“Botulinum toxin is activated by proteolytic cleavage; the activated structure is a 150-kd polypeptide comprising two chains (a heavy chain [100 kd] and a light chain [50 kd]) that are connected by a single disulfide bond. Botulinum toxin enters the circulation and is transported to the neuromuscular junction. At the neuromuscular junction, the heavy chain of the toxin binds to the neuronal membrane on the presynaptic side of the peripheral synapse. The toxin then enters the neuronal cell via receptor-mediated endocytosis. The light chain of the toxin crosses the membrane of the endocytic vesicle and enters the cytoplasm. Once inside the cytoplasm, the light chain of the toxin (which is a zinc-containing endopeptidase) cleaves some of the proteins that form the synaptic fusion complex. These proteins, referred to as SNARE proteins, include synaptobrevin (cleaved by toxin types B, D, F, and G), syntaxin (cleaved by toxin type C), and synaptosomal-associated protein (SNAP-25; cleaved by toxin types A, C, E).The synaptic fusion complex allows the synaptic vesicles (which contain acetylcholine) to fuse with the terminal membrane of the neuron. Disruption of the synaptic fusion complex prevents the vesicles from fusing with the membrane, which in turn prevents release of acetylcholine into the synaptic cleft. Without neuronal acetylcholine release, the affiliated muscle is unable to contract and becomes paralyzed. The blockade of acetylcholine release lasts up to several months; normal functioning slowly resumes either through turnover of SNARE proteins within the cytoplasm or through production of new synapses. “References:Arnon SS, Schechter R, Inglesby TV et al. Working Group on Civilian Biodefense. Botulinum toxin as a biological weapon: medical and public health management.JAMA. 2001 Feb 28;285(8):1059-70.
Transcript of "Bacterial diseases"
ByAli RazaM.Phil Zoology
AIR BORN DISEASESDiphtheria, Legionnaires’ disease and Pontiac fever,Tuberculosis, Streptococcal diseases, andMycoplasmal pneumonia etc. ARTHROPOD BORN DISEASESPlague. Lyme disease, Typhus etc. DIREACT CONTACT DISEASESVaginosis, Chancroid, Gas Gangrene, Leprosy, Peptic ulcerStaphylococcal diseases, Syphilis etc. ZOONOTIC DIDEASESAnthrax, Brucellosis , Psitticosis, Tularemia etc FOOD AND WATER BORN DISEASESBotulism, Cholera, and Staphylococcal food poisoningTyphoid etc. DENTAL DISEASESDental plaque, Dental Decay (Caries) etc.Contents
AIR BORNE DISEASESRESPIRATORY– Most of the airborne diseases caused by bacteriainvolve the respiratory systemExamples− Diphtheria− Legionnaires’ disease− Pontiac fever− Tuberculosis infections− Pertussis− Streptococcal diseases− Mycoplasmal pneumonia
SKIN DISEASESSome airborne bacteria can cause skin diseasesEXAMPLES− Cellulitis− ErysipelasSYSTEMIC DISEASEScause systemic or visceral damage− Meningitis− Glomerulonephritis− Rheumatic fever
DiphtheriaTransmission– Corynebacterium diphtheriae– Airborne; contact with infected persons– Pseudomembrane Formation– May Spread into Bloodstream– Cardiovascular and visceral damage
• This toxin is an exotoxin that causes an inflammatoryresponse and the formation of a grayishpseudomembrane on the pharynx and respiratorymucosa• The pseudomembrane consists of dead host cellsand cells of C. diphtheriae.• Diphtheria toxin is absorbed into the circulatorysystem and distributed throughout the body, where itmay• Cause destruction of cardiac, kidney, and nervoustissues by inhibiting protein synthesis.
• The toxin is composed of two polypeptidesubunits: A and B.• A subunit consists of the catalytic domain;• B subunit is composed of the receptor andtransmembrane domains• The receptor domain binds to the heparin-binding epidermal growth factor receptor onthe surface of various eucaryotic cells.
