Infections Flashcards
Lecture 1 topics covered and LO
- Overview: a little history and current importance of infectious disease
- Molecular strategies used by pathogens to cause disease
- An example – enterohaemorrhagic Escherichia coli
Infectious disease studies are usually focussed on mammals. why is this the case?
- studies focus on mammals… but microbe’s rule
- Studies done on mammals to protect our own health and pets etc. when curing disease as opposed to archaea and bacteria
What did the Hippocrates do in 460-377 B.C.?
Idea that disease might be associated with physical environment
Tell me the scientist who put forward ideas about Germ theory and when in time this was?
What were some of their ideas?
Anton Van Leeuwenhoek (microscopy and animalcules)
- Developed microscopes
- Described the first microorganisms in water and dental plaque in 1683
- Names the single cell bacteria and protists as ‘animalcules’
Tell me about Edward Jenner’s work in 1749-1823
- Pioneered clinical trials for vaccination to control spread of smallpox using similar cowpox
- Jenner’s work influenced many others, including Louis Pasteur who developed vaccines against rabies and other infectious diseases
Tell me about Ignas Semmelweis work in the 1840s
Pioneered handwashing to help prevent the spread of septic infections in mothers following birth
Tell me about John Snow and his contribution to infectious disease history
- Father of epidemiology
- Careful mapping of cholera cases in East London during cholera epidemic of 1854
- Traces source to a single well on Broad street that had been contaminated by sweage
- Source tracking done to this day for corona e.g., lateral flow testing
nb. epidemiology is the study (scientific, systematic, and data-driven) of the distribution (frequency, pattern) and determinants (causes, risk factors) of health-related states and events (not just diseases) in specified populations (neighborhood, school, city, state, country, global).
Tell me about Louis Pasteurs work in the 1860s
- Disproved spontaneous generation; fermentation is caused by microbial growth
- Nothing grew in boiled broths when a filter in place or tortuous tube, therefore living organisms that grew in such broths came from outside, as spores on dust, rather than being generated within the broth
- Developed weakened anthrax vaccine, immunised cattle; rabies etc
- Often regarded as the father of germ theory and bacteriology, together with Robert Koch
Tell me how you would define a pathogenic microbe (The Kochs postulates)
What type of pathogens is this definition for?
- Isolate the organism from every case of disease
- Propagate in pure culture in vitro
- Reproduce disease by exposing suitable host to organism
- Re-isolate the organism
Fine for acute pathogens, but what about chronic or minor conditions, multiple causes, pathogen that can’t be grown in the lab, absence of suitable host?
Tell me about the bacteria Helicobacter pylori
What two scientists did work on this topic?
Helicobacter pylori
- Causative agent of peptic ulcers and gastric cancer (more people in the world have stomach ulcers than any other disease)
- Fulfils Koch’s postulate but…
- Present in >50% of human population
- Doesn’t always cause disease
- May protect against oesophageal cancer
Robin Warren and Barry Marshall (drank solution with ulcer pathogens and infected themselves and then had to treat themselves with antibiotics in order to get better)
What work did Hans Christian Gram do in the 1880s?
- Pioneered gram stain
- Developed to detect bacteria in stained lung sections in Berlin hospital morgue but became universal method of differentiating bacteria
How does the Gram stain, stain the +ve and -ve Gram’s differently? How does it work?
- Based on the chemical and physical properties of their cell walls
- Detects peptidoglycan, a thick layer in Gram-positive bacteria to which crystal violet becomes trapped in the presence of iodine; ethanol dehydrate/ stabilises this but washes CV+I- out of Gram-negative bacteria
- Counterstain (safranin)
- A gram positive gives a purple/ blue colour, Gram negative results in a pink/red colour
Tell me about thyphoid Mary and George Soper in 1904 and how the ideas then relate to now?
- Mary Mallon, a cook responsible for most famous outbreaks of carrier-borne disease in medical history
- Recognised as Asymptomatic carrier during 1904 N.Y. typhoid fever epidemic
- When source of disease was traced, Mary has disappeared only to resurface in 1907 when more cases occurred
- Again, Mary fled, but authorities led by George Soper, caught her and had her quarantines on an island
- In 1910 the health department released her on condition that she never accept employment involving handling of food
- Four years later, Soper began looking for Mary again when two new epidemics broke out; Mary had worked as a cook in both places
- She was found and returned to North Brother Island, where she remained the rest of her life until a paralytic stroke in 1932 led to her slow death, six years later
- Similar to asymptomatic carriers for disease like COVID-19 (1/3 of cases at the moment are because they are asymptomatic)
Tell me about the 4 main pandemics, what bacteria they were due to and when they happened if a specific time frame?
