ch. 15 - Microbial Mechanisms of Pathogenicity Flashcards
Components for the host pathogen interaction
- Invasion of the host through primary barriers
- Evasion of local and tissue host defenses by microbes
- Microbe replication, with or without spread in the body
- A hosts immunologic ability to eliminate or control the microbe
Pathology
study of disease
Etiology
study of the cause of disease
Pathogenesis
development of disease
Infection
multiplication of any parasitic organisms
Disease
disturbance in the state of health
- body can’t carry out all of its normal functions
Order of characteristics of infectious disease
Pathology can cause Etiology
Etiology can cause Pathogenesis
Infection can cause Disease
Microorganisms that can cause disease are known as
pathogens
Signs of Disease
- objective and measurable
- directly observed by a clinician
- changes in any vital signs may be indicative of disease
ex: fever of 102, fluid-filled rash
Symptoms of Disease
- subjective
- felt or experienced by a patient but cannot be confirmed or measured
- changes in any vital signs may be indicative of disease
ex: pain, fatigue
issue with medical professionals relying only on sign and symptoms to diagnose some diseases
medical professionals rely heavily on signs and symptoms to diagnose disease and prescribe treatment, however
- many diseases can produce similar signs and symptoms
Syndrome
A specific group of signs and symptoms
- e.g. chronic fatigue syndrome
Infectious disease
any disease caused by the direct effect of a pathogen/infectious agent
ex: Measles is highly infectious, caused by viral droplets. Ghonorrhea is not as contagious because transmission requires close contact
Noninfectious disease
Those not caused by pathogens.
Can be caused by genetics, the environment, poison etc.
Communicable or contagious diseases
Communicable - can be spread from host to host
Contagious - easily spread from person to person
ex: measles, hepatitis
Non-communicable disease
cannot be spread from host to host
ex: food poisoning, tetanus
iatrogenic disease
diseases that are contracted as the result of a medical procedure
Nosocomial disease
Diseases acquired in hospital settings
ex: patient, staff, visitor etc.
Zoonotic disease
transmitted from animals → humans
ex: rabies
Subclinical disease
no noticeable signs or symptoms (inapparent infection)
The five stages of disease
- incubation
- prodromal
- illness
- decline
- convalescence
stages of disease: Incubation period
occurs after the initial entry (infection) of the pathogen
- but before the first appearance of any signs or symptoms
→ insufficient number of pathogen particles present to cause signs and symptoms of disease
* can vary from a day or two to months
→ during this phase, the number of organisms rises in the body
* until the immune system recognizes that an invader is present
stages of disease: Prodromal period
occurs after the incubation period
* pathogen continues to multiply and host begins to experience mild symptoms
(e.g. aches and malaise)
immune system recognizes that an invader is present
* begins to attack the organism or virus
stages of disease: Period of illness
- occurs after prodromal period
- signs and symptoms are most obvious and severe (sore throat, fever)
- pathogen reaches peak numbers
- immune system is becoming more efficient at killing the pathogen
stages of disease: Decline Phase
- occurs after period of illness
- signs and symptoms begin to decline (e.g. fever decreases)
- however, patients may become susceptible to developing secondary infections because their immune systems are weakened
stages of disease: Convalescence period
- occurs after decline phase
- patient generally returns to normal functions
- the immune system is ready to fight future infections but
its ability to attack the same invader will wane over the long term (years)
Typhoid fever and cholera - the convalescing person carries the pathogenic microorganism for months or even years
fever
natural reaction to infection
- sweating, shivering, and feeling cold
- protective mechanism to fight infection
why are high body temperatures from fevers beneficial?
