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Senior Freshman BY2209 Infection & Immunity Lecture 2: How pathogens make you ill Prof Jay Hinton, Microbiology Department The host from a pathogen’s point of view... 1 How we see the perils of the outside world Major barriers to infection are skin & mucosal surfaces 2 Normal Flora can colonise... ● ● ● ● ● ● ● ● Skin N Nose Mouth Throat Vagina Urethra Gastrointestinal tract Basically every mucosal surface… Except deep lungs Bacteria live everywhere SGM Archive SGM Archive ● They are all over us! Between toes A cough © SGM, 2005 3 Bacteria live everywhere Ear wax Sweaty socks SG GM Archive SG GM Archive SG GM Archive ● They are all over us! Nasal secretion © SGM, 2005 Bacterial distribution in the human GI tract Oesophagus Bacteria from ingested food Duodenum 101-104 cfu/ml Stomach 101-103 cfu/ml The acidic stomach is an excellent barrier that prevents much bacterial infection Colon 109-1012 cfu/g faeces 109-1010 Bifidobacteria 103-105 Lactobacilli Ileum 101-104 cfu/g faeces . 4 How many friendly bacteria do you have inside you? ● 1000 Trillion 1000, 000, 000, 000, 000 ● How many? One thousand million million ● How many? y 1 Kg The Human-microbe relationships ● Microbes colonize the human host Either as members of the normal flora in harmony with the host Or subverting host defenses and causing disease ● Few microbes able to invade tissues, produce toxic substances, or inflict noticeable damage ● That’s lucky! Considering that microbial cells living on the human body, our Normal Flora, outnumber our own cells by 100-fold ● Pathogens... The minority of microorganisms Can cause us harm 5 The GI tract is a harsh environment 37OC p 2 pH (aerobic) pH 7, anaerobic, Digestive enzymes Normal flora (1000 species) The GI tract is a harsh environment 6 Useful Terms - Infection & Immunity Infectious disease Disease caused by infecting micro-organism or virus Disease Noticeable impairment of body function Colonisation Establishment/ growth of micro-organism on body surface Pathogen Any disease-causing micro-organism or virus Opportunistic pathogen Organisms that cause disease ONLY when introduced into unusual location Bacteraemia Bacteria circulating in bloodstream Septicaemia Acute illness due to infectious agents OR their toxins circulating in bloodstream Systemic Infection Widespread infection through blood or lymphatic system Useful Terms – Microbial Pathogenesis Pathogen Any disease-causing micro-organism or virus Pathogenicity Ability of a pathogen to produce an infectious disease in an organism Virulence determinants Attribute of micro-organism or virus that promote pathogenicity Virulence Relative level of symptoms associated with a g given p pathogen g 7 Microbes & Virulence Production & delivery of various factors Adhesion to host tissues Replication & evasion of immunity Damage to host tissues by toxins Microbes and humans ● Disease can come about in several overlapping ways Some S bacteria b t i from f normall flora fl can cause disease if they gain access to deep tissues By trauma, surgery, catheters, or a foreign body e.g. Streptococcus epidermidis ● Immunocompromised patients Many members of normal flora & free free-living living bacteria can cause disease Especially if introduced into deep tissues Clostridium botulinum in heroin! 8 How do we know that a given pathogen causes a specific disease? Robert Koch 1843-1910 ● Founder of public health… ● Developed “Koch’s Postulates” In late 1800’s discovered causal agents of: ● Tuberculosis, ● Mycobacterium tuberculosis ● Cholera ● Vibrio cholerae ● Anthrax. Bacillus anthracis 9 Koch’s Postulates Pure organism causes same disease. Organism grown in pure culture. Together these indicate infectiousdisease causation. Same organism recovered. Process of Disease ● Microbes cause disease while stealing space, nutrients, and/or living tissue from their symbiotic hosts e.g. Us! ● To do this, microbes do most of the following: Gain access to the host - contamination Adhere to the host - adhesion Replicate on the host - colonization Invade tissues - invasion And produce toxins, proteins or other agents that cause host harm - damage 10 For successful infection, bacteria: ● ● ● ● Sense environment Need to know where they are... Must express proteins to survive stress Must express proteins required for adhesion or invasion ● May make toxins ● May enter host cells and replicate ● May spread through host cells The GI tract is a harsh environment 37OC p 2 pH (aerobic) pH 7, anaerobic, Digestive enzymes Normal flora (1000 species) 11 Bacterial Virulence ● Virulence as a process is MULTIFACTORIAL A bacterial army, like a human army, needs more than just its firearms to enter and secure enemy territory… “An army marches on its stomach” - Napoleon MULTIDIMENSIONAL A programme of events organised in time & space Environmental sensing ● Bacteria can sense changes in environment e.g. temperature, nutrient availability, pH ● In simplest cases, change in intracellular concentration of ion linked directly to gene expression e.g. fall in intra-cellular iron levels triggers de-repression of diphtheria toxin gene Bacterial gene regulation is a key part of Microbiology at TCD ● In more complex cases, sophisticated signal transduction cascades allow bacteria to regulate gene expression in response to environmental cues Pathogen as an information processor 12 Stress Survival ● In addition to nutrient-limitation stress, pathogens face many other stresses Acid stress within stomach Heat shock during fever Oxidative stress within macrophages ● Stress response proteins, such as chaperonins feature as immunodominant antigens ● Detoxification proteins play a role in virulence, virulence