Chapter 15: Microbial Mechanisms of Pathogenicity

What's Disease?

a condition where normal structure and/or function are damaged or impaired

What's Infection?

invasion of pathogen or parasite that lead to disease

Evidence for infection comes from what 2 things?

1. Signs

2. Symptoms

What are Signs?

- Things that can be DIRECTLY measured and visually observed by clinician

- Can be qualitative (yes or no) or quantitative

- Ex: blood cell count, rash, vital signs, antibodies, blood in urine

What are Symptoms?

- Things felt by patient that can't be measured

- Ex: nausea, pain, dizziness

What's a Syndrome?

groups of signs & symptoms that help indicate a particular disease

Signs & symptoms help do what?

direct towards diagnosis

Some patients are asymptomatic/subclinical. Explain what this means and provide an example.

- Only signs can be observed thru correct testing

- Ex: Patient w/ herpes & no symptoms

WHO's International Classification of Diseases (ICD) is used globally to what?

classify and monitor diseases

Diseases can be Infectious. Explain.

disease caused by direct effect of a pathogen

Diseases can be Communicable. Explain.

- Capable of spreading person-to-person

- Contagious - highly communicable disease that is easily spread

Diseases can be Iatrogenic. Explain.

- Acquired as a result of medical procedure

- All iatrogenic diseases are nosocomial

Diseases can be Nosocomial. Explain

acquired from hospital setting

Diseases can be Zoonotic. Explain.

acquired from animal

Diseases can be Non-communicable. Explain.

obtained from non-living thing like soil or contaminated object

Diseases can be Non-infectious. Explain.

not caused by pathogen

List what 3 disease types that Malaria falls under.

1. Communicable

2. Infectious

3. Zoonotic

List what 2 disease types that Sickle Cell Anemia falls under.

1. Non-communicable

2. Non-infectious (genetic)

What are the 5 stages of Infectious Disease?

1. Incubation

2. Prodromal

3. Illness

4. Decline

5. Convalescence

Describe Incubation.

- Initial entry of pathogen; replication begins

- No signs or symptoms

Describe Prodromal.

- Replication continues; host shows signs & symptoms

- Early in the infection with general responses (ex. inflammatory immune response, fatigue, fever)

Describe Illness.

- Signs & symptoms are most severe in host

- Highest number of pathogens

Describe Decline.

- Pathogen number starts to decrease

- Host's immune system is weak and most vulnerable to secondary infection

Describe Convalescence.

host starts to recover

What stage of Infectious Disease can patients be contagious?

all 5 stages depending on the pathogen

What's an Acute disease?

- Relatively short (hours/days/week)

- Ex: flu, COVID, GI issues

What's a Chronic disease?

- Longer time (months/years/lifetime)

- Ex: walking pneumonia, HIV (starts latent), chronic gastritis (H. pylori), hepatitis

What's a Latent disease?

- Comes in episodes; pathogen replicates when disease is active

- Ex: shingles, herpes, mononucleosis

What are Koch's Postulates?

- Set of standards that must be met to demonstrate that X pathogen causes X disease

- Developed 1884 and still used today

Explain Koch's Postulates exactly. (4 total)

1. Suspected pathogen must be found in every case of disease and not be found in healthy individuals

2. Suspected pathogen can be isolated and grown in pure culture

3. Healthy test subject infected w/ suspected pathogen must develop same signs and symptoms of disease as seen in postulate 1 (or original host)

4. Pathogen must be re-isolated from new host and must be identical to pathogen from postulate 2

What are the 3 assumptions by Koch that are WRONG?

1. Pathogens found ONLY in disease individuals

2. All subjects equally susceptible to infection

3. All pathogens can be grown in culture

What are Molecular Koch's Postulates?

- Postulates improved w/ molecular methodologies

- Overcame some of Koch's limitations

- Identifies gene instead of pathogen

Explain Molecular Koch's Postulates exactly. (3 total)

1. Phenotype (sign/symptom of disease) should be associated only w/ pathogenic strains of a species

2. Inactivation of suspected gene(s) associated with pathogenicity should result in measurable loss of pathogenicity (phenotype is not expressed)

3. Reversion of the inactive gene should restore the disease phenotype

There's still 2 limitations with Molecular Koch's postulates. Identify them.

1. Genetic manipulation of some organisms isn't possible w/ current techniques

2. Some diseases do not have suitable animal models

What's Pathogenicity?

ability of pathogen to cause disease

What's Virulence?