The transmembrane domain of the toxin embeds itselfinto the target cell membrane causing the catalyticdomain to be cleaved and translocated into thecytoplasm.The cleaved catalytic domain becomes an activeenzyme, catalyzing the attachment of ADP-ribose(from NAD) to elongation factor-2 (EF-2).A single enzyme (i.e., catalytic domain) can exhaust theentire supply of cellular EF-2 within hours, resultingin protein synthesis inhibition and cell death.
Typical symptomsDiphtheria include a thick mucopurulent(containing both mucus and pus) nasal discharge,pharyngitis, fever, cough, paralysis, and death.(C. diphtheriae can also infect the skin, usually at awound or skin lesion, causing a slow healingulceration termed cutaneous diphtheria.)DiagnosisObservation of the pseudomembrane in the throatand by bacterial culture. Diphtheria antitoxin is givento neutralize any unabsorbed exotoxin in the patient’stissues; penicillin and erythromycin are used to treatthe infection.
Preventionactive immunization with DPT (diphtheria-pertussis-tetnus) vaccine;and then boosted with DTap (diphtheria toxoid,tetanus toxoid, acellular B. pertussis vaccine); orTdap (tetanus toxoid, reduced diphtheria toxoid,acellular pertussis vaccine, adsorbed), approved in2005
The clinical appearance includes gross inflammation of the pharynx andtonsils marked by grayish patches (a pseudomembrane) and swelling of theentire area.
PlagueYersinia pestisGram-negative, facultatively anaerobic rodsIn the southwestern part of the United States,plague occurs primarily in wild ground squirrels,chipmunks, mice, and prairie dogs.massive human epidemics occurred in Europeduring the Middle Ages, where the disease wasknown as the Black Death due to black-colored,subcutaneous hemorrhages.
Transmission• Y. pestis secretes plasmid-encoded yersinalouter membrane proteins (YOPS) intophagocytic cells to counter-act natural defensemechanisms• help the bacteria multiply and disseminate inthe host
Types of plaguePneumonic plague occurs when Y. pestis is eitherinhaled directly or reaches the lungs via the blood orlymphatic circulation.• Symptoms are usually absent until the last day or twoof the disease when large amounts of bloody sputumare produced.• Untreated individuals rarely survive more than 2 days.Pneumonic plague is highly contagious and can spreadrapidly via the person-to-person respiratory route ifinfected individuals are not immediately quarantined.
Septicemic plague is the rapid spread of Y. pestisthroughout the body via the bloodstream withoutthe formation of buboes and usually causes deathbefore a diagnosis can be made.Bubonic plagueSymptoms—besides the subcutaneous hemorrhages—include fever, chills, headache, extreme exhaustion,and the appearance of enlarged lymph nodes calledbuboes (hence another old name)
Prevention and control• Prevention and control involve flea and rodentcontrol, isolation of human patients, prophylaxisor abortive therapy of exposed persons, andvaccination (Plague vaccine) of persons at highrisk.• Y. pestis infection is treated with streptomycinor gentamicin.• Alternatively, doxycycline, ciprofloxacin, orchloramphenicol may be given intravenously.
DIRECT CONTACT DISEASESMost of the direct contact bacterial diseases involve theskin, mucous membranes, or underlying tissues.ExamplesVaginosisChancroidGas gangreneLeprosyPeptic ulcer disease and gastritis,Staphylococcal diseasesSyphilis
SyphilisSexually transmitteddisease caused by thespirochete Treponemapallidum
Stages of SyphilisThree recognizable stages of syphilis occur in untreatedadults.In the primary stage, after an incubation period ofabout 10 days to 3 weeks or more, the initialsymptom is a small, painless, reddened ulcer, orchancre [French canker, a destructive sore]with a hard ridge that appears at the infection siteand contains spirochetesContact with the chancre during sexual contact mayresult in disease transmission.
