Access
»Trauma & Treatment
»Tropical Diseases
»Tropical Medicine and Surgery
»Tourism & Hospitality
  
V
»Vaccines & Vaccination
»Vascular Medicine & surgery
»Veterinary Science & Technology
»Virology & Mycology
»Vitamins & Minerals
»Vortex Science and Technology
  
W
»Women's Health Care
  
Y
»Yoga & Physical Therapy
 
   Browse by Subjects
Clinical
» AIDS & Clinical Research
» Anesthesia & Clinical Research
» Angiology
» Cancer Science & Therapy
» Carcinogenesis & Mutagenesis
» Cell Science & Therapy
» Chemotherapy
» Child & Adolescent Behavior
» Clinical & Cellular Immunology
» Clinical Case Reports
» Clinical & Experimental Cardiology
» Clinical & Experimental Dermatology Research
» Clinical & Experimental Ophthalmology
» Clinical & Experimental Pharmacology
» Clinical & Experimental Pathology
» Clinical Microbiology: Open Access
» Clinical Research & Bioethics
» Clinical Research on Foot & Ankle
» Clinical Toxicology
» Clinical Trials
»Clinics in Mother and Child Health
» Communication Disorders, Deaf Studies & Hearing Aids
» Cytology & Histology
» Forensic Research
»Forensic Biomechanics
» Integrative Oncology
»Immunome Research
»JBR Journal of Clinical Diagnosis and Research
» Neurology & Neurophysiology
» Pulmonary & Respiratory Medicine
» Stem Cell Research & Therapy
» Transplantation Technologies & Research
   
Pharmaceutical Sciences
» Advances in Pharmacoepidemiology & Drug Safety
» Alcoholism and Drug Dependence
» Bioanalysis & Biomedicine
» Biochemical Pharmacology
» Bioequivalence & Bioavailability
» Cardiovascular Pharmacology: Open Access
» Clinical Pharmacology & Biopharmaceutics
» Developing Drugs
» Drug Designing
» Drug Metabolism & Toxicology
» Medicinal & Aromatic Plants
» Molecular Pharmaceutics & Organic Process Research
» Pharmaceutica Analytica Acta
» Pharmaceutical Regulatory Affairs
» Pharmacovigilance
» Vaccines & Vaccination
   
Chemistry
» Advanced Chemical Engineering
» Analytical & Bioanalytical Techniques
» Chemical Sciences Journal
» Chromatography & Separation Techniques
» Medicinal Chemistry
» Modern Chemistry & Applications
» Natural Products Chemistry & Research
» Organic Chemistry
» Physical Chemistry & Biophysics
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» Thermodynamics & Catalysis
» Theoretical and Computational Chemistry:Open Access
   
Environmental
» Anthropology
» Aquaculture Research & Development
» Astrobiology & Outreach
» Biodiversity & Endangered Species
» Earth Science & Climatic Change
» Ecosystem & Ecography
» Environmental & Analytical Toxicology
» Fisheries & Livestock Production
»Fundamentals of Renewable Energy and Applications
» Geography & Natural Disasters
» Hydrology: Current Research
»Innovative Energy Policies
»International Journal of waste resources
» Oceanography-Open Access
» Petroleum & Environmental Biotechnology
» Pollution Effects & Control
» Poultry, Fisheries & Wildlife Sciences
   
Omics
» Data Mining in Genomics & Proteomics
»Ergonomics
» Glycomics & Lipidomics
» Health & Medical Informatics
»JBR Journal of Young Scientist
» Metabolomics:Open Access
» OMICS Journal of Radiology
» Pharmacogenomics & Pharmacoproteomics
» Phylogenetics & Evolutionary Biology
» Proteomics & Bioinformatics
» Transcriptomics
   
Life Sciences
» Advanced Techniques in Biology & Medicine
»Advancements in Genetic Engineering
»Advances in Crop Science and Technology
»Advances in Dairy Research
» Aging Science
» Agrotechnology
» Air & Water Borne Diseases
» Antivirals & Antiretrovirals
» Autism-Open Access
» Bacteriology & Parasitology
» Biochemistry & Physiology
» Biochemistry and Analytical Biochemistry
» Bioenergetics
» Bioengineering & Biomedical Science
» Biofertilizers & Biopesticides
» Biological Systems
» Biometrics & Biostatistics
»Biomimetics Biomaterials and Tissue Engineering
» Biomolecular Research & Therapeutics
» Bioremediation & Biodegradation
» Biosafety
» Biosafety & Health Education
» Biosensors & Bioelectronics
» Biosensors Journal
» Biotechnology & Biomaterials
» Bioterrorism & Biodefense
» Cell & Developmental Biology
» Current Synthetic & Systems Biology
» Entomology, Ornithology & Herpetology
» Enzyme Engineering
» Fermentation Technology
» Fertilization: In Vitro - IVF-Worldwide
» Fisheries and Aquaculture Journal
» Forest Research
» Fungal Genomics & Biology
» Gene Technology
» Glycobiology
» Horticulture
» Homeopathy & Ayurvedic Medicine
»International Journal of Swarm Intelligence and Evolutionary Computation
» Marine Science: Research & Development
» Membrane Science & Technology
» Microbial & Biochemical Technology
» Molecular Biology
» Molecular Imaging & Dynamics
» Nanomedicine & Biotherapeutic Discovery
» Nanomedicine & Nanotechnology
» Nutrition & Food Sciences
» Plant Pathology & Microbiology
» Primatology
» Probiotics & Health
» Rice Research: Open Access
» Single Cell Biology
» Sociology and Criminology-Open Access
» Tissue Science & Engineering
» Tropical Diseases
» Veterinary Science & Technology
» Vitamins & Minerals
»Virology & Mycology
   
