ch. 15 - Microbial Mechanisms of Pathogenicity Flashcards
1
Q
Components for the host pathogen interaction
A
- 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
2
Q
Pathology
A
study of disease
3
Q
Etiology
A
study of the cause of disease
4
Q
Pathogenesis
A
development of disease
5
Q
Infection
A
multiplication of any parasitic organisms
6
Q
Disease
A
disturbance in the state of health
- body can’t carry out all of its normal functions
7
Q
Order of characteristics of infectious disease
A
Pathology can cause Etiology
Etiology can cause Pathogenesis
Infection can cause Disease
8
Q
Microorganisms that can cause disease are known as
A
pathogens
9
Q
Signs of Disease
A
- 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
10
Q
Symptoms of Disease
A
- 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
11
Q
issue with medical professionals relying only on sign and symptoms to diagnose some diseases
A
medical professionals rely heavily on signs and symptoms to diagnose disease and prescribe treatment, however
- many diseases can produce similar signs and symptoms
12
Q
Syndrome
A
A specific group of signs and symptoms
- e.g. chronic fatigue syndrome
13
Q
Infectious disease
A
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
14
Q
Noninfectious disease
A
Those not caused by pathogens.
Can be caused by genetics, the environment, poison etc.
15
Q
Communicable or contagious diseases
A
Communicable - can be spread from host to host
Contagious - easily spread from person to person
ex: measles, hepatitis
16
Q
Non-communicable disease
A
cannot be spread from host to host
ex: food poisoning, tetanus
17
Q
iatrogenic disease
A
diseases that are contracted as the result of a medical procedure
18
Q
Nosocomial disease
A
Diseases acquired in hospital settings
ex: patient, staff, visitor etc.
19
Q
Zoonotic disease
A
transmitted from animals → humans
ex: rabies
20
Q
Subclinical disease
A
no noticeable signs or symptoms (inapparent infection)
21
Q
The five stages of disease
A
- incubation
- prodromal
- illness
- decline
- convalescence
22
Q
stages of disease: Incubation period
A
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
23
Q
stages of disease: Prodromal period
A
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
24
Q
stages of disease: Period of illness
A
- 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
25
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
26
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
27
fever
**natural reaction to infection**
- sweating, shivering, and feeling cold
- protective mechanism to fight infection
28
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
29
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_
30
Acute disease
symptoms develop rapidly
ex: common cold
31
Chronic disease
disease develops slowly
ex: Tuberculosis
32
Subacute disease
symptoms between acute and chronic
33
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
34
Koch's postulate
method for determining whether a particular microorganism was the cause of a particular disease
35
Koch's postulates criteria
1. the suspected pathogen must be found in every case of disease but not present in healthy individuals
2. the suspected pathogen must be isolated from the diseased organism and grown in pure culture
3. a healthy test subject infected with the suspected pathogen must develop the same signs and symptoms of disease as seen in postulate 1
4. the pathogen must be re-isolated from the new host and must be identical to the pathogen from postulate 2
36
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
37
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
38
molecular Koch's postulates criteria
1. the phenotype (sign or symptom of disease) should be associated only with pathogenic strains of a species
2. inactivation of the suspected gene(s) associated with pathogenicity should result in a measurable loss of pathogenicity
3. reversion of the inactive gene should restore the disease phenotype
39
molecular Koch's postulates criteria applied to Enterohemorrhagic E. coli (EHEC)
1. EHEC causes intestinal inflammation and diarrhea, whereas nonpathogenic strains of E. coli do not
2. 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
3. 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
40
Pathogenicity
**ability of a pathogen to cause disease**
**factors that pathogenicity depends on:**
- virulence
- attenuation
41
Virulence
**intensity of the disease produced by the pathogen**
* avirulent (not harmful)
* virulent (harmful)
42
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
43
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
44
actual infective dose for an individual depends on what factors?
