Pathogens L1-5
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Pathogens L1-5 - Leaderboard
Pathogens L1-5 - Details
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| Microbial Pathogens Terminology | Pathogen: a microorganism that is able to cause disease in a plant, animal or insect. Pathogenicity: is the ability to produce disease in a host organism. Virulence: the degree of pathogenicity of the microbe. Determinants of virulence: any of its genetic or biochemical or structural features that enable it to produce disease in a host. |
| The Underlying Mechanisms of Bacterial Pathogenicity | Invasiveness: which encompasses mechanisms for colonization (adherence and initial multiplication), ability to bypass or overcome host defence mechanisms, and the production of extracellular substances which facilitate invasion. Toxigenesis: Bacteria produce two types of toxins called exotoxins and endotoxins. Exotoxins: released from bacterial cells and may act at tissue sites removed from the site of bacterial growth. Endotoxins: cell-associated substances that are structural components of the cell walls of Gram-negative bacteria. |
| Establishment of infection | For human pathogens entry into the body can occur through: Respiratory, Gastro-, intestinal, Urinary- or Genital-tracts. Or by insect bites or by accidental or surgical trauma to the skin |
| Cold shock and adaptation e.g. in E.coli | A downshift in T causes a transient inhibition of most protein synthesis. Causes a growth lag known as the acclimation phase, during the acclimation phase a group of cold shock proteins (Csp) are dramatically induced. Some of these cold shock proteins are essential for the cell to resume growth at low temperature. |
| E. coli Cold Shock Proteins | Class I (>10-fold induction): CspA family, CsdA, Rbf A, NusA, PNP Ribonuclease. Class II (<10-fold induction): RecA, GyrA, IF-2, H-NS |
| Listeria | -Non-spore forming Gram positive bacilli. -Causes the disease Listeriosis. -Listeria infections are still quite rare and most healthy adults will not be affected by Listeria. -Pregnant women who have a Listeria infection later in their pregnancy can become ill and the baby may die or be born prematurely. -Immunocompromised people may also become seriously ill if affected with Listeria. -Listeria is capable of growth over a wide range of temperatures (4 to 40oC). |
| Listeria virulence factors | Invasion of mammalian cells: Internalin A and B. Escape from a single membrane vacuole: -LLO (a pore-forming cytotoxin), -PI-PLC (an enzyme that removes charged head groups from phospholipids). Cell-to cell spread: ActA - stimulate actin polymerisation, propels the bacterium, bacteria enter adjacent cells. Escape from double membrane vacuole: PC-PLC (PlcB) – a phospholipase that cleaves the head group from many different kinds of lipids. Regulation of virulence factors: PrfA – is a positive regulator of virulence genes, may respond to temperature |
| Listeria invasion and spread | ActA stimulates host cell proteins ARP and Profilin (which normally participate in nucleation of actin filaments to form host cell cytoskeleton) to polymerise actin at the surface of the bacterium. Listeria polymerises actin at one end of the cell only. Ingestion leads to invasion of intestinal mucosa and subsequently systemic spread from macrophages to the liver. |
| How Is Listeria Controlled In Food? | It can grow and multiply at normal refrigeration temperatures and can survive both freezing and relatively high cooking temperatures. Temperatures of at least 70°C throughout a food for at least two minutes are required to reduce numbers of Listeria to a minimum. Listeria can also: - grow with 12% NaCl, pH: 4.4- 9.8. |
| Legionella pneumophila | -Motile, Gram -ve, complex nutrients. It lives in phagocytic cells. Biofilms or inside protozoa their normal environment. Cause Legionnaires disease. |
| Temperature & Legionella | Temperature affects the motility, piliation, and virulence of L. pneumophila cultured in bacteriological medium. Cells express more flagellin RNA and protein and assemble more flagella when incubated at 30°C. Similarly, production of type IV pili and transcription of the pilBCD pilin locus occurs when bacteria are cultured at 30°C. Adherence is also temperature dependent. The 60-kDa heat shock protein Hsp60 has also been implicated in attachment and entry of L. pneumophila to epithelial cells. |
| Problems posed by acidic conditions (3 aspects) | 1) the capacity for nutrient acquisition and energy generation, 2) cytoplasmic pH homeostasis, 3) protection of proteins and DNA. The latter is critical for cell survival and chaperone proteins and alkalisation of the periplasm are two mechanisms for achieving this. |
| Helicobacter pylori | Characteristics: Gram-ve, Highly motile, Uses glucose, amino acids, organic acids as a C source, Internal pH 7.0-7.3. Disease: Gastric and duodenal ulcers. Reservoir: Human stomach. Main virulence factors: Flagella, Urease, Adhesins, toxin. |