Engineering
» Advances in Automobile Engineering
» Advances in Robotics & Automation
» Aeronautics & Aerospace Engineering
» Applied & Computational Mathematics
» Applied Mechanical Engineering
» Architectural Engineering Technology
» Astrophysics & Aerospace technology
» Biochips & Tissue Chips
» Bioprocessing & Biotechniques
» Chemical Engineering & Process Technology
» Civil & Environmental Engineering
» Computer Science & Systems Biology
» Electrical & Electronics
» Food Processing & Technology
» Geology and Geosciences
» Geophysics & Remote sensing
»Global Journal of Technology and Optimization
» Industrial Engineering & Management
» Information Technology & Software Engineering
» International Journal of Advance Innovations, Thoughts & Ideas
»International Journal of Sensor Networks and Data Communications
» Irrigation and Drainage Systems Engineering
»Generalized Lie Theory and Applications
» Lovotics
» Material Sciences & Engineering
»Physical Mathematics
» Powder Metallurgy & Mining
» Telecommunications System & Management
» Textile Science & Engineering
»Vortex Science and Technology
   
Medical Sciences
» Addiction Research & Therapy
» Allergy & Therapy
» Alternative & Integrative Medicine
» Alzheimers Disease & Parkinsonism
» Anaplastology
» Anatomy & Physiology
» Ancient Diseases & Preventive Remedies
» Andrology
» Arthritis
» Autacoids
»Automatic Control of Physiological State and Function
» Bioceramics Development and Applications
» Biology and Medicine
» Biomusical Engineering
» Blood & Lymph
» Blood Disorders & Transfusion
» Bone Marrow Research
» Brain Disorders & Therapy
» Cardiovascular Diseases & Diagnosis
» Cloning & Transgenesis
» Community Medicine & Health Education
» Dentistry
» Depression and Anxiety
» Diabetes & Metabolism
» Emergency Medicine
» Endocrinology & Metabolic Syndrome
» Epidemiology: Open Access
» Family Medicine & Medical Science Research
» Gastrointestinal & Digestive System
» General Medicine
» General Practice
» Genetic Syndromes & Gene Therapy
» Gynecology& Obstetrics
» Gerontology & Geriatrics Research
» Hematology & Thromboembolic Diseases
» Hair: Therapy & Transplantation
» Health Care : Current Reviews
» Hereditary Genetics
» Human Genetics & Embryology
» Hypertension-Open Access
» Infectious Diseases & Therapy
» International Journal of Genomic Medicine
» Internal Medicine
»International Journal of Biomedical Data Mining
» International Journal of Physical Medicine & Rehabilitation
»JBR Journal of Interdisciplinary Medicine and Dental Science
» Leukemia
» Liver
»Malaria Chemotherapy, Control & Elimination
» Medical & Surgical Urology
» Medical Diagnostic Methods
» Medical Microbiology & Diagnosis
» Metabolic Syndrome
» Molecular Biomarkers & Diagnosis
» Molecular and Genetic Medicine
» Mycobacterial Diseases
» Neonatal Biology
» Nephrology & Therapeutics
»Neuroinfectious Diseases
» Neurological Disorders
» Novel Physiotherapies
» Nuclear Medicine & Radiation Therapy
» Nursing & Care
» Nutritional Disorders & Therapy
» Obesity & Weight Loss Therapy
» Occupational Medicine & Health Affairs
» Oral Health and Dental Management
» Oral Hygiene & Health
» Orthopedic & Muscular System
» Osteoporosis & Physical Activity
» Otolaryngology
» Pain & Relief
» Palliative Care & Medicine
» Pancreatic Disorders & Therapy
» Pediatrics & Therapeutics
» Primary Health Care
» Psychological Abnormalities in Children
» Psychology & Psychotherapy
» Reproductive System & Sexual Disorders
»Research and Development
» Rheumatology: Current Research
» Sleep Disorders & Therapy
» Spine
» Sports Medicine & Doping Studies
» Steroids & Hormonal Science
» Surgery: Current Research
» Thyroid Disorders & Therapy
» Translational Medicine
» Trauma & Treatment
» Tropical Medicine and Surgery
» Vascular Medicine & surgery
» Women's Health Care
» Yoga & Physical Therapy
 
Management
» Accounting & Marketing
» Arabian Journal Business and Management Review
» Arts and Social Sciences Journal
» Business and Economics Journal
» Business and Financial Affairs
» Civil & Legal Sciences
» Defense Management
» Entrepreneurship & Organization Management
» Global Economics
» Hotel & Business Management
» Intellectual Property Rights: Open Access
»International Journal of Accounting Research
» International Journal of Economics & Management Sciences
» Mass Communication & Journalism
» political Sciences & public affairs
»Review of Public Adminstration and Management
» Socialomics
» Stock & Forex Trading
» Tourism & Hospitality
 
