Bacterial Pathogenesis and Host Defense

Question 1

Overview of pathologic effects of infection:

Answer 1

Direct Effects:

Indirect Effects due to immune cells via natural immune mechanisms:

Indirect Effects via adaptive immune mechanisms (hypersensitivity)

Once virus can affect host in all 3 ways at once. With viruses, need lots of them to have their affect. Some baceria (like gram neg’s that release endotoxins) can cause disease w/o limited #.

Answer 2

Hypersensitivity –> many issues

Question 3

Important Terms

Answer 3

Pathogen – bacteria capable of causing disease

Virulence – quantitative measure of pathogenicities measured by the number of bacteria required to cause disease

LD50 – number of bacteria necessary to kill half the host

ID50 – number of bacteria necessary to cause infection in half the hosts

Virulence Factors – properties of a bacteria which assist in causing disease ex: pili, capsules, toxins, etc.

Question 4

Stages of Bacterial Pathogens

Answer 4

1. Transmission from an external source into the body
2. Evasion of initial host defenses
3. Attachment to mucous membranes
4. Colonization at attachment site
5. Sometimes spread and reattachment
6. Disease symptoms caused by toxins or tissue invasion followed by inflammation
7. Non specific and specific immune host responses
8. Progression or resolution of the disease or resolution

Question 5

Mechanisms of Bacterial Disease

Answer 5

1. Tissue invasion followed by inflammation
2. Toxins (exotoxins…enter body from eating food. Don’t have to replicate. and endotoxins also don’t need to replicate, but need enough that endotoxin is sufficient tot cause disease…gram-‘s)
3. Immunopathogenesis eg. Rheumatic fever

Question 6

Transmission Mechanisms I

Answer 6

Human to human
*Direct contact cg infections mono

*Non-direct contact eg. fecal-oral

*Transplacental

*Transferred blood products or contaminated needles

Question 7

Transmission Mechanisms II

Answer 7

II. Non-human to human
*Contaminated soils eg. Tetanus

*Contaminated water eg. Legionnaires’ disease

*Direct from animals eg. Cat Scratch fever

*Insect vectors eg. Lyme disease

Question 8

Portals of Entry

Answer 8

Respiratory tract - largest route

GI tract - 2nd largest route

Skin

Genital tract

Question 9

Virulence Factors I.

Answer 9

I. Bacterial Structures
Pili eg. N. gonorrhea to urinary tract epithelium

Capsules eg. Strep. pneumonia

Glycocalyx eg. Strep. viridans in heart valves
Endotoxin eg. Gram negative bacteria

Biofilms eg. Pseudomonas in cystic fibrosis patients
Bacterial Secretion Systems eg. T3SS in Salmonella typhimurium

Question 10

Virulence Factors II.

Answer 10

II. Secreted Enzymes
Collagenase & hyaluronidase eg. Strep. pyogenes cellulitis

Coagulase eg. Helps coat Staph. aureus with fibrin to help protect from phagocytosis

Immunoglobulin A protease eg. Degrades IgA (immunoglobulin) allowing Strep. Pneumonia to adhere to mucous membranes

Leukocidins Destroy neutrophilic leukocytes and macrophages eg. Staphylococci and group A Streptococci

Question 11

Virulence Factors III

Answer 11

III. Other Bacterial Factors
*M protein - antiphagocytic protein produced by Strep. pyogenes

*Protein A - binds to IgG and prevents activation of complement that is necessary to lyse

*Invasins - bacterial molecules which promote bacterial entry or contact with host cells - eg. Heliobacter pylori

*Outer membrane proteins - produced by Yersinia species to inhibit phagocytosis and cytokine production
***Pathogenicity Islands (PAIs) – code for groups of virulence factors particularly in Gram negatives - get rid off pathogenicity island, bacteria can’t cause disease. some islands are located on their chromosomes

Answer 12

IV. Exotoxins
Polypeptides secreted by bacteria

• **Become toxoids when treated with formaldehyde, and/or heat and used for protective vaccines*
• **Frequently have an A-B subunit structure (A portion has toxic activity and B portion is involved in binding to cells)*
• **Are genetically coded on the bacterial chromosome, plasmid or phage*

Have one of five biological effects:
^Alter cellular components
*Are superantigens
^Inhibit protein synthesis
^Increase synthesis of cAMP
^Alter nerve impulse transmissions

Question 13

Exotoxin Action 1

Answer 13

He went trough this fairly thoroughly - “know later”

Question 14

Exotoxin Action 2

Type 3 bacteria w/ injectosomes that secrete exotoxin.

Antibody cant prevent these b/c cell injects the endotoxin rather than through receptor (which antibody essentially normally blocks)

Answer 14

Question 15

Table 2.2 - re-examine this…
Superantigens–> cytokinines –> bad effects

Salmonella - type 3 ctyotoxin

Diptheriea toxin resides on phage. If get phage out of diptheria cell, diptheria can’t cause disease.

Increased synth of cAMP. –> problems for cell

Alterned nerve impulse transmission

Question 16

Lots of diseases associated with production of exotoxins…

example; superantigens - toxic shock

Question 17

Virulence Factors V.

