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Pathogenesis What is pathogenesis? It comes from Greek. Patho disease Genesis causing Bacterial pathogens are therefore bacteria that cause disease. Infectious diseases are a major cause of death worldwide (more than cancer, cardiovascular diseases, etc. Even for premature deaths). Secondary bacterial infections are also important causes of death in viral illnesses. 25-40% of AIDS fatalities are caused by bacteria. Another reason to study pathogenesis is the prevalence of antibiotics-resistant “superbugs”. There is therefore a need to develop new drugs. Infection and disease - When a pathogen is established in a body : infection Infection when producing symptoms : disease Infection without disease : asymptomatic carriage When a non-pathogen persists in the body : colonization (e.g. normal flora) o Normal flora is very important for health o Human body = 1013 cells + 1014 microbes Are we organisms or ecosystems? Example of commensalism Host-pathogen relationship - Parasitism : one partner (pathogen) benefits and the other (host) is harmed. Pathogens : o Primary: causes disease by direct interaction with host. o Opportunistic : causes diseases under certain conditions. Pseudomonas aeruginosa is an opportunistic pathogen. Found in soil and water, it can colonize skin and intestinal tract. Our defenses are strong enough to prevent infection and disease. However, it can cause fatal systemic diseases in immunocompromised people and cystic fibrosis patients (thick mucus cannot clear bacteria). It is the cause of death of many CF patients. Host-pathogen relationship - “Normal” host : susceptible host, e.g. humans Reservoir host : nonhuman organism infected with pathogen that can also infect humans (e.g. cows in pathogenic E. coli infections, chickens for Salmonella) Not all infections lead to disease. What factors determine whether infection leads to disease or not? Number of organisms present (disease) Virulence of pathogen (disease) o Products or structural components that contribute to virulence or pathogenicity Host’s defences (health) How to describe infections Acute , if short/severe VS chronic if persistent Latent – persistent with few to no symptoms Nosocomial – develops during hospital stay Zoonosis – Associated with animals. Virulence Degree or intensity of pathogen Determined by 3 characteristics of pathogen o Invasiveness : ability to spread to adjacent tissues o Infectivity : ability to establish focal point of infection o Pathogenic potential : degree to which pathogen can cause damage to host Toxigenicity : ability to produce toxins Immunopathology : ability to trigger exaggerated immune response Measuring virulence o LD50 : number of pathogens that’ll kill 50% of an experimental group of hosts o ID50 : number of pathogens that’ll infect 50% of ... Pathogenesis for bacterial disease There are steps for infection by pathogenic bacteria. 1. Maintain a reservoir (place to live b4/after infection) a. For humans, most reservoirs are : i. Other humans (Mycobacterium tuberculosis) ii. Animals 1. Cow E.coli 2. Poultry Salmonella, Campylobacter 3. Rats Yersinia pestis iii. Environment 1. Soil Clostridium tetani 2. Be transported to host a. Direct-contact : host-to-host (coughing, touching, sex, kiss) b. Indirect contact : vehicles (soil, water), vectors, fomites – inanimate objects that harbor and transmit pathogens (utensils, doorhandles). 3. Adhere to, colonize and invade host. a. Adherence : mediated by special molecules or structures called adhesins i. ii. iii. iv. v. vi. Fimbriae : filamentous structures that help attach Capsule : inhibits phagocytosis and aids in adherence. Pili : Bind prokaryotes together for transfer of genetic material. S layer : outermost regularly structured layer of cell envelopes. Slime layer : bacterial film, less compact than a capsule, easily removed. Teichoic and lipoteichoic acids : cell wall components in G+ that aid in adhesion. b. Colonization/Invasion : establishment of a site of microbial reproduction on or within host. i. Can be active penetration of cell. 1. Production of substances that disrupt cell surface or cell-cell junctions. 2. Salmonella, for instance, produce proteins that induce massive rearrangements of the cell surface and cause the cell to engulf bacteria. 3. Many intestinal pathogenic bacteria attack and dismantle cell-cell junctions in the intestinal epithelium and gain access between cells. ii. Can be passive penetration. 1. Not related to pathogen itself (skin lesion, bite) 2. Once below mucous membrane, bacterium can spread to deeper tissue (involves production of virulence factors – enzymes or specific products). 3. If bacteria gains access to circulatory system, there is an access to all organs and systems. 