   Conferences
Upcoming Conferences
»3rd International Conference and Exhibition on Biosensors & Bioelectronics August 11-13, 2014 San Antonio, USA
»2nd World Associations Congress August 11-13, 2014 San Antonio, USA
»International Meeting on Space- Open Debate August 12-13, 2014 San Antonio, USA
»5th International Conference and Exhibition on Analytical & Bioanalytical Techniques August 18-20, 2014 Beijing, China
»2nd International Conference on Epidemiology and Evolutionary Genetics August 18-19, 2014 Beijing, China
»2nd International Conference and Exhibition on Pharmacognosy, Phytochemistry & Natural Products August 25-27, 2014 Beijing, China
»2nd International Conference and Exhibition on Traditional & Alternative Medicine August 25-26, 2014 Beijing, China
»2nd International Conference and Exhibition on Mechanical & Aerospace Engineering September 08-10, 2014 Philadelphia, USA
»2nd International Conference and Exhibition on Lasers, Optics & Photonics September 08-10, 2014 Philadelphia, USA
»3rd International Conference and Exhibition on Neurology & Therapeutics September 08-10, 2014 Philadelphia, USA
»4th International Conference on Pharmaceutical Regulatory Affairs September 08-10, 2014 Raleigh, USA
»2nd International Conference on Radiology and Imaging September 08-09, 2014 Raleigh, USA
»2nd International Conference on Genomics & PharmacogenomicsSeptember 08-09, 2014 Raleigh, USA
»2nd International Conference on Alzheimer's Disease and Dementia September 23-25, 2014 Valencia Convention Centre, Valencia, Spain
»3rd International Conference and Exhibition on Nutrition & Food Sciences September 23-25, 2014 Valencia, Spain
»3rd International Conference on Clinical Microbiology & Microbial Genomics September 24-26, 2014 Valencia, Spain
»3rd International Conference on Tissue Science & Regenerative Medicine September 24-26, 2014 Valencia, Spain
»4th International Conference on Vaccines & Vaccination September 24-26, 2014 Valencia, Spain
»3rd International Summit on GMP, GCP & Quality Control September 25-26, 2014 Valencia, Spain
»5th World Congress on Bioequivalence and Bioavailability: Pharmaceutical R&D Summit September 29-October 01, 2014 Baltimore, USA
»2nd International Conference on Hematology & Blood Disorders September 29-October 01, 2014 Baltimore, USA
»3rd International Conference and Exhibition on Clinical & Cellular Immunology September 29-October 01, 2014 Baltimore, USA
»3rd International Conference and Exhibition on Materials Science & Engineering October 06-08, 2014 San Antonio, USA
»3rd International Conference on Forensic Research and Technology October 06-08, 2014 San Antonio, USA
»4th World Congress on Virology October 06-08, 2014 San Antonio, USA
»2nd International Conference on Endocrinology October 20-22, 2014 Chicago, USA
»3rd 3rd International Summit on Toxicology & Applied Pharmacology October 20-22, 2014 Chicago, USA
»3rd 4th World Congress on Cancer Science and Therapy October 20-22, 2014 Chicago, USA
»3rd 3rd International Conference and Exhibition on Cell & Gene Therapy October 27-29, 2014 Las Vegas, USA
»2nd International Conference on HIV/AIDS, STDs & STIs October 27-29, 2014 Chicago, USA
»2nd World Congress on Petrochemistry and Chemical Engineering October 27-29, 2014 Las Vegas, USA
»3rd International Conference and Exhibition on Pharmacovigilance & Clinical Trials October 27-29, 2014 Hyderabad, India
»3rd International Conference and Exhibition on Biowaivers and Biosimilars October 27-29, 2014 Hyderabad, India
»3rd International Conference on Translational Medicine November 03-05, 2014 Las Vegas, USA
»2nd International Conference on Predictive, Preventive and Personalized Medicine & Molecular Diagnostics November 03-05, 2014 Las Vegas, USA
»5th International Conference on Diabetes & Metabolism November 03-05, 2014 Las Vegas, USA
»2nd International Congress on Bacteriology and Infectious Diseases November 17-19, 2014 Chicago, USA
»2nd International Conference on Nursing & Healthcare November 17-19, 2014 Chicago, USA
»3rd International Conference on Surgery and Anesthesia November 17-19, 2014 Chicago, USA
»4th International Conference on Nanotek & Expo December 01-03, 2014 San Francisco, USA
»3rd International Conference and Exhibition on Obesity & Weight Management December 01-03, 2014 San Francisco, USA
»2nd International Summit on Clinical PharmacyDecember 02-03, 2014 San Francisco, USA
»3rd International Conference on Medicinal Chemistry & Computer Aided Drug Designing December 08-10, 2014 San Francisco, USA
»3rd International Conference and Exhibition on Probiotics & Functional Foods December 08-10, 2014 San Francisco, USA
Previous Conferences Organized/Co-organized
»Health Informatics & Technology Conference July 28-29, 2014 Baltimore, USA
»3rd International Conference on Gastroenterology & Urology July 28-30, 2014 San Francisco, USA
»3rd International Conference on Earth Science & Climate Change July 28-30, 2014 San Francisco, USA
»3rd International Conference and Exhibition on Orthopedics & Rheumatology July 28-30, 2014 San Francisco, USA
»International Conference on Business Economics of Broadcasting Media & Film Industry July 28-30, 2014, Baltimore, USA
»4th International Conference on Proteomics & Bioinformatics August 04-06, 2014 Chicago, USA
»3rd International Conference and Exhibition on Addiction Research & Therapy August 04-06, 2014 Chicago, USA
»2nd International Conference on Integrative Biology Summit August 04-05, 2014 Chicago, USA
»3rd International Conference and Exhibition on Cosmetology & Trichology July 21-23, 2014 Las Vegas, USA
»3rd International Conference and Exhibition on Food Processing & Technology July 21-23, 2014 Las Vegas, USA
»2nd International Conference on Oceanography July 21-23 , 2014 Las Vegas USA
»4th International Conference on Clinical & Experimental Ophthalmology July 14-16, 2014 Baltimore, USA
»3rd International Conference & Exhibition on Biometrics & Biostatistics July 14-16, 2014 Baltimore, USA
»2nd International Conference and Exhibition on Physical Medicine & Rehabilitation July 14-16, 2014 Baltimore, USA
»International Conference on Geriatrics & Gerentology July 08-10, 2014 Chicago , USA
»International Conference on Women's Health, Gynecology & Obstetrics July 08-10, 2014 Chicago, USA
»International Conference on Computer Graphics and Media Design July 08-10, 2014 Chicago, USA
»4th International Conference on Clinical & Experimental Cardiology April 14-16, 2014 San Antonio, USA
