Bacterial Pathogenesis Flashcards
Climate change alters the range of pathogens
Lyme disease-Borrelia burgdorferi
Carried by deer tick
Modern big bacterial killers
Tuberculosis caused 1.3 million deaths in 2022, second only to COVID-19 (Mycobacterium tuberculosis)
Pneumonia accounts for 14% of all deaths of children under 5 yrs old,
killing 740 180 children in 2019 (Streptococcus pneumoniae, H. influenzae most common)
Stomach ulcers experiment to prove it caused by bacteria
Dr. Barry Marshall
Helicobacter pylori
-Gram-negative bacterium, opportunistic pathogens
-ulcers
-Infects 30–50% of the population in the developed world
-Majority are asymptomatic
-Neutralizes the stomach acid by producing urease (enzyme)
-Causes inflammation, disrupts stomach mucosa, which can cause of gastric ulcers
-Strong link to gastric cancer – Only bacteria to be classified as a carcinogen by the WHO
How to define a pathogen?
Koch’s postulates
But:
Some “pathogens” may be isolated from healthy individuals without disease, some diseases have multiple causes
Some organisms are hard/impossible to culture, only 10 % of the bacteria are culturale
Disease can depend on the health status of the host, genetics of the host, environmental factors, site of introduction etc.
Not all host/bacteria interactions
lead to disease
Influence Factors
Bacterial:
-Route: position of get in contact
-Number
-Virulence potential
Host:
-host health status
-host defenses/genetics
Infection definition
When a pathogen becomes established in the body:
infection
Disease definition
Infection which produces signs & symptoms: disease
Symptoms definition
Subjective characteristics felt only by the patient
Signs definition
Objective manifestations observed or measured by others
Asymptomatic carriage
Infection without disease
Pseudomonas aeruginosa & CF
-Found in soil and water, can colonize skin and intestinal
tract
-Normally, our defenses are sufficient to prevent infection
-Cystic fibrosis patients: have a mutation at a specific transporter in their epithelial cells that lie in lung
thick mucous in lungs – cannot clear bacteria
-Cause of death of many CF patients
-“Opportunistic infection”: bacteria take the advantage of the opportunity to colonize the lungs of people with cystic fibrosis
other infections impact susceptibility
Tuberculosis is the direct cause of death of >50% of all AIDS patients(HIV positive) worldwide
“Secondary infection”: An infection that develops in an individual who is already infected with a different pathogen
Microbiome impacts susceptibility
Microbiome impacts susceptibility
Intestine have many bacteria help us
Colonization resistance: keep the population of harmful or potentially harmful bacteria a little bit at bay
Required steps of pathogenesis of bacterial disease
- Maintain a reservoir
- Be transported to the host
- Adhere to, colonize, and/or invade host
- Multiply or complete life cycles on or in host
- Evade host defenses
- Leave host and return to reservoir or enter new host
Maintaining a reservoir —concepts
The reservoir of an infectious agent is the habitat in which the agent normally lives, grows, and multiplies
Include human, animals, and the environment
The reservoir may or may not be the source from which an agent is transferred to a host.
Human reservoirs may or may not show the effect of illness
A carrier is a person with inapparent infection who is capable of transmitting the pathogen to others.
Reservoir
Specific for each pathogen
common reservoirs for human pathogen:
-Animals
• Cow: Enterohemorrhagic E. coli
• Poultry: Salmonella and Campylobacter
-Environment
• Soil: Clostridium tetani
-Other humans
• e.g. Typhoid Mary(a healthy carrier worked as a cook) for Salmonella typhi
Direct transport of the bacterial pathogen to the host
Direct contact
• Skin-skin, kissing, sexual contact
Droplet spread
• relatively large, short-range,
• Sneezing, coughing, even talking
Indirect Transport of the bacterial
pathogen to the host
Airborne
– Small particles suspended in air for long periods
Vehicle-borne
– indirectly transmit an infectious agent- food, water, biologic products (blood), and fomites (inanimate objects such as handkerchiefs, bedding, or surgical scalpels).
Vector-borne
– Living beings such as mosquitoes, fleas, and ticks
may carry an infectious agent through purely
mechanical means or may support growth or changes in the agent.