4. Multiply or complete life cycles in host. a. Occurs when pathogen finds appropriate environment within hosts b. Important factors include access to nutrients, pH, temperature, redox potential, protection from host “attack” c. Different bacterial pathogens have evolved to survive and multiply within different environments in host d. Suitable environments vary greatly depending on species e. Intracellular pathogens/Extracellular pathogens f. Some bacteria invade specific cells and live inside g. Some actively grow in plasma i. Bacteremia : presence of viable bacteria in blood ii. Septicemia : presence of bacteria or toxins in bloodstream 5. Initially evade host defences 6. Damage host 7. Leave host, return to reservoir or get to a new host. The few last steps must occur if the microbe is to be perpetuated. Most bacteria leave by passive mechanisms (feces, urine, droplets, saliva, desquamated cells). Many symptoms of disease aid in this purpose (coughing, sneezing, runny nose and diarrhea). Koch’s postulates (1890): They establish a casual relationship between a disease and a microbe. ++ Corrections from researches. 1. Microorganisms found in abundance in all organisms suffering from the disease and not in healthy animals. a. No. Opportunistic pathogens may be isolated from healthy individuals without diseases or diseases with multiple causes. 2. Microorganisms should be isolated from diseased organism and grown in pure culture. a. No. Some microorganisms are hard or nearly impossible to culture. 3. Cultured microorganisms should cause the disease when introduced in a healthy organism. a. No. Disease can depend on the health status of the host. 4. Microorganisms must be reisolated from step3 host and identified as identical. Helicobacter pylori and ulcers - G- bacterium that live in stomach Cause of gastric ulcers Strong link to gastric cancer 50% of the world has it 80% are asymptomatic Until 1980, people didn’t think bacteria could live in the stomach because of its acidity. Ulcers were thought to be caused by stress or spicy food This bacterium is hard to culture Barry Marshall drank a culture of Helicobacter, got ill and showed the organism and the pathology on biopsy (then took antibiotics). He won a Nobel prize in 2005. Virulence factors : Molecular Koch’s Postulates, by Falkow (1988) 1. 2. 3. 4. 5. 6. Gene encoding factor present in strains of bacteria that cause disease Not present in avirulent strains Disrupting the gene reduces virulence Re-introduction of the gene reintroduces virulence. Gene is expressedduring infection. Specific immune response to gene protects the host. That’s it for lecture 1 from Gruenheid...Lecture 2 right below Ignaz Semmelweis : In the 1800s, the rate of death in childbirth was very high. Physicians did not scrub up/wash hands between patients. They commonly went from dissecting patients to delivering babies. Women who had babies in hospitals were 4x more likely to contact childbed fever. With handwashing, Semmelweis reduced the mortality to 1%. Practice wasn’t widely used until his death (ppl realized diseases were caused by microbes) Koch’s postulates demonstrated causative agents of anthrax and tuberculosis. Falkow followed the postulates with a genetic approach on what he called virulence factors. How are virulence factors acquired? Transfer of extrachromosomal genetic elements, plasmids and phages Many genes that encode bacterial virulence factors are encoded on plasmids and phages. These mobile genetic elements can transfer virulence factors between members of the same species or different species. Recombination can occur between the extrachromosomal elements and the bacterial chromosome, making the virulence gene chromosomal. Pathogenicity Islands : o Large segments of DNA that carry virulence genes. o Acquired during evolution of pathogen by horizontal gene transfer. Regulation of Bacterial Virulence Factors o Environmental factors control expression of virulence genes o Signals can turn the genes on. Others are specific to the bacterial niche within the host. Corynebacterium diphteriae Gene for diphtheria toxin regulated by iron. Higher expression in low iron. Low iron is characteristic of the host. Bordetella pertussis (whooping cough) Expression of virulent genes increased at body T compared to Rt o Type III Secretion Factors (works like a needle, somewhat...) Encoded by approximately 20 genes Present in G- negative pathogens (Salmnella, Shigella, Yersinia, E.Coli) Absent from non-pathogenic bacteria Secretion triggered by contact with host The arsenal of proteins varies greatly even though the set of genes no. o Type IV secretion systems look very much like conjugation apparatus Virulence Factors : Toxins Exotoxins – Secreted. Four types o AB exotoxins A subunit has enzyme activity (responsible for toxic effort). B mediates cell entry (binds to specific receptors on target cell). o Specific host site exotoxins (can be AB) Neurotoxins Target nerve