| How does H. pylori survive in the acidic pH of the stomach? | Colonises the mucin layer that covers the gastric mucosa. Mucus resists diffusion of protons from stomach acid because it is composed of negatively charged sulphated polysaccharides. Urease hydrolyses the urea secreted by gastric cells to produce ammonia and CO2. The urease is intracellular exports ammonia very efficiently to the periplasm. |
| Gastric epithelium | BabA: adhesin recognising Lewis b antigen which binds sulphated mucin sugars on epithelial cells. NAP: neutrophil activation protein – activates neutrophils leads to inflammation. VacA: Vacuolating cytotoxin Produces large vacuoles in mammalian cell. |
| UreI is a H. pylori pH sensor | UreI is an inner membrane protein that facilitates urea entry in a pH-controlled way. UreI consists of six transmembrane region. UreI protein the sensory residues are located on the periplasmic face of the membrane. The periplasmic loops and carboxy terminus contain a number of histidine and acidic residues that act as pH sensors through their ionisation. |
| Salmonella typhimurium | Gram-negative rod, motile, Gastroenteritis, Human carriers, livestock animals, reptiles, Contaminated food, Acid tolerance response, Adhesins, Invasion of mucosal cells, Type III secretion system, Proper food handling; antibiotics |
| Salmonella typhimurium acid tolerance response | Induction of a type III secretion system associated with Salmonella survival within animals is only induced within acidified phagosomes of macrophages. Fur appears to regulate a subset of acid shock proteins. So, Fur senses pH as well as iron. |
| PH tolerance in Gram positive bacteria | Proton pumps: F1F0 -ATPases from tolerant bacteria are less sensitive to low pH, -Glutamate decarboxylases (GAD) : consume protons via glutamate decarboxylation; the reaction product γ γ-aminobutyrate (GABA) is exported from the cell. Protein repair/DNA repair. Regulators. Altered metabolism. Cell density. Envelope alterations. Production of alkali : |
| The Effect of O2 on Growth | Obligate aerobes, Obligate anaerobes, Facultative anaerobes, Aerotolerant anaerobes. |
| The response of an organism to O2 in its environment | Depends upon the occurrence and distribution of various enzymes which react with O2 and various oxygen radicals that are invariably generated by cells in the presence of O2. All cells contain enzymes capable of reacting with O2. Chlorophyll and other pigments in cells can react with O2 in the presence of light and generate singlet oxygen. |
| Solving the oxygen problem | All organisms that live with O2, have enzymes catalase and superoxide dismutase to decompose H2O2. If there is not catalase, they use the electron from NADH2 to turn H2O2 into H2O. Photosynthetic org. contain carotenoids that help them to reduce the toxicity caused by O2 radicals. |
| Clostridium spp. – obligately anaerobic pathogens | Most Clostridia lack respiratory chain cytochromes, catalase, peroxidases and superoxide dismutase. They obtain ATP only by substrate-level phosphorylation (in which high energy phosphate bonds from organic intermediates are transferred to ADP). A number of clostridia ferment sugars, producing butyric acid (and also acetone & butanol); others ferment amino acids. Clostridia are ubiquitous in soil and some are part of the normal human flora |
| Clostridium botulinum | Botulinum toxin extremely potent. Clostridia can form spores = many processed foods are processed based on the need to protect consumers from botulinum outbreaks in food. Different strains within this species produce one of 7 exotoxin types (A,B,C1,D,E,F,G). Types C and D are encoded by lysogenic bacteriophage that infect the bacteria. |
| Botulism | Types A, B, E and F - most toxic for humans. These protein exotoxins are often released in an inactive form; proteolytic cleavage activates them. These toxins block the release of the neurotransmitter acetylcholine resulting in double vision, slurred speech, decreased saliva, difficult swallowing and general weakness. |
| Botulinum toxin mode of action | Botulinum toxin is expressed as an inactive 150 kDa polypeptide comprising a 100kDa heavy chain (HC) and a 50 kDa light chain (LC) linked through a disulphide bridge. HC binds the toxin to the presynaptic receptor; toxin enters the cell & the disulphide bond is cleaved. Cleavage liberates the LC into the cytoplasm and endosomal compartment. LC acts as a zinc endopeptidase, cleaving the synaptosomal-associated protein (SNAP), vesicle-associated membrane protein (VAMP) and syntaxin. This prevents fusion of acetylcholine vesicles at the cell membrane. |
| Clostridium tetani | Causative agent of tetanus (lockjaw). Tetanus results from trauma or a puncture wound leading to tissue contamination. Tetanus caused by the release of a single antigenic type of exotoxin by C. tetani. Tetanus exotoxin circulates in blood & adheres to neuronal receptors. Specifically, the toxin fixes to gangliosides thereby blocking the release of the neurotransmitters glycine and γ-amino butyric acid (GABA). Glycine normally prevents contraction of antagonistic muscles; therefore, muscle spasms and convulsions (lockjaw) may occur. |