Adherence
mediated by special molecules or structures
called adhesins
Colonization
establishment of a site of microbial reproduction
on or within host
Types of adhesions
Non-fimbrial adhesion: embedded in membrane
Fimbrae: hairy surface
Type IV pili: threads
Curli: coiled surface, curved/curled
Adhesins
They attach to specific structures on host cells
Usually proteins, glycoproteins, or glycolipids
Presence or absence of the receptor can determine the host susceptibility
1 amino acid makes all the difference
Listeria monocytogenes non-fimbrial adhesin
Binds the mammalian protein E-cadherin
Humans and guinea pigs are susceptible to Listeria
– Mice are not.
Mice have a single amino acid difference in E – cadherin
-Changing this amino acid makes the mice susceptible
Invasion of the bacterial pathogen
- Can be active penetration into host cells
-ex. Type 3 secretion system: inject bacterial proteins into the host cell, can zombifies the actin cytoskeleton of the host cell, the host cell start to rearrange all its action to engulf the salmonella and bring it inside the host cell - Can be active penetration between host cells
Ex. Secrete factors or other ways to chew up these tight junctions and the bacteria can slip in between cells - Can be passive
-not related to pathogen itself
Ex. Skin lesions, insect bites, wounds
-can use existing host pathways of internalization
Ex. Phagocytosis
Multiply or complete life cycles on or in host
Occurs when pathogen finds appropriate environment within host
Important factors include: access to nutrients, pH, temperature, redox potential, protection from host
“attack”
Different bacterial pathogens have evolved to survive and multiply within different environments within the host
Intracellular/extracellular pathogens
Some bacteria invade specific cells and have adapted strategies to live inside
Ex. Mycobacteria growing inside a macrophage
Evasion of Host Defenses by Bacteria
mechanisms to resist host defenses such as complement system, phagocytosis, and specific immune responses
Bacterial capsule
Composed of chemicals not recognized as foreign
Slippery and difficult for phagocytes to engulf
Leaving the host
Most bacteria leave by passive mechanisms
– in feces, urine, droplets, saliva, or desquamated (sloughed) cells
Many symptoms of disease aid in this process
– Sneezing, coughing, runny nose, diarrhea
Different strains might have different virulent
Commensal E. coli strains rarely cause disease
Different pathogenic strains cause different diseases
Virulence factors confer an increased ability to cause disease, what can they improve?
- Colonization or invasion of the host
- Ability to multiply and complete life cycles on or in host
- Ability to evade host defenses
- Ability to leave host and enter new host
“Molecular Koch’s postulates”
a framework to define virulence factors
- Gene is present in strains of bacteria that cause the disease
- Not present in avirulent strains
- Disrupting the gene reduces virulence
- Re-introduction of gene restores virulence.
- The gene is expressed during infection
- Specific immune response to the gene protects
Receptor decoys used as anti-virulence drugs
E.coli with type 1 fimbriae, which bind with oligomannosides, small molecule mannoside inhibitors can bind with fimbriae, therefore prevent the bind with host cell
Capsule
Outside the cell wall
Usually polysaccharide, can be other
Can protect from phagocytosis by host cells
Streptococcus pneumoniae:
– With capsule: kills mice
– No capsule: no disease
Virulence-associated secretion systems
Different types of (3, 4, 6)
Type III secretion system
- Encoded by approximately 20 genes
- Present in Gram-negative pathogens
(Salmonella, Shigella, Yersinia…)
-Injects bacterial proteins directly into host cells
“Syringe” genes: similar between the different species
Injected proteins and cellular effects: vary between the different bacteria
Related to the flagella’s basal body (evolution)
Different T3SS effectors
Salmonella: T3SS induces uptake into host cells
Yersinia: T3SS blocks uptake into host cells
Toxins
Endotoxin - part of the bacterial cell
Exotoxins – secreted
Endotoxin
LPS of Gram-negative bacteria
Structural component of Gram –ve OM
•released when bacteria lyses
•released during bacterial multiplication
Toxic component is Lipid A
Heat stable
Toxic only at high doses
How does LPS cause its effect?