4th is COVID-19 (2020- present)
Why are vaccines given every year for Influenza?
Whats the idea about COVID-19?
Influenza mutates at a very high rate and hence why lots of vaccines have to made and distributed each year
This could be the case with corona
Tell me about the bacteria Phytophora infestans and what it caused in 1845?
- Major fungal pathogen in broad host specificity
- Responsible for the Irish potato famine (1845-1847)
- 1 million deaths and massive emigration (population drop: 10 –> 4 million)
Microbial pathogens cause what % of deaths per year?
Tell me the leading causes of deaths due to infectious diseases?
25-33% of all deaths per year
Microbial pathogens today (resurgence of TB in the old world)
Tell me some trends seen in microbial pathogens today
- Emergence of new pathogens and return of old ones
- Effect of population increases
- Climate change
- Resistance to chemotherapeutics
Tell me some examples of Emergence of new pathogens and return of old ones trend in microbial pathogens?
E.g. Bartonella, cryptosporidium, Ebola, HIV, Helicobacter, Legionella and SARS have all emerged in the last 30 years; anthrax etc. as bioterrorism agents…
Tell me the Effect of population increase on microbial pathogens?
E.g. average number of malaria cases has quadrupled since the 1980s- at present rate of increase, half the world’s population will soon live in malaria-infected areas (as climate change is causing the cooler changes to warm up and the animal vectors for malaria can start to spread to those areas)
Tell me the effect of climate change on microbial pathogens
E.g. Northwards spread of malaria and West Nile Virus etc.
Tell me the stages of infection (an infection may be asymptomatic)
An overview of bacterial mechanisms for pathogenicity
Tell me the following about Attachment…
Host defence
Microbial strategies
Microbial mechanisms
Examples
- Host defence: microbes rinsed away from epithelial surface by host secretions (+ ciliary activity in respiratory tract); produce secretory immunoglobulin (IgA).
- Microbial strategies: bind firmly to epithelial surface (and if relevant, interfere with ciliary activity); inactivate IgA.
- Microbial mechanisms: surface molecule(s) on microbe attaches to receptor on epithelial cell (and, if relevant, production of ciliotoxic/ciliostatic molecule); produce IgA protease.
Tell me the following about Invasion…
Host defence
Microbial strategy
Microbial mechanisms
Examples
- Host defence: host cell membrane poses barrier to intracellular microbe
- Microbial strategy: traverse host cell membrane; endure or trigger uptake by phagocyte and resist killing
- Microbial mechanisms: fusion protein in viral envelope; inject proteins that trigger uptake and/or block intracellular killing
Tell me the following about Intracellular survival I
Host defence
Microbial strategies
Microbial mechanisms
Examples
- Host defence: ingestion and killing of microbe by phagocyte
- Microbial strategies: block phagocyte chemotaxis; kill phagocyte before or after phagocytosis; inhibit phagocytosis; inhibit lysosome fusion; resist killing and multiply in phagocyte
- Microbial mechanisms: release leucocidins, antiphagocytic haemolysins etc.; use of microbial cell wall or capsule components to inhibit phagocytosis; intracellular microbe inhibits one or more cell components needed for fusion of phagosome with lysosome; diversion of toxic compounds away from subcellular compartment containing microbe; ill-defined resistance mechanisms; escape from phagosome into cytosol
Tell me the following about intracellular survival II
Host defence (x2)
Microbial strategies (x2)
Microbial mechanisms (x2)
examples
- Host defence: restriction of Fe(III)
- Microbial strategies: microbe scavenges iron in competition with the host.
- Microbial mechanisms: microbe secretes molecules – siderophores - that bind Fe(III) in the host with extremely high affinity. The complexes are imported to the cytosol where the captured iron is released
- Host defence: production of reactive oxygen and nitrogen species
- Microbial strategies: microbe avoids oxidative burst or removes ROS and RNS
- Microbial mechanisms: microbe diverts vesicles bearing NADPH oxidase so that they don’t fuse with phagosome; production of enzymes (catalse; superoxide dismutase etc.) to inactivate ROS and RNS
Tell me the following about extracellular survival I?