| Tetanus toxin mode of action | Tetanus toxin is synthesised as a 150kDa polypeptide chain (100kDa heavy chain (HC) required for cell entry and a 50kDa light chain (LC) which causes disease. The C-terminal domain of the HC binds to gangliosides, whilst the N-terminal domain of the HC allows the LC to cross into the cell cytoplasm. Once in the cytoplasm the LC interrupts release of neurotransmitters. LC is a zinc metalloprotease which cleaves synaptobrevin 2, a SNARE protein involved in the fusion of neurotransmitter vesicles with the neuronal membrane. By cleaving synaptobrevin 2 vesicles containing GABA and glycine are not allowed to dock and hence no neurotransmitter can be released. |
| Clostridium difficile | Gram positive, obligately anaerobic, spore former. Antibiotic use (e.g. β-lactam antibiotics) reduces concentration of normal microbiota. C. difficile overgrows, produces toxins A and B. Toxins cause diarrhoea & lesions on colon surface which coalesce forming extensive tissue damage – known as pseudomembranous colitis. Can be rapidly fatal. Toxins A and B – large exotoxins that modify host cell membrane G proteins. Mode of action is to alter actin cytoskeleton of mammalian cells. Mediated by toxins glucosylating G-proteins. Glucosyl group (from UDP-glucose) added to specific threonine residue on the G protein. |
| Microbial Pathogens: Slow growing pathogens | 1. Infections featuring slow growing bacteria, 2. Tuberculosis and its re-emergence, 3. Environmental mycobacteria |
| Ionophores | A common feature of all membrane-active agents is their high lipophilic content, which enables them to interact with the hydrophobic membrane. These compounds all have reported anti-biofilm properties. |
| The intracellular parasite/pathogen | An intracellular location provides a survival niche for bacteria, because the micro-organisms are protected against antibiotic therapy and host defences. SCV internalization is mediated by fibronectin bridging between the bacterial fibronectin-binding proteins (FnBPs) and the receptor α5β1-integrin, which is present at the surface of eukaryotic cells |
| The facts about leprosy | Is a chronic infectious disease of the skin and nerves. The causal agent is Mycobacterium leprae. Symptoms are loss of sensation in hands and feet, leading to disability through injury, and blindness. It is mainly spread through droplets from the nose and mouth by coughing and sneezing. Also via skin particles in dust within housing of infected individuals can be inhaled and transmit the infection. Leprosy is curable through Multidrug Therapy (MDT). MDT is a combination of two or three drugs, clofazimine, rifampicin and dapsone which are administered over two years. |
| The leprosy spectrum and possible mechanisms of tissue damage | Clinical spectrum of tuberculoid (TT), borderline tuberculoid (BT), borderline borderline(BB), borderline lepromatous (BL), and lepromatous (LL) leprosy. Each has characteristic cell-mediated or humoral immune profile. Lepromatous leprosy is characterized by aTh2 T-cell immune response, antibody complex formation, the absence of granulomas, and failure to restrain M. leprae growth. Tuberculoid leprosy features Th1 T-cell cytokine response, vigorous T-cell responses to M. leprae antigen, and containment of the infection in well-formed granulomas. |
| The leprosy spectrum of infection | The cell-mediated (Th1) response of the TT pole features the elimination or containment of the organism in granulomas, while the ineffective humoral response at the LL (Th2) pole allows the proliferation of mycobacteria within and around foamy macrophages. Reversal reactions reflect a sudden shift toward the Th1 pole from the BT, BB, or BL state and can lead to irreversible nerve damage (neuritis). Erythema nodosum leprosum (ENL) reactions occur in patients with BL or LL leprosy and reflect an increase in both cell-mediated and humoral responses to M. leprae. ENL is associated with the systemic release of TNF and IL-4, a brisk polymorphonuclear leukocyte (PMN) influx, and antigen-antibody (Ag/Ab) complex deposition. |
| The immune response | Laminin binding protein 21 (LBP21) and phenolic glycolipid 1 (PGL-1) in the M. leprae cell wall bind to the 2 chain of laminin-2 (LAMA2) and α-dystroglycan on the Schwann cell membrane. This permits entry and subsequent damage to the peripheral nerve. The pronounced specificity of M. leprae for Schwann cells is related to the tissue-specific expression of laminin-2 on Schwann cells. M. leprae phenolic glycolipid (PGL-1) binds to the G domain of the LAMA2. The uptake of M. leprae into the Schwann cell is thought to occur when the PGL–laminin-2 complex interacts with the α-dystroglycan, the laminin-2 receptor located on the Schwann cell membrane. Laminin binding protein 21 (LBP21) also mediates the intracellular entry of M. leprae into the Schwann cell. |