high body temperatures can help our immune system function better
- can also inhibit microbial growth
note: ideal growth temperature for many microbes is 37 degrees C
Pyrogens
substances that cause fever
- chemicals released by the immune system that cause the body temperature to rise, resulting in a fever
- fevers are meant to create an unfavorable environment for the pathogen
Acute disease
symptoms develop rapidly
ex: common cold
Chronic disease
disease develops slowly
ex: Tuberculosis
Subacute disease
symptoms between acute and chronic
Latent disease
disease with a period of no symptoms
- when the causative agent is inactive (dormant)
ex: cold sore produced by a reactivated herpesvirus hiding latent in nerve cells
Koch’s postulate
method for determining whether a particular microorganism was the cause of a particular disease
Koch’s postulates criteria
- the suspected pathogen must be found in every case of disease but not present in healthy individuals
- the suspected pathogen must be isolated from the diseased organism and grown in pure culture
- a healthy test subject infected with the suspected pathogen must develop the same signs and symptoms of disease as seen in postulate 1
- the pathogen must be re-isolated from the new host and must be identical to the pathogen from postulate 2
Limitations to Koch’s postulate
- it assumes pathogens are only found in diseased individuals, which is not true
- assumes all healthy tests subjects are equally susceptible
- assumes all pathogens can be grown in pure culture
Molecular Koch’s postulates
- Stanley Falkow proposed a revised form of Koch’s postulates in 1988
- relies not on the ability to isolate a particular pathogen, but rather to identify a gene that may cause the organism to be pathogenic
- usual harmless bacteria, such as E. coli, can acquire genes that now make them pathogenic
molecular Koch’s postulates criteria
- the phenotype (sign or symptom of disease) should be associated only with pathogenic strains of a species
- inactivation of the suspected gene(s) associated with pathogenicity should result in a measurable loss of pathogenicity
- reversion of the inactive gene should restore the disease phenotype
molecular Koch’s postulates criteria applied to Enterohemorrhagic E. coli (EHEC)
- EHEC causes intestinal inflammation and diarrhea, whereas nonpathogenic strains of E. coli do not
- one of the genes in EHEC encodes for Shiga toxin, a bacterial toxin (poison) that inhibits protein synthesis
- inactivating this gene reduces the bacteria’s ability to cause disease - by adding the gene that encodes the toxin back into the genome (e.g. with a phage or plasmid), EHEC’s ability to cause disease is restored
Pathogenicity
ability of a pathogen to cause disease
factors that pathogenicity depends on:
- virulence
- attenuation
Virulence
intensity of the disease produced by the pathogen
- avirulent (not harmful)
- virulent (harmful)
Attenuation
- weakening of the disease-producing ability of the pathogen
- attenuated vaccines contain crippled viruses or bacteria that are injected into a host to stimulate an immune response
Two indicators of virulence
1. median infectious dose (ID50)
- measured by determining how many microbes are required to cause disease symptoms in 50% of the experimental group of hosts
2. Median lethal dose (LD50)
- number of bacteria or virus particles (virions) required to kill 50% of an experimental group of animal hosts
actual infective dose for an individual depends on what factors?
- route of entry
- age
- health of the host
- immune status of the host
- environmental factors
- pathogen-specific factors
- e.g. susceptibility to the acidic pH of the stomach
what are the types of pathogens
- primary pathogen
- opportunistic pathogen
Primary pathogen
always cause disease
- regardless of the hosts’s resident microbiota or immune system
Opportunistic pathogen
can only cause disease when the host’s defenses are compromised
Stages of Pathogenesis
- exposure or contact
- adhesion
- invasion
- infection
- pathogen exit
stages of pathogenesis: Adhesion
the capability of pathogenic microbes to attach to the cells of the body
e.g.
Glycocalyx produced by bacteria in a biofilm allows the cells to adhere to host tissues and to medical devices such as the catheter
- glycocalyx is an adhesin
Adhesins/Ligands
both bind to receptors on host cells
- adhesins help ligands bind to receptors
Adhesins: any microbial factor that promotes attachment
- they also help form biofilms
examples of adhesins:
- Type I Fimbriae
- Type IV Pili
- cell wall components
- virus envelope receptors
ex:
1. Glycocalyx: Streptococcus mutans
2. Fimbriae: Escherichia coli
3. M protein (on fimbriae): *Streptococcus pyogenes
- helps with evading phagocytosis
stages of pathogenesis: Invasion
the entry of a pathogen into a living cell, where it then lives
- once adhesion is successful, invasion can proceed
Invasion involves the dissemination of a pathogen
- throughout local tissues or the body
ex: H. pylori is able to invade the lining of the stomach by producing virulence factors that allow it to pass through the mucin layer covering epithelial cells
- i.e. releases urease
Invasiveness
the ability of a bacterial pathogen to spread rapidly through tissues
Infection
multiplication of the pathogen
Portals of exit
generally the same as the portals of entry
- mucous membranes
- skin
- respiratory
- urogenital
- GI tract
Once organisms enter a host, how do they cause disease?