Host defence
Microbial strategies
Microbial mechanisms
Examples
- Host defence: production of complement and antimicrobial peptides
- Microbial strategies: microbes alter their cell surfaces; inactivate complement; or bind complement non-productively
- Microbial mechanisms: sialylation of bacterial cell surface or alterations in LPS structure; production of proteases; C3b receptor on microbe competes with that on phagocyte to hinder production of membrane attack complex
Tell me the following about extracellular survival IV
Host defence
Microbial strategies
Microbial mechanisms
examples
- Host defence: antimicrobial immune responses
- Microbial strategies: infect glands or epithelial surfaces that are relatively inaccessible to circulating antibody or immune cells; suppress immune responses; vary microbial antigens either in a single host or during spread in host community
- Microbial mechanisms: trophism for cells in glands or on surfaces; invade immune tissues; switch on different surface antigens; use of mutation and/or genetic recombination
Tell me the following about Shedding- exit strategies
Host defence
Microbial strategies
Microbial mechansism
Examples
- Host defence: Apart from innate and acquired immunity, none apparent
- Microbial strategies: stimulate host processes that increase chances of transmission by key routes: respiratory, faecal-oral, or venereal; transmission by other routes, e.g. from blood via arthropods or needles; milk or saliva
- Microbial mechanisms: trigger sneezing; trigger diarrhoea; induction of processes in microbe that favour survival in biofluids and/or the environment (resistance to desiccation etc.)
Tell me about the cholera disease caused by Vibrio cholerae
- What is the mechanism behind the disease?
- What did people die of when they had cholera?
Lethality of bacteria protein toxins
Tell me the key features of Enterohaemorrhagic E.Coli (EHEC)?
- Major food-borne infectious pathogen
- Causes diarrhoea, haemorrhagic colitis, haemolytic uraemic syndrome
- Destruction of red blood cells (hemolytic anemia), destruction of platelets (responsible for clotting; low counts = thrombocytopenia), and acute renal failure.
- Most common cause of acute renal failure in children
- Significant health risk due to disease severity, lack of effective treatment and the potential for large-scale outbreaks from contaminated food
950 reported cases in UK in 2005 (36% increase on previous year); USA estimates: ~75,000 p.a.
- Typically caused by E. coli O157:H7 serovar
- EHEC produce several toxins – major one is Shiga-like toxin (SLT)
- Adhere to enterocytes in large intestine and remove (‘efface’) microvilli
- Trigger characteristic structural changes on host cell known as attaching-effacing lesions
Tell me about EHEC and the ‘island’ of pathogenicity genes in the EHEC genome
- Genetic studies show EHEC has a >30 kb cluster of pathogenicity genes do not present in E. coli K-12
- Such clusters, termed Pathogenicity Islands, are common in disease-causing bacteria.
- Pathogenicity islands are acquired by horizontal gene transfer from other bacteria and typically have a C + G content that differs from the rest of the genomic DNA
Tell me about the EHEC locus of enterocyte effacement (LEE)
- Major pathogenicity island in EHEC is termed Locus of Enterocyte Effacement (LEE)
- LEE encodes proteins that form a specialized secretion system that injects EHEC proteins into the host cell as well as some of the injected proteins
Tell me about the A and B subunits of Shiga-like toxin?
What are the stx1 and stx2 genes carried by?
- A subunit inhibits protein synthesis – cells are unable to recover once toxin is removed. A subunit is an N-glycosidase - specifically depurinates adenosine 4324 in 28S rRNA
- B subunits bind to ceramide host cell receptors, e.g globotriaosylceramide (Gb3): present in greater amounts in renal epithelial tissues (explains renal toxicity of Shiga toxin); also found in CNS neurons and vascular endothelium (blood vessels) (lead to neurotoxicity). Gb3 not present in human intestine.
- stx1 and stx2 genes carried by bacteriophage lysogens in EHEC cells
Activation and motility and adhesion factors?
Stx production occurs in the intestine. Lee mutants can still infect. Why?
Stx production occurs in the intestine. Lee mutants can still infect. Why?
- The bacteria can also cross the intestinal barrier through M cells on Peyers patches in ileum small intestine– long polar fimbriae adhesins
- In the lamina propria, bacteria enter, survive, and produce Stx within resident macrophages.
- Following replication of bacteria in macrophages, extensive Stx production induces host cell death.
- Subsequently, released Stx could cross the downstream blood vessels to reach the kidneys, intestine, and brain.
- Damage to these organs results in serious life-threatening complications in humans.