Answer 17

IV. Endotoxins
Are integral parts of the cell wall of Gram negative rods and cocci

Involve the Lipid A component of lipopolysaccharide

Only weakly antigenic; no toxoids made

Induced biological effects focus on fever and shock

Question 18

Biological Effects of Endotoxin

Answer 18

Induce the release of endogenous pyogenes

Increase vascular permeability

Imitate complement and blood coagulation cascades

Cause fever, hypotension, disseminated intracellular coagulation and shock

Question 20

Important Components of Host Defenses

Answer 20

_ Innate Immunity_
*Macrophages - Phagocytize and digest bacteria
*Complement - Assist host immune cells and antibody in lysis of bacteria and virus-infected cells

Question 21

Important components of Host Defenses

Answer 21

Acquired Immunity
-Antibodies
*Cytolytic
****Neutralizing - antibody sits on virus so can’t infect
*Opsonins

-Cytotoxic T Cells
*Kill antibody-coated bacteria and virus-infected cells. See when antibodies interact with pathogen.

Question 22

Passive vs. Active Immunity

Answer 22

• *Active Immunity**
• Administration of specific antigens to stimulate an individual to develop immunity to help protect from a disease ex. Influenza vaccine
• *Passive Immunity**
• Administration of preformed antigen-specific antibodies to help protect from disease ex. Human rabies immune globulin given to someone suspected to be suffering with disease right now.

Question 23

Vaccines: live vs killed

Answer 23

Influenza - has live, but less virulent version of virus (get thru nose). Also get inactivated cocktail of killed versions of most likely-to-infect versions of influenza thru shot.

Live are always preferred b/c they go through the natural progression yielding a natural immune response.

Hep B - identified viral attachment gene. Use it to make attachment proteins that are injected. In process, body makes antibodies, too.

Tetanus toxoid & typhoid - ex of bacterial vaccines.

Question 24

Human Immune Globulins; active v passive

Question 25

Avoiding the innate immune response

Answer 25

Dealing with phagocytes and complement:
There are essentially three categories of bacterial strategies to deal with phagocytic cells:
*Avoiding contact with phagocytes
*Inhibition of engulfment
*Survival within the phagocyte

Question 26

Avoiding Contact with Phagocytes:

Answer 26

The bacteria can reside in a niche not patrolled by phagocytes.
The bacteria can suppress inflammation and/or chemotaxis.
The bacterium can coat itself with host proteins (more later).

Question 27

Inhibition of Engulfment by Phagocytes

Answer 27

Many bacterial capsules are anti-phagocytic.
Some surface polysaccharides (such as those that aid in biofilm structure) are anti-phagocytic.
Some bacteria produce specific anti-phagocytic products.

Capsules can inhibit phagocytosis AND complement activation

Question 28

Survival within Phagocytes

Answer 28

Intracellular survival is mediated by bacteria in three basic ways:
Escape the phagosome
Shigella, Lysteria
Adapt to the phagosome
Coxiella, Leishmania
Modify the phagosomal compartment
Salmonella, Legionella, Mycobacteria, etc.

Answer 29

Other methods of phagocytic or complement avoidance by bacteria:
LPS O-antigen
Blocks MAC access - keeps at “arm’s length.”
Complement component peptidases
Destroy complement components. This inactivates the components AND stops complement activation.

Answer 30

Antigenic variation
Some bacteria spontaneously change the profile of the surface proteins that they express.
Antibodies are formed in response to specific antigens on the bacteria.
Because of a delay in the immune response (antibody formation), the bacteria can stay one step ahead by producing variants of itself.

Example: Trypanosome Variant-Specific Glycoprotein (VSG) cassettes.

Bacteria: B. recurrentis
Neisseria

Answer 31

3rd type of immunity avoidance:
Immunological disguise
Bacteria coat themselves with host proteins
Disguised by “self” proteins – camouflage!
E.g. proteins produced by some bacteria bind Antibodies – BACKWARDS!

Answer 32

Immunological disguise
E.g. The Treponema pallidum parasite coats itself with host fibronectin.
E.g. S. aureus produces coagulase and clumping factor. This leads to the deposition of host fibrin on the bacterial surface.

Question 33

Protein A - A Staphylococcal Virulence Factor

Answer 33

Staph synthesizes protein A, which can bind IgG so bacteria looks normal to host immune system. Thus, not killed. Remember this one and others he spent time on.

Look to right of this complicated slide. Note diseases caused and how.

produces toxins. Note this and all things that lead to it’s virulence. Systemic infections, and toxin-mediated infections.

Question 34

Pseudamonas aeruginosa

Answer 34

Gram-

involved in cystic fibrosis patients

Of its virulence factors, one is formation of biofilm. Hip replacement - good place to crx biofilm.

Quarum sensing - P. aeruginosa and Salmonella. Don’t synthesize full arsenal of virulence factors, but do synth autoinducers that sit out there while bacteria multiply. When cricital mass is reached, autoinducers release whole repitoire of virulence factors.