The spirochetes typically enter the bloodstream and aredistributed throughout the body. Within 2 to 10weeks after the primary lesion appears, the diseasemay enter the secondary stage, which ischaracterized by a highly variable skin rashBoth the chancre and the rash lesions are infectious.After several weeks the disease becomes latent.
After many years a tertiary stage develops in about40% of untreated individuals with secondarysyphilis. During this stage degenerative lesionscalled gummas form in the skin, bone, andnervous system as the result of hypersensitivityreactions.Involvement of the central nervous system may resultin tissue loss that can lead to cognitive deficits,blindness, a ―shuffle‖walk (tabes), or insanity.
Treatment• In the early stages of the disease is easilyaccomplished with long-acting benzathine penicillinG or aqueous procaine penicillin.• Later stages of syphilis are more difficult to treatwith drugs and require much larger doses over alonger period.• For example, in neurosyphilis cases, treponemesoccasionally survive such drug treatment.
FOOD-BORNE AND WATERBORNE DISEASES• Humans contract the food-borne and water-bornebacterial diseases when they ingest contaminatedfood or water.These diseases are essentially of two types:• Infections and intoxications. An infection occurswhen a pathogen enters the gastrointestinal tractand multiplies.Examples include Campylobacter gastroenteritis,salmonellosis, listerosis, shigellosis, Escherichia coliinfections and typhoid etc.
• An intoxication occurs because of theingestion of a toxin.• Examples include botulism, cholera, andstaphylococcal food poisoning.• Because these toxins disrupt the functioningof the intestinal mucosa, they are calledenterotoxins.
BotulismCause: Clostridium botulinum– Properties of the Clostridium• Gram-positive rod• Strictly anaerobic• Spore-former• Widely distributed, especially in soiland water
Transmission• A neurotoxin that binds to the synapses of motorneurons• It selectively cleaves the synaptic vesiclemembrane protein synaptobrevin, thuspreventing exocytosis and release of theneurotransmitter acetylcholine.• As a consequence, muscles do not contract inresponse to motor neuron activity, and flaccidparalysis results
Symptoms and Diagnosis• Symptoms of botulism occur within 12 to 72hours of toxin ingestion and include blurredvision, difficulty in swallowing and speaking,muscle weakness, nausea, and vomiting.• Laboratory diagnosis is restricted toLaboratory Response Network facilities and isby demonstration of the toxin in the patient’sserum or vomitus.
Prevention & ControlPrevention and control of botulisminvolves(1)strict adherence to safe food-processingpractices by the food industry(2)educating the public on safe home-preserving (canning) methods for foods,(3)not feeding honey to infants younger than 1year of age.
ZOONOTIC DISEASES• Diseases transmitted from animals tohumans are called Zoonotic diseases.Examples• Anthrax• Brucellosis• Psitticosis• Tularemia
Anthrax• The causative bacterium is the relatively large, gram-positive, aerobic, endospore-forming BacillusanthracisHuman infection is usually• cutaneous anthraxthrough a cut or abrasion of the skin• pulmonary anthrax (woolsorter’s disease)inhaling spores• gastrointestinal anthraxspores reach the gastrointestinal tract
Cutaneous Anthrax(a) A protein called protective antigen (PA) deliverstwo other proteins, edema factor (EF) and lethal factor(LF), to the capillary morphogenesis protein-2 (CMP-2)receptor on the cell membrane of a target macrophagewherePA, EF, and LF are transported to an endosome. PA thendelivers EF and LF from the endosome into thecytoplasm of the macrophage where they exert theirtoxic effects.(b) A cutaneous anthrax papule will ulcerate andnecrose(c) an eschar will form
Role of EF and LF• EF has adenylate cyclase activity, similar to diphtheriatoxins; increasing intracellular cAMP releases fluid orthe formation of edema.• Additionally, LF interferes with a transcription factor,nuclear factor B (NFB), which regulates numerouscytokine and other immunity genes, promotingmacrophage survival.As thousands of macrophages die, they release theirlysosomal contents, leading to fever, internal bleeding,septic shock, and rapid death.