- Degree of pathogenicity

- Continuum among many pathogen types

Give an example of a highly virulent disease.

Bacillus anthracis induces severe signs & symptoms

Give an example of a low virulent disease.

Rhinovirus induces low signs & symptoms

What are the 2 ways Virulence can modeled in controlled experiments?

1. Median infectious dose (ID 50)

2. Median lethal dose (LD 50)

What's Median Infectious Dose (ID 50)?

- No. of pathogens required to infect 50% of those inoculated

- Keywords: number infected

Does this graph show ID 50 or LD 50?

- ID 50

- Know how to read the graphs and what the red lines are showing

What's Median Lethal Dose (LD 50)?

- No. of pathogens required to kill 50% of those infected

- Keywords: number of deaths

Does this graph show ID 50 or LD 50?

- LD 50

- Know how to read the graphs and what the red lines are showing

What's a Primary Pathogen? Give an example.

- Can cause disease in a host regardless of host's resident microbiota or immune system

- Enterohermorrhagic E. coli (mainly due to Shiga toxin)

What's an Opportunistic Pathogen? Give an example.

- Can only cause disease in situations that compromise host's defenses (protective barriers, immune system, normal microbiota)

- Candida albicans w/ disrupted microbiota, UTI caused by E. coli

What 4 factors can influence susceptibility to disease?

1. Drugs

2. Resident microbiota

3. Genetics

4. Age

What are the 5 stages pathogens go through to achieve Pathogenicity/Infection?

1. Exposure to host

2. Adhesion

3. Invasion

4. Infection

5. Transmission

Describe Exposure.

- Aka contact, can occur in many ways

- Pathogens must be exposed to portals of entry to begin adhesion

- Some portals are worse than others (ex. mucosa)

What are TORCH infections?

pathogens that can cross placental barrier as portal of entry

Describe Adhesion.

- Aka colonization

- Pathogens have varying capabilities of colonization

- Adhesion factors: Adhesins and Biofilm

What are Adhesins?

molecules/structures that aid in binding to certain host receptors

What's Biofilm?

- Production of community glycocalyx

- If enough glycocalyx is produced (slime), a biofilm forms

Describe Invasion.

- Occurs when colonization is established

- Pathogens generally produce toxins to allow further colonization into body/tissue and protection from immune system

How does Virulence affect Invasion? Provide an example.

- It plays a role in the DEGREE of invasion

- Ex: Helicobacter pylori urease production

Intracellular pathogens invade via...

endocytosis and evasion of host immune defenses

Describe the 2 Invasion Mechanisms.

1. Effector proteins secreted to trigger entry…membrane ruffling and pathogens can squeeze between ruffles (ex. Salmonella and Shigella spp.)

2. Surface proteins allow for binding to host cell (trojan horse approach)

List 2 examples of pathogens that can survive Phagolysosomes within WBCs.

1. Listeria monocytogenes

2. Mycobacterium tuberculosis

Describe Infection.

multiplication and replication leads to established host infection

What are the 3 types of Infections?

1. Local infection

2. Focal infection

3. Systemic infection

What's Local Infection?

- Small area of body

- Ex: one organ or one hair follicle

What's Focal infection?

pathogen or toxin spreads to secondary location

What's Systemic infection?

- Occurs throughout entire body

- Ex: septicemia

Primary infections can lead to....

Provide an example.

- Can lead to secondary infection of different pathogen

- Ex: HIV lowers immune system and opens door for yeast and others

- Ex: Rhinoviruses can lead to bacterial pneumonia

Describe Transmission.

- Persistence requires transmission to a new host through a portal of exit

- Route of spread is typically the same as the route of entry (ex. entry through GI tract = exit through GI tract)

Describe Virulence Factors.

- Pathogen product that assists in ability to cause infection & disease

- Dictate how severe & extensive a disease is

- Some have more than one = more virulent

What are the 4 examples of Virulence Factors?

1. Adhesion factors

2. Exoenzymes

3. Toxins

4. Immune evasion

Describe Adhesins.

- Found in all microbial types (viral/fungal/bacterial/etc.)

- Commonly found on fimbriae or pilli

- Can initiate biofilm formation in some species

What does -emia mean?

- Presence of pathogen in blood

- Many pathogens achieve invasion via bloodstream

What's -bacteremia?

bacteria in blood

What's -viremia?

viruses in blood

What's -toxemia?

toxins in blood

What's -septicemia?

bacteria present and actively multiplying in blood

Patients with septicemia (septic) can lead to....

shock (life threatening decrease in BP)

Describe how Shock happens.