tissue Botulinum toxin causes paralysis Enterotoxins Target intestinal mucosa Cholera toxin causes secretory diarrhea Cytotoxins Target general tissues Nephrotoxin (kidney) o Membrane-disrupting exotoxins Not AB Attack host cell membranes Lyse host cells by disrupting plasma membrane integrity Two types: Pore-forming exotoxins o Leukocidins : kill phagocytic leucocytes o Hemolysins : kill erythrocytes, leucocytes Phospholipases o Remove the charged polar heads from the phospholipid part of the host cell membrane. o Destabilizes the membrane, causing the host cell to lyse. o Superantigens Stimulates T cells to release cytokines Endotoxins – Part of bacterial cell o Heat labile proteins inactivated at 60-80 degrees o Among the most lethal substances known to man Botulinum toxin is the most poisonous substance naturally occurring A gram of crystalline toxin evenly dispersed and inhaled would kill 1mln ppl. o Associated with specific diseases, have specific mechanisms of action o Highly immunogenic (antitoxins = neutralize antibodies) o Easily inactivated to form toxoids – inactivated toxins used to elicit immune response o Unable to produce a fever in the host directly Toxigenicity Intoxications o Diseases that result from an entry of a specific preformed toxin into host. Botulinum Staphylococcus aureus (1/3 are carriers) o Doesn’t require entry of bacteria o Usually very fast onset o Different from infections in that, during an intoxication, the toxin is produced by a bacteria IN THE FOOD, before it is ingested. On the other hand, an infection involves the entry of the bacteria inside the patient. Spores are ingested, growth in GI tract, toxin produced inside the body. Both lead to paralysis though. Endotoxins LPS of G- bacteria Bound to the bacteria, released when cell lyses Some released during bacterial replication Toxic component is lipid A Heat stable Toxic only at high doses Weakly immunogenic Generally similar, despite source Produce general systematic effects Usually capable of producing general systematic effects (fever, shock, blood coagulation, weakness, diarrhea, inflammation, intestinal hemorrhage, fibrinolysis) Brings about these effects indirectly o Endotoxins interacts with host molecules and cells o Activating host systems o Interaction with macrophages and monocytes through binding of LPS-BS release cytokines which produce fever (IL-1, IL-6, TNF-alpha) Evasion of host defences by bacteria Have mechanisms to resist complement system, phagocytosis, and specific immune response. EHEC : an extracellular bacterial pathogens Cattle are the major reservoir o Asymptomatic carriers of EHEC in their intestine o EHEC is shed in manure and can contaminate meat during slaughter o Usually associated with ground beef, manure contaminated produce and water. o Many outbreaks occurred (Mexico, Canada,) o They have their pathogenicity islands as well Upon ingestion of contamination of food or water, bacteria colonize the intestinal tract of humans Adherence is mediated by Type III Secretion System (attaching/effacing lesions) implicated in colitis and diarrhea Shiga-like Toxins AB Toxins which acts on the lining of blood vessels (vascular endothelium) Inactivated protein synthesis by modifying RNA component of ribosomes leads to cell death This causes breakdown of the lining haemorrhages Implicated in more symptoms : bloody diarrhea, kidney failure Cattle lack the specific receptors for the toxin, which is why they are asymptomatic carriers. How does it work? Looks like Type II Secretion System. Throws in “translocated effector protein” through a needle look-alike. Mechanism of pedestal formation : EHEC has intimins that bind to “TiREHEC” bound to IRSp53, itself bound to EspFU, bound to NWASP that leads to actine polymerization... There is a tight junction disruption during EHEC infection. Depends on Type III-secreted effector proteins EspF, Map, NIeA Shiga Toxins (EHEC) : Shiga toxin (Stx) AB toxin : B subunit binds to lipid on the cell surface, whereas A subunit cleaves rRNA, causing an arrest to protein synthesis. Receptors on kidney, intestinal cells Leads to kidney damage and hemorrhagic colitis EHEC illness : Hemorrhagic colitis : watery diarrhea leading to bloody diarrhea Infectious dose may be as few as 10 organisms. 0-20% of patients (children, elders), develop haemolytic uremic syndrome: o Haemolytic anemia o Renal failure (most common cause of acute renal failure in kids) o Thrombocytopenia (decrease in platelets, tissue, haemorrhages) o Can lead to permanent loss of kidney function Can be fatal, may lead to neurological symptoms, will probably cause chronic renal problems. Prevention and treatment Contaminated drinking water o Leakage of sewage into pipes of fresh water o Boil water o Replace aging water supply systems Contaminated ground meat o Thorough cooking Contaminated juices o Pasteurization