»4th International Conference on Clinical & Experimental Dermatology April 14-16, 2014 San Antonio, USA
»3rd International Conference and Exhibition on Pathology April 14-16, 2014 San Antonio, USA
»5th International Conference on Biomarkers and Clinical Research April 15-17, 2014 University of Oxford, UK
»2nd International Conference on Business Economics and Management April 21-23, 2014 Dubai, UAE
»2nd International Conference on Dental and Oral Health April 21-23, 2014 Dubai, UAE
»4th World Congress on Cell Science & Stem Cell Research June 24-26, 2014 Valencia, Spain
»3rd International Conference on Biodiversity & Sustainable Energy Development June 24-26, 2014 Valencia, Spain
»3rd International Conference and Exhibition on Occupational Health & Safety June 24-25, 2014 Valencia, Spain
»5th World congress on Biotechnology June 25-27, 2014 Valencia, Spain
»3rd International Conference on Nephrology & Therapeutics June 26-27, 2014 Valencia, Spain
»2nd International Conference on Bioprocess and Engineering June 26-27, 2014 Valencia, Spain
»2nd International Conference on Dental and Oral Health April 21-23, 2014 Dubai, UAE
»5th International Conference on Biomarkers and Clinical Research April 15-17, 2014 University of Oxford, UK
»3rd International Conference and Exhibition on Pathology April 14-16, 2014 San Antonio, USA
»4th International Conference on Clinical & Experimental Dermatology April 14-16, 2014 San Antonio, USA
»4th International Conference on Clinical & Experimental Cardiology April 14-16, 2014 San Antonio, USA
»4th International Conference and Exhibition on Pharmaceutics & Novel Drug Delivery Systems March 24-26, 2014 San Antonio, USA
»3rd International Conference and Exhibition on Metabolomics & Systems Biology March 24-26, 2014 San Antonio, USA
»2nd International Conference on Agricultural & Horticultural Sciences, February 03-05, 2014 Hyderabad, India
»International Conference and Exhibition on Traditional & Alternative Medicine, December 09-11, 2013 Hyderabad, India
»2nd International Conference and Exhibition on Obesity & Weight Management, December 02-04, 2013 Las Vegas, USA
»International Conference on Nursing & Emergency Medicine, December 02-04, 2013 Las Vegas, USA
»3rd International Conference on Nanotek & Expo, December 02-04, 2013 Las Vegas, USA
»3rd World Congress on Virology, November, 20-22, 2013 Baltimore, USA
»International Congress on Bacteriology and Infectious diseases, November 20-22, 2013 Baltimore, USA
»3rd World Congress on Cell Science & Stem Cell Research, November 20-22, 2013 San Antonio, USA
»2nd International Conference and Exhibition on Pharmacovigilance & Clinical Trials, November 18-19, 2013 San Antonio, USA
»International Summit on Clinical Pharmacy & Dispensing, November 18-20, 2013 San Antonio, USA
»World Congress on Petrochemistry and Chemical Engineering, November 18-20, 2013 San Antonio, USA
»International Conference on Functional and Comparative Genomics & Pharmacogenomics, November 12-14, 2013 Chicago, USA
»2nd International Conference and Exhibition on Cosmetology & Trichology, November 12-14, 2013 Chicago, USA
»2nd International Summit on GMP, QA & QC, November 12-14, 2013 Chicago, USA
» International Conference on Fermentation Technology, Bioprocess and Cell Culture, October 28-30, 2013 Kansas City, USA
»2nd International Conference and Exhibition on Food Processing & Technology, October 28-30, 2013 Kansas City, USA
»International Conference on HIV/AIDS, STDs, & STIs, October 24-25, 2013 Orlando-FL, USA
»2nd International Conference and Exhibition on Cell & Gene Therapy, October 23-25, 2013 Orlando, USA
»2nd International Conference and Exhibition on Probiotics & Functional Foods, October 23-25, 2013 Orlando, USA
»International Conference and Exhibition on Pharmacognosy, Phytochemistry and Natural Products, October 21-23, 2013 Hyderabad, India
» 3rd World Congress on Cancer Science & Therapy, October 21-23, 2013 California, USA
»3rd International Conference on Pharmaceutical Regulatory Affairs, October 21-23, 2013 California, USA
»2nd International Conference on Clinical & Cellular Immunology, October 15-17, 2013 Las Vegas, USA
»2nd International Conference on Medicinal Chemistry & Computer Aided Drug Designing, October 15-17, 2013 Las Vegas, USA
»4th International Conference and Exhibition on Analytical & Bioanalytical Techniques, October 15-17, 2013 Las Vegas, USA
»2nd International Summit on Toxicology, October 07-09, 2013 Las Vegas, USA
»International Conference and Exhibition on Lasers, Optics & Photonics, October 7-9, 2013 San Antonio, USA
»2nd International Conference and Exhibition on Materials Science & Engineering, October 07-09, 2013 Las Vegas, USA
»International Conference and Exhibition on Biochemical & Molecular Engineering, October 07-08, 2013 San Antonio, USA
»International Conference on Psychology, Autism and Alzheimer's Disease, September 30-October 01, 2013 San Antonio, USA
»International Conference and Exhibition on Mechanical & Aerospace Engineering, September 30-October 02, 2013 San Antonio, USA
»2nd International Conference and Exhibition on Biowaivers & Biosimilars, September 23-25, 2013 Raleigh, USA
»4th World Congress on Biotechnology, September 23-25, 2013 Raliegh, USA
»International Conference on Hematology & Blood Disorders, September 23-25, 2013 Raliegh, USA
»2nd International Conference on Surgery and Anesthesia, September 16-18, 2013 Las Vegas, USA
»2nd International Conference on Clinical Microbiology & Microbial Genomics, September 16-18, 2013 Las Vegas, USA
» International Conference on Omics Studies, September 04-06, 2013 Orlando-FL, USA
»International Symposia on Entomology, September 04-06, 2013 Miami, USA
» World Congress on Endocrinology, August 26-28, 2013 Raleigh, USA
»2nd International Conference on Hydrology and Groundwater Expo, August 26-27, 2013 Raleigh, USA
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Review Article Open Access
Role of Phospholipid Metabolism and G Protein in the Action Induced by Clostridium Perfringens Alpha-Toxin
1Department of Microbiology, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima 770-8514, Japan
2Department of Microbiology, School of Medicine, Fujita Health University, Toyoake, Aichi 470-1192, Japan
*Corresponding author: Masahiro Nagahama
Department of Microbiology
Faculty of Pharmaceutical Sciences
Tokushima Bunri University, Yamashiro-cho
Tokushima 770-8514, Japan
Tel: +81-088-622-9611
Fax: +81-088-655-3051
E-mail: nagahama@ph.bunri-u.ac.jp
 