- Bacteria engulfed by immune system phagocytes

- Release of tumor necrosis factor causes severe inflammatory reaction & loss of fluid from circulatory system

- Too much fluid loss causes a drastic decrease in blood pressure, which leads to organ failure

What are Exoenzymes?

extracellular enzymes used to invade host tissues

What are the 4 types of Exoenzymes?

1. Glycohydrolases

2. Nucleases

3. Phospholipases

4. Proteases

What do Glycohydrolases do? Give an example.

- Degrades hyaluronic acid that cements cells together to promote spreading through tissues

- Ex. Hyaluronidase S in S. aureus

What do Nucleases do? Give an example.

- Degrades DNA released by dying cells (bacteria & host cells) that can trap the bacteria, thus promoting spread

- Ex. DNAse produced by S. aureus

What do Phospholipases do? Give an example.

- Degrades phospholipid bilayer of host cells, causing cellular lysis

- Degrades membrane of phagosomes to enable escape into cytoplasm

- Ex: Phospholipase C of Bacillus anthracis

What do Proteases do? Give an example.

- Degrades collagen (protein) in connective tissue to promote spread

- Ex: Collagenase in C. perfringens

What are Toxins?

biological poisons that assist in ability to invade and cause tissue damage (toxigenicity)

What are Endotoxins?

- Lipopolysaccharides that triggers host inflammatory responses

- Can cause severe fever and shock

What are Exotoxins?

- Proteins mostly produced by Gram+

- Targets receptors on specific cells

Compare Endotoxin and Exotoxin Sources.

- Endotoxin = Gram-negative bacteria

- Exotoxin = Gram-positive (primarily)

Compare Endotoxin and Exotoxin Compositions.

- Endotoxin = Lipid A component of lipopolysaccharide

- Exotoxin = Protein

Compare Endotoxin and Exotoxin Host Effects.

- Endotoxin = General systemic symptoms of inflammation and fever

- Exotoxin = Specific damage to cells dependent upon receptor-mediated targeting of cells and MOAs

Compare Endotoxin and Exotoxin differences in Heat Stability.

- Endotoxin = Heat stable (because it is lipid based)

- Exotoxin = Most are heat labile, heat sensitive (will be on exam)

Compare Endotoxin and Exotoxin LD50s.

- Endotoxin = High (you need more endotoxin to kill somebody)

- Exotoxin = Low

What are the 2 ways to detect Endotoxins?

1. Limulus amebocyte lysate (LAL) Test

2. ELISA aka enzyme-linked immunosorbent assay

Describe the Limulus amebocyte lysate (LAL) Test to detect endotoxins.

- Blood cells of the horseshoe crab mixed w/ patient's serum

- Observed chromogenically or by coagulation

Describe ELISA to detect endotoxins.

uses antibodies to detect endotoxins

What're the 3 ways Exotoxins can be further divided?

1. Intracellular targeting

2. Membrane-disrupting

3. Superantigen

Describe Intracellular targeting.

- With A & B regions for activity and binding

- A subunit - activity, damages inside of the cell

- B subunit - binding, recognizes and attaches specific cell, allows endotoxin to be taken into the cell

- Ex: diphtheria & botulinum toxin

Describe Membrane-disrupting.

- Phospholipases that degrade bilayer membrane

- Ex: Bacillus anthracis & Rickettsia spp.

- Hemolysins & Leukocidins can target RBC, WBC, and other cells

Describe Superantigens.

- Trigger excessive production of cytokines by immune cell

- Cause strong, severe, and excess immune responses

- Ex: S. aureus & Toxic Shock Syndrome

What's Host Evasion?

mechanisms to evade phagocytosis

What are 2 examples of Host Evasion?

1. Capsules that enlarge bacterial cell so phagocytes can't engulf pathogens

2. Proteases digest host antibody molecules

What are 3 more examples of Host Evasion?

3. Mycolic acid in acid fast bacteria (M. tuberculosis) helps evade phagolysosomes

4. Coagulose pos. microbes can coagulate blood cells to keep immune cells out of reach

5. Alteration of cell surface proteins to hide from immune cell recognition (antigenic variation)

What properties of Virulence in Viruses are similar to bacteria?

adhesins & antigenic variation

What are 2 examples of Virulence in Viruses being similar to bacteria?

1. HIV glycoprotein 120 for binding to CD4 T-cells

2. Influenza virus' high mutation of envelope spikes allows for antigenic variation