1. route of entry
2. age
3. health of the host
4. immune status of the host
5. environmental factors
6. pathogen-specific factors
- e.g. susceptibility to the acidic pH of the stomach
45
what are the types of pathogens
- primary pathogen
- opportunistic pathogen
46
Primary pathogen
**always cause disease**
- regardless of the hosts's resident microbiota or immune system
47
Opportunistic pathogen
can only cause disease when the *host's defenses are compromised*
48
Stages of Pathogenesis
1. exposure or contact
2. adhesion
3. invasion
4. infection
5. pathogen exit
49
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*_
50
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
51
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
52
Invasiveness
the ability of a bacterial pathogen to spread rapidly _through tissues_
53
Infection
multiplication of the pathogen
54
Portals of exit
generally the same as the portals of entry
* mucous membranes
* skin
* respiratory
* urogenital
* GI tract
55
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
56
Intracellular pathogens
**avoid immune mechanisms**
- by living _inside_ host cells
57
Facultative intracellular pathogens
can invade host cells but can also survive outside the host cell
ex: *Salmonella*, *Shigella*, *Listeria*
58
Obligate intracellular pathogens
**invade and reproduce inside a host cell _only_**
ex: *Rickettsia*, *Coxiella*, *Bartonella*
59
what do pathogens produce to invade host cells
- exoenzymes
- toxins
60
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
61
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*
62
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
63
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*
64
exoenzyme: Nucleases
**degrades DNA released by dying cells that can trap the bacteria,**
- thus promoting spread
e.g. DNAse produced by *S. aureus*
65
exoenzyme: Proteases
**degrades collagen** in connective tissues to promote spread
- exoenzyme
e.g. Collagenase in *C. perfringens*
66
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
67
Toxigenicity
ability to produce a toxin
68
Toxemia
presence of toxin in the host's blood
69
Toxoid
**inactivated toxin used in a vaccine**
- tetanus
70
Antitoxin
antibodies against a specific toxin
71
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
72
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
73
exotoxin vs. endotoxin
**exotoxins** are _proteins_ which are _released from the cell_
- **endotoxins** are composed of _lipids_ and are _part of the cell membrane_
74
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_
75
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
76
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)
77
exotoxin categories
**grouped into three categories _based on their target_:**
**1.** intracellular-targeting toxins
- *A-B exotoxins*
**2.** membrane-disrupting toxins
**3.** superantigens
78
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*
79
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
80
AB subunit mechanism
1. The **B component** binds to the host cell by _interacting with specific cell surface receptors_
2. the toxin is brought in through **endocytosis**
3. 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**
81
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
82
Primary infection
**acute infection**
- causes the _initial illness_
83
Secondary infection
**opportunistic infection**
- after a primary (predisposing) infection
**occurs during _decline stage of disease_**
- immune system susceptible to secondary infections here
84
Local infection
Pathogens are **limited to a small area of the body**
85
Systemic infection
an infection _throughout the body_
86
Focal infection
**systemic infection** that _began as a local infection_
87
Sepsis
**toxic inflammatory condition**
- arising from the _spread of microbes → bloodstream_,
- especially _bacteria or their toxins_, from a focus of infection
88
Bacteremia
bacteria in the blood
89
Septicemia
**growth of bacteria** in the blood
- causes sepsis
90
Viremia
viruses in the blood
91
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
92
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
93
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**
94
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
95
antigenic drift
**form of _slight_ antigenic variation**
- occurs because of point mutations in the genes that encode surface proteins
96
antigenic shift
form of **_major antigenic variation_**
- occurs because of *gene reassortment*
97
Antigenic drift in influenza virus
**mutations in the genes for the _surface proteins neuraminidase and/or hemagglutinin_**
- result in _small_ antigenic changes over time
98
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_
99
protozoa: Antigenic Masking
**protozoans coat themselves in host antigens**
- to avoid detection by the _immune system_
100
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
101
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
102
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
103
protozoa intracellular location: Toxoplasma
1. Toxoplasma approaching a host cell uses MIC proteins to attach to host cell membrane
2. the myosin motor propels the organism through the membrane
- _without forming a phagocytic vacuole_
3. a protease located at the parasite's posterior cleaves the adhesin
- allows internalization
104
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_
105
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*
106
Systemic fungal pathogens cause
**diseases in:**
- central nervous system
- GI tract
- tissues
- respiratory system (serious)
note: diseases all around the body
107
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_
108
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
1. H: toxic compounds production → F: robustness/stress resistance
- cell wall
- detoxification
2. H: recognition and phagocytosis → F: immune evasion
- masking of PAMPs: capsule, pigments
- escape from immune cells
3. H: inflammation → F: damage
- physical forces
- secreted enzymes
- toxins
4. H: epithelial barriers → F: adhesion/invasion
- biofilm formation
- translocation
5. 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
6. H: danger response → F: morphological transition
- yeast ↔ hypha
- spore ↔ yeast
- spore ↔ hypha
109
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
110
Aflatoxin
virulence factor produced by the fungus *Aspergillus*
- type of mycotoxin
* enter the body via contaminated food or by inhalation
* chronic pulmonary disease aspergillosis
111
who is at highest risk for fungal infections
immunocompromised patients
*Candida albicians* can cause _opportunistic infections_ if they breach normal innate defense mechanisms
112
host injury during most fungal infections is due primarily to...
collateral damage produced by the immune system
- as a result of fighting the infection