Indirectly
-No enzymatic activity on host
-Interaction with host cells through binding of a receptor complex
-Induced transcriptional response in the host cell
-Increased production of host cell proteins which produce severe host-mediated inflammatory response
-In the case of sepsis: fever, increased heart rate, increased breathing rate, low blood pressure…
Example of exotoxin
Botulinum toxin (Clostridium botulinum)
-the most poisonous naturally occurring substance in the world
-One of the greatest threats for biological warfare
-Cleaves a protein involved in neurotransmission from motor neurons to muscles
Effects of Botulinum toxin
Double vision/blurred vision
Droopy eyelids
Slurred speech
Difficulty swallowing
Muscle weakness
Injection of minute amounts leads to localized paralysis
Characteristics of Exotoxins
Usually easily inactivated (eg by heat)
inactivated toxin can be used to elicit immune response
Toxin-specific antiserum can be used to treat disease
Antitoxin= antibody used to neutralize a specific toxin
Categories of Exotoxins
• AB exotoxins
– A subunit has enzyme activity
– B subunit mediates cell binding/entry
– Both activity and binding can vary depending on specific toxin
• membrane-disrupting exotoxins
– Attack host cell membranes
– E.g. hemolysins, phospholipases
• Superantigens
– Stimulates T cells —> exaggerated immune response
• Can also be categorized by site of action: neurotoxin, enterotoxin etc.
Diversity of AB Toxins
Different AB toxins have:
• Different receptors on host cells
• Different enzymatic activities
• Different biological effects
• Similar overall organization
Membrane-disrupting exotoxins
Pore-forming and phospholipases
Intocxications
-Does not require entry of bacteria into host or bacterial replication in host to cause disease
-diseases that result from entry of a specific pre-formed toxin into host
-Usually very fast onset: e.g. 30 min- 6 h
Example of intoxication
Bacillus cereus
• Spore forming bacteria found in the soil and several foods
• Produces a toxin that causes vomiting
• Contamination and improper storage of food-> growth
• Ingestion of toxin pre-formed in food-> vomiting
• Onset within 1–5 hours of ingestion
• Recovery usually within 6–24 hours
Enterohemorrhagic E. coli (EHEC) transmission & virulence
Cattle are asymptomatic carriers (reservoir)
Outbreaks commonly associated with ground beef, manure-contaminated produce
Infectious dose may be as few as 10 organisms
EHEC illness
• Diarrhea which can become bloody (hemorrhagic colitis)
• 0-20% of patients: hemolytic uremic syndrome (HUS):
– Hemolytic anemia
– Platelet deficiency
– Kidney failure
• 50% of HUS patients: chronic renal problems
• 25% of HUS patients: neurological symptoms (seizures, stroke, coma)
• Fatality of HUS: 3-5%
EHEC’s T3SS
Inject Tir into host cell : a protein inserts into the host cell membrane and becomes areceptor for EHEC on the host cell
~30 other proteins which dissociate tight junctions between intestinal epithelial cells, block host phagocytic pathways and interfere with the host immune response
EHEC—Shiga toxin
• AB toxin
• Encoded by bacteriophages which have integrated into the chromosome (“prophage”)
• B subunit binds specific glycolipids on host cells (Gb3)
• A subunit inhibits protein synthesis by modifying the 60S subunit of the ribosome
Correlates of Shiga toxin receptor with disease
• Present in intestinal epithelium ->bloody diarrhea
• Present in high amounts in kidney-> kidney problems
• Present in neurons-> neurological complications
• Absent in cow intestine -> asymptomatic carriers
EHEC treatment
• Supportive care and monitoring for the development of complications
• Antibiotic therapy NOT recommended: lyses of EHEC will release more toxin (increased risk of HUS)
• Antiperistaltic agents (eg imodium) not: help EHEC to gather and attach recommended (increased risk of HUS)
• HUS: treat the symptoms, watch and wait
– Fluid administration
– Platelet, RBC transfusion
– Kidney dialysis
Prevention of EHEC
• Handwashing
• Thorough cooking of beef
• Keep raw/cooked utensils separate
• Pasteurization for milk, juice