Received February 06, 2012; Accepted March 20, 2012; Published March 23, 2012
 
Citation: Nagahama M, Oda M, Ochi S, Kobayashi K, Sakurai J (2012) Role of Phospholipid Metabolism and G Protein in the Action Induced by Clostridium Perfringens Alpha-Toxin. J Glycom Lipidom S3:001. doi:10.4172/2153-0637.S3-001
 
Copyright: © 2012 Nagahama M, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
 
Abstract
 
Alpha-toxin (370 residues) of Clostridium perfringens is the key virulence determinant in gas gangrene and has also been implicated in the pathogenesis of sudden death syndrome in young animals. Alpha-toxin possesses phospholipase C (PLC), sphingomyelinase (SMase) and biological activities causing hemolysis and lethality. The structure of the toxin reveals two domains: the N-terminal domain containing the catalytic active site and the C-terminal domain involving the binding to membranes. Recent research data showed that alpha-toxin-induced biological activities are responsible for the activation of phospholipid metabolism via a pertussis toxin (PT)-sensitive GTP-binding protein, Gi. In this review, we summary the role of phospholipid metabolism and G protein in the biological activities induced by alpha-toxin. Discussed are activations of the arachidonic acid cascade (Section 1), the phospholipid metabolism (Section 2), the sphingomeylin metabolism (Section 3) and TrkA signaling (Section 4) induced by alpha-toxin.
 
Keywords
 
C. perfringens alpha-toxin; Phospholipase C; Sphingomyelinase; Diacylglycerol; Ceramide
 
Abbreviations
 
AA: Arachidonic Acid; CF: Caboxyfluorescein; DAG: Diacylglycerol; PA: Phosphatidic Acid; PC: Phosphatidyl Choline; PI: Phosphatidyl Inositol; PLC: Phospholipase C; PT: Pertusis- Toxin; S1P: Sphingosine 1-Phosphate; SMase: Sphingomyelinase; Tm: Phase Transition temperature; TXA2: Thromboxane A2
 
Introduction
 
Clostridium perfringens produces alpha-toxin, which is an important virulence factor in gas gangrene [1-3]. Alpha-toxin is hemolytic, dermonecrotic, and lethal. Furthermore, it has phospholipase C (PLC) and sphingomyelinase (SMase) activities [1- 3]. The toxin has been shown to damage the membranes of various mammalian cells [1-3] as well as artificial membranes [4]. The structure of alpha-toxin shows two domains, the N-domain (residues 1-250) contains the catalytic active site and the C-domain (residues 251-370) responsible for the binding to membranes (Figure 1) [5]. The gene encoding alpha-toxin [6], Bacillus cereus PLC (BCPLC) [7], and PLCs from C. bifermentans [8] and Listeria monocytogenes [9] have been isolated and their nucleotide sequences were determined. The results show that the deduced amino acid sequences of alpha-toxin and these enzymes exhibit significant homology up to approximately 250 residues from the N-terminus. From these findings, alpha-toxin was found to belong to the PLC family. The C-domain is similar to the C2 domain of intracellular eukaryotic proteins involved in vesicular transport and signal transduction [10,11].
 
Figure 1: Structure of alpha-toxin.
 
We reported that alpha-toxin has two tightly bound zinc metals and an exchangeable divalent cation: residues His-68, -126 and -136 bind an exchangeable divalent cation required for binding to membranes, His-148 and Glu-152 bind one zinc ion essential for the active site of the toxin, and His-11 and Asp-130 tightly bind the other zinc ion required for maintenance of the structure [12,13]. We also reported that Tyr-57 and –65 plays a role in the penetration of the toxin into the bilayer of membranes and access of the catalytic site to sphingomyelin in membranes, but do not participate in the enzymatic activity (Figure 1) [14].
 
Alpha-toxin induced the leakage of caboxyfluorescein (CF) from liposomes composed of cholesterol and phosphatidylcholine (PC) containing unsaturated fatty acyl residues or shorter chains of saturated fatty acyl residues (12 and 14 carbon atoms), and the toxin-induced release of CF decreased as the chain of the acylresidues of PC increased in length [4]. Therefore, it is possible that the membrane-damaging effect of alpha-toxin on liposomes is related to the phase transition temperature (Tm) of PC in PC-cholesterol liposomes [4]. We prepared various PCs (C18:0/C18:1) with an unsaturated bond in the sn-2 acyl chain. Differential scanning calorimetry showed that Tm was minimal when the triple bond was positioned at C (9) in the sn-2 acyl chain. Our result shows that the binding to liposomes of the toxin and the alpha-toxin-induced release of CF from liposomes increased with a decrease in the Tm of the PC in liposomes, suggesting that an increase in membrane fluidity promotes the binding of the toxin to liposomes [15]. It appears that an increase in membrane fluidity results in the toxin being inserted into the bilayer of the membrane. Accordingly, it is concluded that the membrane-damaging action of alpha-toxin is closely related to the membrane fluidity of liposomes.
 