e.g. periplasmic Cu/Zn-superoxide dismutases ● Infectious dose for enteric pathogens much lower in people with achlorhydria No need to overcome acid stress Adhesion ● To avoid physical & immunological removal, bacteria must adhere to Cell surfaces and extracellular matrix e.g. in respiratory, gastrointestinal genitourinary y tracts &g Solid surfaces e.g. teeth, heart valves, catheters Other bacteria ● Direct interaction mediated by cell-surface adhesin proteins Often located at ends of fimbria or curli & other outer membrane proteins ● Viruses have surface attachment proteins ● Adherence often combined with manipulation of host cell signalling and cytoskeleton (Salmonella) Adhesion followed by Invasion 13 Adhesion Diseases caused by intracellular bacteria that can invade & replicate inside mammalian cells ● Salmonella Gastroenteritis or Typhoid ● Shigella Bacterial dysentery 14 Salmonella typhimurium invades host cells and replicates... ● Lecture L t 9! Shigella replicates and spreads inside host cells 15 Actin-based motility Actin-based motility of Listeria monocytogenes Wild-type actA mutant 16 Manipulation of host cell processes by intracellular pathogenic bacteria Mycobacterium tuberculosis enters host cells and replicates... ● Lecture L t 10! 17 Damaging host tissues with toxins ● Endotoxin Endotoxin of Gram-negative bacteria G Gramnegative cell cytopl. mem. peptidoglycan outer mem. Lipopolysaccharide (LPS) Lipid A The toxic part Core polysaccharide Helps solubilise Lipid A O sidechain Somatic antigen 18 Endotoxin = lipopolysaccharide = LPS Impact of Endotoxin on the host ● Actions of Endotoxin Fever Hypotension Life-threatening complication of septicaemia Endotoxic shock seen with dirty intravenous equipment ■ e.g. in meningococcal infection, in ITU or oncology patients ● Most of the effects of endotoxin are mediated by tumour necrosis factor Attempts at therapy using anti-endotoxin or anti-TNF antibodies 19 Damaging host tissues with toxins ● Endotoxin ● Exotoxins Toxins acting on cell membranes Toxins active inside cells Membrane-Damaging Exotoxins ● Many bacterial toxins form pores in eukaryotic cell membranes, producing oligomeric rings Streptolysin O of Streptococcus pyogenes Listeriolysin of Listeria monocytogenes Alpha-toxin of Staphylococcus aureus ● Other toxins, such as phospholipases, degrade components of the membrane e.g. Clostridium perfringens alpha toxin 20 Cholera Exotoxin Production of watery diarrhoea If you’d like to hear a bit more... ● TCD Open Day Lecture 2011 ● Google G l Jay Hinton Dead YouTube It's amazing you're not dead yet! - and more reasons to study microbiology 21 Toxins & Vaccination ● Some bacterial proteins (exotoxins) can elicit the features of a bacterial infection when injected as pure proteins, e.g. tetanus toxin, botulinum toxin diphtheria toxin, anthrax toxin ● Vaccination with inactivated toxins (toxoids) led to a huge decline in the incidence of many bacterial infections ● Led to simplistic idea that all bacteria need to cause disease is a single toxin… `Did you know that beansprouts could kill you? ● Particularly if they’re Organic... 22 The German E. coli O104 outbreak May – June 2011 ● E. coli adhering to gut wall Variation in types of pathogenic E. coli Eliza cartoon Acquires ‘tools’ that make it more able to cause disease 23 Variants of E. coli have different combinations of ‘tools’ that help them persist in a host and cause disease EAEC EHEC Strain emergence: The German E. coli outbreak strain – a hybrid + EHEC = EAEC Stx-EAEC O104 Cartoons and concept – David Gally and Eliza Wolfson, Roslin Institute 24 The German O104 outbreak strain – a hybrid Enteroaggregative E. coli EAEC Shiga toxin virus (f (from EHEC) = + German O104 outbreak strain Introduces Shiga g toxin genes into bacterium Human-adapted & adheres well to gut wall The dangerous combination of Adhesion & Toxin production The German E. coli O104 outbreak May – June 2011 ● Over 3,200 cases ● 50 deaths 845 cases of kidney damage due to the toxin 25 Where did the E. coli come from? ● Was it Spanish cucumbers? No ● Was it German Lettuce? No ● Was it German beansprouts Yes But the seeds came from Egypt… And finally... ● The example of a bacterial pathogen that does not enter human cells, but causes inflammation... inflammation 26 Characteristics of H. pylori • Microaerophilic (5% O2, 10%CO2) • Cork-screw morphology • Highly motile (flagella) Helicobacter pylori lumen pH <4 pH 4 p • • Colonizes mucus layer • Able to grow at moderate acidity • Adheres to epithelial cells mucus layer pH 6.5 cells Figure 10-28& ulcers H. pylori infection 27 Peptic ulcer disease Pre-1990’s • caused by stress/environmental factors • incurable disease, often requiring surgery • ulcers often returned despite surgery • debilitating disease, often lethal in long term 1984 • Marshall and Warren describe isolation and culture of Campylobacter-like micro-organism from patients with peptic ulcer disease Lancet. 1984 Jun 16;1(8390):1311-5 Figure 10-28 H. pylori infection, ulcers & cancer 28 Inflammatory response to colonisation LPS, peptides IL-8 LPS, peptides neutrophil chemotaxis monocyte infiltration IL-1 TNF O2 - lamina propria PGE Inflammatory response initiated by presence of bacteria H. pylori and gastrointestinal disease Environmental factors Atrophic gastritis Gastric carcinoma MALTlymphoma Chronic gastritis H. pylori (Virulence factors) inflammation p ulcer Peptic disease Host factors 29 Nobel Prize: don't try this at home! An attempt to fulfil Koch’s Postulates for Helicobacter pylori Marshall, B.J. (1985) Med J. Aust 143:319. Barry Marshall drank Helicobacter pylori Caused gastric inflammation Cured with antibiotic Fulfilled Koch's postulates Proof !! 30