Treatment• The incubation period for cutaneousanthrax is 1 to 15 days• The eschar dries and falls off in 1 toweeks with little scarringAntibioticsCiprofloxacinPenicillinDoxycycline
Pulmonary Anthrax• In inhalation anthrax, the spores (1 to 2 µm indiameter) are inhaled and lodge in the alveolar spaceswhere they are engulfed by alveolar macrophages.• Pulmonary anthrax results in massive pulmonaryedema, hemorrhage, and respiratory arrest.• The medial lethal inhalation dose for humans has beenestimated to be about 8,000 spores.
Two phase Illness• In the initial phase, which follows an incubation periodof 1 to 6 days, the disease appears as a nonspecificillness characterized by mild fever, malaise,nonproductive cough, and some chest pain.• The second phase begins abruptly and involves ahigher fever, acute dyspnea (shortness of breath), andcyanosis (oxygen deficiency).• This stage progresses rapidly, with septic shock,associated hypothermia, and death occurring within 24to 36 hours from respiratory failure.
Gastrointestinal Anthrax• The symptoms of gastrointestinal anthrax appear 2 to5 days after the ingestion of undercooked meatcontaining sporesSymptoms• nausea, vomiting, fever, and abdominal pain.• The manifestations progress rapidly to severe,bloody diarrhea. The primary lesions are ulcerativeenabling B. anthracis to become bloodborne.• Mortality is greater than 50 percent.
Diagnosis• Presumptive identification in sentinel laboratories ofthe Laboratory Response Network (LRN) is based onthe direct• Gram stained smear of a skin lesion, cerebrospinalfluid, or blood that shows encapsulated, broad, gram-positive bacilli.• Presumptive identification is also made on the basisof growth and biochemical characteristics of cultures:large, flat, nonhemolytic colonies; nonmotile; positivefor catalase and positive for capsule production.• Confirmatory diagnosis is performed by PCR andserological tests for toxins at a reference laboratoryof the LRN.
DENTAL INFECTIONS• Only a few bacteria can be considered true dentalpathogens, or odontopathogens.• The hard enamel surface selectively absorbs acidicglycoproteins (mucins) from saliva, forming amembranous layer called the acquired enamel pellicle.• sulfate (SO4-2) and carboxylate (–COO) groups that confer anet negative charge to the tooth surface.Most common bacterial diseases in humans:• Dental Plaque/tooth decay• Periodontal disease
Dental Plaque• Dental plaque formation begins with the initialcolonization of the pellicle by Streptococcus gordonii, S.oralis, S. sobrinus, S. mutans and S. mitis• Coaggregation is the result of cell-to-cell recognitionbetween genetically distinct bacteria• Many of these interactions are mediated by a lectin (acarbohydrate-binding protein) on one bacterium.
Plaque Formation• S. mutans and S. sobrinus produce extracellular enzymes(glucosyltransferases) that polymerize the glucose part ofsucrose into a heterogeneous group of extracellular,water-soluble and water-insoluble glucan polymers andother polysaccharides.• Glucans are branched-chain polysaccharides composedof glucose units acting like a cement to bind bacterial cellstogether, forming a plaque ecosystem.• Once plaque becomes established, the surface of thetooth becomes anoxic.
Demineralization• This leads to the growth of strict anaerobic bacteria(Bacteroides melaninogenicus, B. oralis, and Veillonellaalcalescens), especially between opposing teeth and thedental-gingival crevices.Bacteria produce lactic, acetic and formic acids fromsucrose and other sugars.Because plaque is not permeable to saliva, the acids arenot diluted or neutralized, and they demineralize theenamel to produce a lesion on the tooth.It is this chemical lesion that initiates dental decay.