We have reported that the alpha-toxin-induced contraction of isolated rat aorta and ileum [16-18], and hemolysis of rabbit erythrocytes [19-21] are dependent on the activation of glycerophospholipid metabolism. We have also demonstrated that the alpha-toxin-induced hemolysis of sheep erythrocytes is dependent on the activation of the sphingomyelin metabolic system through GTP-binding proteins, especially the formation of sphingosine 1-phosphate [22,23].Therefore, the toxin-induced activation of phospholipid metabolism through G protein is closely involved in the biological activities. In the present review, we demonstrate the relationship between phospholipid metabolism via G protein and the biological activities induced by alpha-toxin.
 
Activation of the arachidonic acid cascade by alpha-toxin
 
Alpha-toxin potentiated contractions of the isolated rat vas deferens elicited by noradrenaline [24], and caused a rise in blood pressure with a decrease in blood flow [25]. The toxin caused contractions of the isolated rat aorta in a dose-dependent manner [16]. The response to repeated doses of the toxin was found to be tachyphylactic. The toxininduced contractions were not inhibited by an alpha-adrenoreceptor blocking agent (phentolamine), a histamine receptor blocking agent (chlorpheniramine), or a muscarinic receptor blocking agent (atropine). The response to the toxin therefore seems to be the result of a direct effect on the aorta. Alpha-toxin-induced contractions were inhibited by Ca channel blockers such as verapamil and nifedipine [16]. Furthermore, the toxin-induced contractionswere not observed in Ca-free medium. The data indicate that the direct action of the toxin is mainly due to an increase in Ca permeability across the smooth muscle cell membranes [16]. Labelling by 32P phosphate of phosphatidylinositol (PI) and phosphatidic acid (PA) in fragments of the aorta was enhanced by alpha-toxin [16]. Therefore, Ca influx caused by the toxin is thought to be associated with the stimulation of phospholipid metabolism. On the other hand, it is possible that the increased turnover of phospholipids caused by the toxin stimulates the breakdown of PI into diacylglycerol (DAG) and inositolphosphates. Alpha-toxin-induced contractions were significantly inhibited by cyclo-oxygenase inhibitors such as indomethacin and aspirin [17]. Furthermore, the toxin was found to stimulate release of arachidonic acid (AA), indicating that stimulation of AA release relates to activation of phospholipid metabolism by the toxin. The release of AA caused by the toxin was greater in the presence than absence of indomethacin, suggesting that AA is mainly metabolized to cyclo-oxygenase products, indicating the toxin-induced contraction to be associated with cyclooxygenase product(s) metabolized from AA [17]. The toxin-evoked contraction and AA release were unaffected by the phospholipase A2 inhibitor quinacrine. Therefore, the release of AA seems to be due to the hydrolysis of diacylglycerol by diacylglycerol lipase. The thromboxane synthetase inhibitor OKY-046 and thromboxane A2 (TXA2) antagonist ONO-3708 were found to inhibit contractions of the aorta produced by the toxin. OKY-046 and indomethacin blocked the production of TXA2 caused by the toxin. TXA2 is produced enzymatically by endothelial cells of rabbit, bovine and human umbilical blood vessels [17]. The toxin did not induce contractions after treatment of the isolated aorta with collagenase or rubbing of the tissue to remove endothelial cells from the intimal surface of the tissue [17]. Thus, the toxin-induced contractions of the isolated rat aorta associated with the production of TXA2 required an intact endothelium. Furthermore, TMB-8 (intracellular Ca2+ antagonist), trifluoperazine, W-7(calmodulin inhibitor) and H-7 (PKC inhibitor) significantly blocked the toxininduced contractions [16]. From these observations, in endothelial cells of the rat aorta, alpha-toxin stimulates phosphotidylinositol metabolism and arachidonic acid release, leading to the production of TXA2 and the phosphorylation of myosin light chain which then elicits contractions of the adjacent aorta smooth muscle (Figure 2).
 
Figure 2: Mechanism of aortic contraction induced by alpha-toxin.
 
Activation of phosholipid metabolism through GTP-binding protein induced by alpha-toxin in rabbit erythrocytes
 
Alpha-toxin induces hot-cold hemolysis of rabbit erythrocytes. The toxin induced production of PA in a dose-dependent manner when incubated with erythrocytes at 37°C. We have reported that incubation of rabbit erythrocyte membranes with the toxin results in biphasic production of PA [19] (Figure 3). When erythrocyte membranes are incubated with the toxin in the presence of [γ32P]ATP at 37°C, the formation of [32P] phosphatidic acid (PA) is biphasic, the first phase lasting 30s and the second phase, c. 20 min [19]. Treatment of erythrocyte membranes with alpha-toxin resulted in the biphasic formation of 1,2-diacylglycerol and PA as well as an increase of inositol-1,4,5-trisphosphate (IP3) and decrease of phosphatidylinositol- 4,5-bisphosphate (PIP2) within 30 s.The formation of PA in the first and secondphases was stimulated by AlF4 - and/or GTP [γS] [19]. The former was inhibited by phorbol ester and stimulated by protein kinase C inhibitor; however, these agents had no effect on thesecond phase [20]. It therefore seems that thetoxin-induced formation of PA in the first phase is stimulated by endogenous PLC which is activated by G-protein and is inhibited by protein kinase C, and the formation of PA inthe second phase is stimulated by endogenous phospholipase D which is activated by G-protein, but is not controlled by protein kinaseC [20]. Treatment of rabbit erythrocytes simultaneously with neomycin resulted in inhibition of the toxin-induced formation of PA and hemolysis. Furthermore, GTP [γS] stimulated the toxin-induced formation of PA and hemolysis, and GDP [βS] inhibited them in a dose-dependent manner [21]. Accordingly, it seems likely that the toxin-induced formation of PA is tightly linked to hemolysis elicited by the toxin. Enzymatic activities of alpha-toxin are essential for hemolysis [21]. We have reported that the PLC activity of the toxin plays a role in the activation of endogenous PIP2-specific PLC in rabbit erythrocytes, which stimulates the glycerophospholipid system in the membrane, and that activation of the system leads to hemolysis of the erythrocytes [21]. The mechanism of the formation of PA is thought to be as shown in Figure 3. First, hydrolysis of membrane phospholipids by PLC activity of the toxin causes activation of G-protein. Second, activation of endogenous PI-PLC and PLD via G-protein activated by the toxin results in stimulation of PA formation, which leads to hemolysis of rabbit erythrocytes. These results demonstrate that the toxin-induced hemolysis is due to activation of phospholipid metabolism systems through GTP-binding proteins.
 