virulence factors
- pili
- enzymes that harm the host or prevent detection
- proteins that disrupt normal cellular function
- capsule
- enzymes that inactivate antibiotics
Pathogenicity island: a genomic island that contains virulence factors
Intracellular pathogens
avoid immune mechanisms
- by living inside host cells
Facultative intracellular pathogens
can invade host cells but can also survive outside the host cell
ex: Salmonella, Shigella, Listeria
Obligate intracellular pathogens
invade and reproduce inside a host cell only
ex: Rickettsia, Coxiella, Bartonella
what do pathogens produce to invade host cells
- exoenzymes
- toxins
exoenzyme
enzymatic virulence factors that help bacteria invade tissue and evade host defenses
- e.g. S. aureus produces coagulase, blood clot protects bacteria, also produces streptokinase which dissolves clot and releases bacteria to invade
four classes mentioned:
1. glycohydrolase
2. nuclease
3. phospholipases
4. proteases
exoenzymes: Glycohydrolases
degrades hyaluronic acid (i.e. hyaluronan) that cements adjacent cells together in the epidermis
- promotes spreading through tissues
e.g. Hyaluronidase S in S. aureus
hyaluronidase S in Staphylococcus aureus
hyaluronidase S = glycohydrolase (exoenzyme)
- allows for passage between cells that would otherwise be blocked (deeper tissues)
hyaluronidase produced by S. aureus degrades hyaluronan (hyaluronic acid) in the extracellular matrix
note: S. pyogenes also has hyaluronidase
exoenzyme: Phospholipases
degrades phospholipid bilayer (membrane) of host cells
- causing cellular lysis, and degrade membrane of phagosomes
- enables escape into the cytoplasm
e.g. Phospholipase C of Bacillus anthracis
exoenzyme: Nucleases
degrades DNA released by dying cells that can trap the bacteria,
- thus promoting spread
e.g. DNAse produced by S. aureus
exoenzyme: Proteases
degrades collagen in connective tissues to promote spread
- exoenzyme
e.g. Collagenase in C. perfringens
Toxin
substance produced by pathogen, contributes to pathogenicity
- allows microorganisms to colonize and damage the host tissues
e.g. patient with edema
- bacteria causes the release of pro-inflammatory molecules from immune cells
- these molecules cause an increased permeability of blood vessels, allowing fluid to escape the bloodstream and enter tissue
Toxigenicity
ability to produce a toxin
Toxemia
presence of toxin in the host’s blood
Toxoid
inactivated toxin used in a vaccine
- tetanus
Antitoxin
antibodies against a specific toxin
Exotoxins
toxic substances (proteins) produced inside pathogenic bacteria and are released outside the cell
- most commonly Gram-positive bacteria, as part of their growth and metabolism
exotoxins are secreted into the surrounding medium
- done during log phase
e.g. Clostridium botulinum which is a Gram-positive bacteria that produces exotoxins
Endotoxins
the lipid A portion of the lipopolysaccharides (LPS) that are part of the outer membrane of the cell wall of Gram-negative bacteria
- endotoxins are released when the bacteria die and the cell wall breaks apart
- fever, clotting factors, vasodilation, shock, and death may result when endotoxin is released into the blood
e.g. Salmonella typhimurium is a Gram-neg bacteria that produces endotoxins
exotoxin vs. endotoxin
exotoxins are proteins which are released from the cell
- endotoxins are composed of lipids and are part of the cell membrane
characteristics of endotoxins:
the source of endotoxins are Gram-negative bacteria
- it is found in the outer membrane (lipid A part of the lipopolysaccharide)
endotoxins have the ability to produce a fever
- unable to be neutralized by antitoxin
LD50 (lethal dose 50%) level is relatively large
- it is also relatively stable
the effect on tissues are non-specific
- cannot convert to a toxoid or be used as one
characteristics of exotoxins:
found in mostly Gram-positive bacteria
- they are protein by-products of the growing cell
exotoxins are unable to cause a fever
-they have a highly specific effect on tissues
- the LD50 (lethal dose median) is small
unstable
- they denature at temperatures above 60 degrees C
- UV can also denature them
converted to a toxoid by heat or chemical treatment
- the toxoid can be used against the toxin
- or can be neutralized by an antitoxin
what are the highly specific effects that exotoxins can do
1. plasma membrane disruption
2. cytoskeleton alterations
3. protein synthesis disruption
4. cell cycle disruption
5. signal transduction disruption
6. cell-cell adhesion disruption
7. vesicular trafficking
8. exocytosis
e.g. E. coli binds to the villus and secretes toxins that disrupt normal function (plasma membrane disruption)