| TLR1 and HLA-DRB1/DQA1 as major leprosy susceptibility genes. | The hydrophilic serine substitution (TLR1 I602S) is result of mutation and is rare in Africa and Asia, but a significant proportion of individuals of European descent are homozygous for this knockout variant. These functional TLR1 knockout individuals have a normal immunological phenotype and are protected against leprosy, suggesting that M. leprae may have utilized TLR1 as part of its pathogenesis mechanisms. |
| Treatment and chemotherapy | Treatment of leprosy with sulphones was first introduced in 1943 and the use of dapsone (DDS; 4,4-diaminodiphenyl sulphone), in 1947. In 1981, the WHO, recommended the use of multidrug therapy comprising of dapsone, clofazimine and rifampin. Since then the number of registered cases under treatment worldwide has declined from about 12 million to less than one million in 1999. |
| Clofazimine is a membrane-disrupting agent | Killing mechanisms of membrane-damaging agents: Toroidal pore formation, aggregation of the antimicrobial bends the lipid bilayer, forming a pore. Barrel-stave pore formation: the hydrophobic portion of the antimicrobial aligns with membrane lipids, with the hydrophilic portion facing inward to form a pore. Carpet-like pore formation: coating of the bilayer is proposed to result in micelle formation and membrane dissolution. |
| Diaminodiphenylsulfone (dapsone, DDS) | DDS acts as a synthase inhibitor in the folate synthesizing enzyme system. DDS reacts with the substrate 7,8-dihydro-6-hydroxymethylpterinopyrophosphate to form a 7,8-dihydropteroic acid analog. Thus inhibiting the dihydropterate synthase (DHPS). Dapsone, first developed in 1908, was initially intended for oral treatment of infectious diseases; however, dapsone was later shown to have potent anti-inflammatory properties. |
| Rifampicin | One of the ansamycin class of antibiotics semisynthetic as it is modified from the natural product rifamycin. Action is a RNA polymerase inhibitor, the only one in clinical use for blocking bacterial transcription. RNA pol has core tetramer of αββ’γ subunits. Rifampicin binds to β subunit at an allosteric site not the active site. |
| The life cycle of M. tuberculosis | The infection is initiated when Mtb bacilli, present in exhaled droplets or nuclei, are inhaled and phagocytosed by resident alveolar macrophages. The resulting proinflammatory response triggers the infected cells to invade the subtending epithelium. This response also leads to the recruitment of monocytes from the circulation, as well as extensive neovascularization of the infection site. The macrophages form the granulomas along with epithelioid cells, multinucleate giant cells, and foamy cells filled with lipid droplets, a fibrous cuff of extracellular matrix material may form. Progression toward disease is characterized by the loss of vascularization, increased necrosis, and the accumulation of caseum in the granuloma centre. |
| Cell mediated immune response | Apoptosis of infected macrophages provides an important link to adaptive immunity, as apoptotic vesicles containing bacterial antigens are taken up by dendritic cells. The dendritic cells can efficiently present these antigens to naive T cells, leading to their activation. |
| The immune response to M. tuberculosis infection | APCs modify antigen into peptides. MHC Class 2 molecules bind. They then translocate peptides to CD4 and T-cells. MHC Class 1 translocate to CD8 and T-cells. Granulomas develop through the secretion of tumour necrosis factor and other effector cytokines |
| Diagnosis of TB | 1. Smear test- microscopic visualization of acid-fast bacilli in the sputum. 2. X-ray of the chest to detect patches on the lungs. 3. Physiology- night sweats, temperature, persistent cough, weight loss, fatigue. 4. Cultivation sputum using highly growth sensitive systems such as the MGIT. 5. Tuberculin skin test (Mantoux test) for hypersensitivity to antigens of Mtb. 6. IFN-gamma release assay. 7. T-SPOT.TB assay for activated TB-specific effector T cells (TB ELISpot). 8. Detection of Mtb specific antigens in the blood. 9. Detection of specific genes using qPCR GeneXpert targets Mtb using rpoB, also will detect rifampicin resistance. |
| Research into biomarkers of TB | Most biomarkers are determined in peripheral blood, either in serum/plasma or in leukocytes. Other, less invasive sources for biomarkers are breath, sputum and urine. |
| Drug resistant TB and mycobacterial latency | MDR-TB is resistant to at least isoniazid and rifampicin. XDR-TB is resistant to isoniazid and rifampicin as well as any fluoroquinolone and any of the second-line anti-TB injectable drugs |
| Strategies for fighting resistance | Alter the MPC eg C8-methoxy fluoroquinolones. Design more drugs to attack targets such as mycolic acid synthesis. mechanisms. Multiple drug therapy- alternate drugs eg TB. New drug reduce concentration for MPC relative to MIC. Manage MPC dosing threshold |