Figure 3: Relationship between phospholipid metabolism and biological activities of alpha-toxin.
 
Activation of sphingomyelin metabolism through GTPbinding protein induced by alpha-toxin in rabbit erythrocytes
 
Alpha-toxin induces hemolysis of rabbit erythrocytes through the activation of glycerophospholipid metabolism [19-21]. Sheep erythrocytes contain large amounts of sphingomyelin (SM) but not PC. Alpha-toxin simultaneously induced hemolysis and a reduction in the levels of SM in the membrane and an increase in ceramide and sphingosine 1-phosphate (S1P) [22]. It seemed that the toxin-induced hemolysis of sheep erythrocytes is closely related to the hydrolysis of SM in the membrane by the SMase activity of alpha-toxin. Moreover, the level of phosphorylcholine markedly increased in the cells treated with the toxin, compared with that of ceramide. PC was not detected in sheep erythrocytes. These results show that the phosphorylcholine released is mostly derived from SM. The levels of phosphorylcholine released by treatment with the toxin were significantly higher than those of ceramide, suggesting that ceramide is rapidly metabolized to sphingosine. However, a markedly lower level of sphingosine, compared with S1P, was detected, although S1P increased with an increase in the dose of the toxin. It therefore is likely that sphingosine is rapidly metabolized to S1P in the cells treated with the toxin [22]. N-Oleoylethanolamine, a ceramidase inhibitor, inhibited the toxin-induced hemolysis and caused ceramide to accumulate in the toxin-treated cells. The data show that the agent specifically suppresses ceramidase to block hemolysis. Furthermore, DL-threodihydrosphingosine and B-5354c, isolated from a novel marine bacterium, both sphingosine kinase inhibitors, blocked the toxininduced hemolysis and production of S1P and caused sphingosine to accumulate. S1P potentiated the toxin-induced hemolysis of saponinpermeabilized erythrocytes but had no effect on that of intact cells suggesting that intracellular S1P is important for the toxin-induced hemolysis and that the hemolytic effect is not dependent on the action of S1P outside the cells. These observations indicate that S1P plays an intracellular role in the toxin-induced hemolysis, not an extracellular one, suggesting that it functions as a second messenger in the process. S1P itself caused no hemolysis of saponin-permeabilized cells, suggesting that hemolysis may be induced by a combination of S1P and other events elicited by the toxin in the cells [22] (Figure 3). GTP[γS] stimulated alpha-toxin-induced hemolysis, hydrolysis of SM, and formation of S1P in sheep erythrocytes. It therefore appears that the activation of GTP-binding proteins is required in the toxin-activated SM metabolic system. Preincubation of lysated sheep erythrocytes with pertussis toxin blocked the alpha-toxin-induced formation of ceramide from SM, suggesting that alpha-toxin activates endogenous SMase through a pertussis toxin-sensitive Gi type GTP-binding protein. In addition, incubation of C. botulinum C3 exoenzyme-treated lysates of sheep erythrocytes with alpha-toxin caused an accumulation of sphingosine and inhibition of the formation of S1P, indicating that sphingosine kinase is controlled by Rho (small molecular GTPbinding protein) in the cells. Therefore, it appears that Rho activated directly or indirectly by alpha-toxin stimulates sphingosine kinase. These observations suggest that the alpha-toxin-induced hemolysis of sheep erythrocytes is dependent on the activation of the SM metabolic system through GTP-binding proteins, especially the formation of S1P [23].The level of C24:1-ceramide was highest among the ceramides with an unsaturated bond in the fatty acyl chain in the detergentresistant membranes (DRMs). The toxin specifically bound to DRMs, resulting in the hydrolysis of N-nervonoic sphingomyelin (C24:1-SM) in DRMs [23] (Figure 3). Treatment of the cells with pertussis toxin (PT) inhibited the alpha-toxin-induced formation of C24:1-ceramide from C24:1-SM in DRMs and hemolysis, indicating that endogenous sphingomyelinase, which hydrolyzes C24:1-SM to C24:1-ceramide is controlled by a PT-sensitive GTP-binding protein in membranes. In summary, alpha-toxin hydrolyzes the unsaturated SM, especially C24:1-SM, by activating endogenous SMase through Gi in the DRMs of sheep erythrocyte membranes, indicating that alpha-toxin activates endogenous SMase specific for C24:1-SM. C24:1-ceramides are rapidly metabolized to sphingosine in the cells treated with the toxin, implying that the toxin activates ceramidases which selectively recognize unsaturated ceramides as a substrate [23]. These results show that the toxin-induced metabolism of C24:1-SM to S1P in DRMs plays an important role in the toxin-induced hemolysis of sheep erythrocytes (Figure 3).
 