exotoxin categories
grouped into three categories based on their target:
1. intracellular-targeting toxins
- A-B exotoxins
2. membrane-disrupting toxins
3. superantigens
Superantigens
- exotoxins that trigger an excessive activation of the immune and inflammatory response
- high fevers, low blood pressure, multi-organ failure, shock, and death
- e.g. pyrogenic (fever-producing) toxins of S. aureus such as toxic shock syndrome and S. pyogenes
A-B exotoxins
type of intracellular-targeting toxins (exotoxin) comprised of two components:
- A subunit and B subunit
A subunit
* A subunit is for activity and is toxic
* The A subunits of some AB toxins posses an ADP-ribosyltransferase enzymatic activity → changes specific host cell functions (e.g. diphtheria toxin)
B subunit
* B subunit binds host cell receptors → delivers the A subunit to the host cell
* Many B subunits are complexes of 5 units arranged as a ring
AB subunit mechanism
- The B component binds to the host cell by interacting with specific cell surface receptors
- the toxin is brought in through endocytosis
- once inside the vacuole, the A component separates from the B component
- A component gains access to the cytoplasm
- B subunit remains in the vacuole
Mechanism of diphtheria AB toxin
inhibits protein synthesis
- A subunit inactivates elongation factor 2 (EF-2) by transferring an ADP-ribose
→ this stops protein elongation, inhibiting protein synthesis, and killing the cell
type of A-B subunit that exhibits ADP-ribosyltransferase enzymatic activity
- which changes specific host cell functions
Primary infection
acute infection
- causes the initial illness
Secondary infection
opportunistic infection
- after a primary (predisposing) infection
occurs during decline stage of disease
- immune system susceptible to secondary infections here
Local infection
Pathogens are limited to a small area of the body
Systemic infection
an infection throughout the body
Focal infection
systemic infection that began as a local infection
Sepsis
toxic inflammatory condition
- arising from the spread of microbes → bloodstream,
- especially bacteria or their toxins, from a focus of infection
Bacteremia
bacteria in the blood
Septicemia
growth of bacteria in the blood
- causes sepsis
Viremia
viruses in the blood
virulence factor: immune evasion
evading the immune system is important to invasiveness
- specifically evading phagocytosis by cells of the immune system
examples:
- capsules formed around bacteria cells
- proteases break down host antibodies to evade phagocytosis
immune evasion (virulence factor): proteases
antibodies normally function by binding to antigens (molecules on surface of pathogenic bacteria)
- phagocytes bind to antibody → initiate phagocytosis
some bacteria can produce proteases (exoenzyme)
- they break down host antibodies → evasion of phagocytosis
immune evasion (virulence factor): fates of bacterial pathogens inside phagosome
a bacterial pathogen attaches to a host cell membrane
- pathogen induces phagocytosis
- once inside the phagosome, pathogen has 1 of 3 fates, depending on the pathogen:
fate 1: pathogen undergoes phagosome-lysosome fusion
- differentiates into a form that is able to replicate in the phagolysosome
- results in inclusion bodies
e.g. Coxiella burnetii
fate 2: no fusion of phagosome with lysosome
2a: pathogen prevents fusion with lysosome (e.g. Salmonella)
2b: phagosome moves to host membrane and expels pathogen into extracellular space (e.g. Salmonella Typhi)
2c: bacterium can be engulfed by a microphage and survive within the phagosome
2d: the macrophage travels to regional lymph nodes and disseminate the organism through the circulatory system
fate 3: pathogen lyses phagosome before fusion with lysosome
- and then moves throughout the cytoplasm into adjacent cells by forming actin tails
e.g. Shigella and Listeria
viral virulence: antigenic variation
changing surface antigens so that they are no longer recognized by the host immune system
- occurs in certain types of enveloped viruses
- this includes influenza viruses
exhibits two forms of antigenic variation
- antigenic drift
- antigenic shift
antigenic drift
form of slight antigenic variation
- occurs because of point mutations in the genes that encode surface proteins
antigenic shift
form of major antigenic variation
- occurs because of gene reassortment
Antigenic drift in influenza virus
mutations in the genes for the surface proteins neuraminidase and/or hemagglutinin
- result in small antigenic changes over time
Antigenic shift in influenza virus
- simultaneous infection of a cell with two different influenza viruses results in mixing of genes