Activation of TrkA signaling through GTP-binding protein induced by alpha-toxin
 
Alpha-toxin stimulated adhesion to the matrix and the generation of O2 – in rabbit neutrophils due to the formation of DAG through activation ofendogenous PLC by a PT-sensitive GTP-binding protein [26,27]. Treatment of the cells with the toxin resulted in tyrosine phosphorylation of TrkA (nerve grown factor high-affinity receptor) [27]. Anti-TrkA antibody inhibited the productionof O2 – and binding of the toxin to the TrkA. It has been reported that the phosphatidylinositol 3-kinase (PI3K) signaling pathway has an important role in several effector functions including the generation of O2 − [28]. PI3K is known to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3), which is recognized by a pleckstrin homology domain identified as a specialized lipid-binding module [29]. Several studies have reported that 3-phosphoinositide-dependent proteinkinase 1 (PDK1) requires PIP3 as its activator for effective catalytic activity [29]. The toxin induced phosphorylation of PDK1. K252a, an inhibitor of the TrkA receptor and LY294002, an inhibitor of PI3K, reduced the toxininduced production of O2 – and phosphorylation of PDK1, but not the formation of DAG. The result shows that the toxin-induced activation of PI3K occurs upstream of the phosphorylation of PDK1, which is an important step in the toxin-induced generation of O2 − [27]. It is likely that the toxin-induced phosphorylation of PDK1 is a process independent of the toxin-induced formation of DAG. Alpha-toxin induced phosphorylation of PKCθ and PKCζ/λ, and the generation of O2 − induced by the toxin was inhibited by rottlerin and calphostin C, an inhibitor of PKCθ. We reported that the formation of DAG induced by alpha-toxin in rabbit neutrophils plays an important role in the generation of O2 − [26]. K252a and LY294002 inhibited the toxininduced phosphorylation of protein kinase Cθ (PKCθ). It therefore appears that the toxin-induced generation of O2 − is dependent on the activation of PKCθ, through binding of PKCθ phosphorylated by PDK1 to DAG [27]. U73122, a PLC inhibitor, and pertussis toxin inhibited the toxin-induced generation of O2 – and formationof DAG, but not the phosphorylation of PDK1. These observations show that the toxin independently induces production of DAG throughactivation of endogenous PLC and phosphorylation of PDK1 via the TrkA receptor signaling pathway and that these events synergistically activate PKCθ in stimulating an increase in O2 – [27]. In addition, several studies have reported that the activation of PKC by various stimuli results in the generation of O2 − via the activation of mitogen-activated protein kinase (MAPK) systems [30-32]. The toxin causes phosphorylation of ERK1/2, but not p38 and SAPK/JNK, implying that the process is dependent on a MAPK system containing MEK1/2 and MAPK/ERK1/2, but not systems containing p38 and SAPK/JNK. We showed the participation of MAPK-associated signaling events via activation of PKCθ in the toxininduced generation of O2 –. In conclusion, we demonstrated that alphatoxin induces formation of DAG through the activation of endogenous PLC by a PT-sensitive GTP-binding protein and phosphorylation of PDK1 via stimulation of the TrkA receptor, so that DAG and PDK1 synergistically activate PKCθ, and that the activation of PKCθ stimulates generation of O2 – through MAPK-associated signaling events in rabbit neutrophils [27] (Figure 3). To clarify the mechanism responsible for the toxin-induced activation of TrkA, the effect of alphatoxin on TrkA in PC12 cells, a model for studying the differentiation of neuronal cells in response to TrkA [33], was investigated. The toxin induced neurite-outgrowth and phosphorylation of TrkA in the cells in a dose-dependent manner [34]. TrkA inhibitor K252a and shRNA for TrkA inhibited the toxin-induced neurite-outgrowth, and phosphorylation of TrkA and ERK1/2. Furthermore, the binding of the toxin to PC12 cells transfected with TrkA-specific shRNA vectors decreased, compared with that to the intact cells, suggesting that the binding of the toxin to TrkA and the activation of TrkA are required for neuritogenesis. Nerve growth factor (NGF), which binds to TrkA, is reported to be required for the differentiation and survival of nerve cells [35]. Several studies have reported that neurite-outgrowth induced by NGF is dependent on the activation of MAPK systems [36-38]. Alphatoxin caused the phosphorylation of ERK1/2, but not that of p38 and SAPK/JNK, and PD98059, an inhibitor of Erk1/2 cascade, attenuated the neurite-outgrowth and the phosphorylation of ERK1/2 induced by alpha-toxin. K252a inhibited the phosphorylation of ERK1/2. These results showed that the toxin-induced neurite-outgrowth is dependent on activation of the ERK1/2 pathway via TrkA [34]. The wild-type toxin induced the formation of DAG, and neurite-outgrowth, but H148G, a variant toxin which binds to cell membranes and has lost the enzymatic activity, did not. Therefore, it appears that the phospholipid metabolism caused by the enzymatic activity of alpha-toxin plays an important role in the activation of TrkA-ERK1/2 signal transduction and neurite-outgrowth. We demonstrated that the phosphorylation of TrkA through the phospholipid metabolism induced by the toxin synergistically plays a key role in neurite-outgrowth [34] (Figure 3).
 
Conclusion
 
C. perfringens alpha-toxin is an important agent of gas gangrene. Alpha-toxin induces the hemolysis of rabbit erythrocytes and the generation of superoxide anion in rabbit neutrophils through the activation of endogenous PLC via a PT-sensitive GTP-binding protein, Gi. On the other hand, the toxin also induces the hemolysis of sheep erythrocytes through the activation of endogenous SMase via Gi and Rho. The enzymatic activity of the toxin is essential for activation of phospholipid metabolism via G protein.
 
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