- resultant virus possess a mixture of the proteins of the original viruses
process:
virus A & virus B both infect same host cell → mixing of genes
- A & B have different influenza viruses
- resultant virus has mixture of proteins from original viruses
(e.g. virus C has hemagglutinin from B and neuraminidase from A)
influenza pandemics can be traced back to antigenic shifts
protozoa: Antigenic Masking
protozoans coat themselves in host antigens
- to avoid detection by the immune system
protozoan pathogenesis: Antigenic Variation
some protozoans can alter their surface antigens to prevent antibody binding
- just like viruses and bacteria,
example: Trypanosoma brucei - the causative agent of sleeping sickness,
- contains hundreds of silent variant surface glycoproteins (VSG) genes that can become activated one at a time → different antigen with each VSG gene
antigenic variation in Typanosoma brucei
T. brucei coated with one type of variant surface glycoprotein (VSG) antigen (“green”)
- eventually, antibodies build up that can attack the green form of VSG and kill the cells
however, a few protozoa will begin expressing a different VSG (“blue”) that the antibody does not recognize
- these variants survive and repopulate the blood
this cycle continues because the T. brucei genome contains hundreds of silent VSG genes that can become activated
- one at a time is activated
protozoa: Intracellular Location
protozoans have found ways to live inside the host cell to prevent detection
- just like some bacteria
example:
* Toxoplasma species use an actin-myosin motor of their own
- to forcibly drive themselves into a host cell
protozoa intracellular location: Toxoplasma
- Toxoplasma approaching a host cell uses MIC proteins to attach to host cell membrane
- the myosin motor propels the organism through the membrane
- without forming a phagocytic vacuole - a protease located at the parasite’s posterior cleaves the adhesin
- allows internalization
protozoa: Immunosuppression
Some protozoans induce the secretion of anti-inflammatory cytokines
- to reduce the innate immune response
e.g. Plasmodium makes a protein that mimics human macrophage inhibitory factor
- this malarial protein alters the blend of cytokines
Medically important fungi include
Trichosporon species
- can infect hair, skin, and nails
Malassezia species
- infect skin to produce hyper pigmented patches
- a disease called tinea versicolor
Systemic fungal pathogens cause
diseases in:
- central nervous system
- GI tract
- tissues
- respiratory system (serious)
note: diseases all around the body
examples of pathogenic fungi that can produce virulence factors similar to bacterial virulence factors
Candida albicans is an opportunistic fungal pathogen
- produces adhesions (surface glycoproteins) → assist in spread and tissue invasion
- produces proteases and phospholipases → increases ability of the fungus to invade host tissue
Cryptococcus’ main virulence factor is capsule production
- causes pneumonia and meningitis
Histoplasma and Blastomyces are thermally dimorphic fungi
- most grow as hyphae at 25 degrees C
- when temperature rises to 37 degrees C (body temperature), they grow as yeast which is the most pathogenic form
human host defense mechanisms and fungal virulence factors
X. H: human host defense → F: fungal virulence factor
- aspect of fungal virulence factor
H: human, F: fungi
- H: toxic compounds production → F: robustness/stress resistance
- cell wall
- detoxification - H: recognition and phagocytosis → F: immune evasion
- masking of PAMPs: capsule, pigments
- escape from immune cells - H: inflammation → F: damage
- physical forces
- secreted enzymes
- toxins - H: epithelial barriers → F: adhesion/invasion
- biofilm formation
- translocation - H: nutritional immunity → F: growth in the host
- 37 degrees C (some forms of fungi can survive at body temp)
- host derived nutrients
- adaptation to niches - H: danger response → F: morphological transition
- yeast ↔ hypha
- spore ↔ yeast
- spore ↔ hypha
Mycotoxins
Fungal toxins
- Claviceps purpurea, a fungus that grows on rye and related grains,
- produces a mycotoxin called ergot toxin, an alkaloid responsible for the disease known as ergotism
Aflatoxin
virulence factor produced by the fungus Aspergillus
- type of mycotoxin
- enter the body via contaminated food or by inhalation
- chronic pulmonary disease aspergillosis
who is at highest risk for fungal infections
immunocompromised patients
Candida albicians can cause opportunistic infections if they breach normal innate defense mechanisms
host injury during most fungal infections is due primarily to…
collateral damage produced by the immune system
- as a result of fighting the infection
