MI-06: introduction to bacterial pathogenesis

Normal Microbiota

More bacterial than human cells in the body
– provide some nutrients (vitamin K)
– stimulate immune system, immunity can be cross-reactive against certain pathogens
– Prevent colonization by potential pathogens (as evidenced by antibiotic-associated colitis, by Clostridioides difficile aka “C. diff”)

types of pathogens

1. primary pathogens

2. opportunistic pathogens

primary pathogens

cause disease upon infection

not normally associated with host

ex: influenza virus, coronavirus

Opportunistic Pathogens

Cause disease under some circumstances

sometime members of normal microbiota

ex: Candida albicans

progression of disease

1. transmission

2. incubation period

3. illness

4. convalescence

1. transmission

infectious dose from 10-10^8 organisms

2. incubation period

the time from when you are exposed to when you experience symptoms

few days (common cold)

weeks (hepatitis A)

months (rabies)

3. illness

once you develop the disease

days-chronic

4. convalescence

feeling healthy again
Clearing + Latency

latent infection

not active disease but it stays with you forever and can become recactivated

kochs postulates

a microbe causes a particular disease

Must fulfill four postulates:
1. Microorganism must be present in every case of the disease

2. Organism must be grown in pure culture from diseased hosts

3. Produce the same disease (in an animal model) from the pure culture

4. Organism recovered from experimentally infected hosts

limitations on koch’s postulates

• Some microorganisms cannot be cultured

• Some diseases have no animal model

• Some infections are polymicrobial

Molecular Postulates

Describe virulence factors

Four postulates:
1. Virulence gene or its product must be present

2. Virulence gene must transform a non-pathogen into a pathogen

3. Virulence gene must be expressed during disease process

4. Antibodies against gene products should be protective

why microbiology?

causes dental caries, periodontal disease, and soft tissue infections

You will encounter various oral infections in your practice

Recognize oral manifestations of systemic infections

Be familiar with transmission of disease and its ramifications (When are patients infectious?)

Immunizations (Can recommend patients to prevent infectious diseases)

familiar with treatment effects of treatment on host and microbiota (Antibiotics)

Understanding your patient (Immunocompromised, medically compromised, elderly, pregnant)

Training to be a health care provider not a technician

Must be able to relate oral health to overall health and vice versa

Will be conversing with physicians about medical consultations

Personal/family protection through awareness of infectious disease

establishing an infection

1. encounter

2. adherance

3. colonization

4. molecule delivery

1. encounter

– fecal-oral (cholera)
– human-human (tuberculosis, COVID-19)
– animal-human (rabies)
– vector-borne (plague, lyme disease)
– environmental contact (anthrax)

2. Adherence

– Prevents early clearance (like peeing or coughing it out)
– Often bind host tissues via pili
– Specificity can determine host range of pathogen

3. Colonization

multiplication and maintainance in host

Competes with normal microbiota

Resist:
• bile
• stomach acid
• peristalsis
• skin secretions
• IgA (mucosal antibodies)
• compete with host for iron

4. Molecule Delivery

Affects target cell structure and host response

can suppress cytokine production

Invasion: Breaching Anatomical Barriers

Skin: tough barrier, rely on wounds or insect vectors
Crossing mucous membrane requires invasion
e.g. intestinal epithelial cells

Use bacterial surface molecules to drive invasion into cells, sometimes through cells (transcytosis) or between cells

Invasiveness

the ability of the microorganism to invade human tissues

enzymes pathogens use to invade the host

1. hyaluronidase

2. lecithinase

3. collagenase

4. fibrinolysin

Hyaluronidase

“spreading factor”, to get into deeper tissue
breaks down extracellular matrix (ECM)
– Staphylococcus, Streptococcus pyogenes

Lecithinase

breaks down host cell membranes

Clostridium perfringens

Collagenase

collagen is in connective tissue

makes up 25-35% of total body protein

C. perfringens

Fibrinolysin

disrupt fibrin clots that wall off infection
– streptococci, staphylococci

Invasins

proteins that can directly mediate cell invasion

Zippering Model of Bacterial Invasion

Tight ligand-receptor interactions direct uptake

“one at a time” uptake

ruffling method of bacterial invasion

Bacteria induce a cellular response of membrane rearrangements

Can lead to co-invasion of other bacteria in close proximity

M cell Invasion (ADD PICS FROM SLIDES)

M cells are a portal to the immune system embedded into mucosal surfaces

Important site of “antigen sampling”

Some pathogens use the phagocytic nature of M cells to access deeper tissues by transcytosis

DONE BY SHINGELLA SPECIES (KNOW)

M cell invasion by _______ species

1. shigella cross the mucous membrane into tissues by passing through M cells (transcytosis)

2. macrophages engulf bacteria + shigella grows inside of the macrophage + kills it

3. pathogen is released + infects neighboring cells

4. move cell to cell using actin fillaments

transcytosis

large molecules are packaged in vessicles + transported to the other side of the cell

Avoiding the Host Defenses

1. Hiding within host cells

2. avoid complement killing

3. avoiding phagocytosis

1. Hiding within host cells

Avoid exposure to host antibodies if remain intracellular

Access to rich source of nutrients

ex: shigella, antibody mediated immunity is not effective but cell mediated immunity is

cell to cell spreading

Shigella and Listeria species lyse out of vacuole

assemble actin at pole

actin propels them into neighboring cell

“convergent evolution”

convergent evolution

two bacteria solved the same problem differently

ex: shigella + lysteria

2. Avoiding complement killing

Complement factors in blood serum can assemble into MAC “membrane attack complex” that are bactericidal

C3b is first component of complex to bind

Some bacteria bind host factors that regulate C3b activity, prevent MAC assembly
“serum-resistance”

“serum-resistance”

bacteria can recruit host proteases that degrade C3b

Inhibition of Complement-Mediated Killing

1. C3b attaches to bacterial surface

2. other complement proteins attach to the C3B → complement cascade pokes holes in cells

we have complement regulatory proteins for our cells to prevent the other complement proteins from binding to CB3

pathogens have found a way to do this

MAC (membrane attack complex)

bactericidal complement complex

final MAC assembly → cell lyses + contents are released

complement regulatory proteins block these steps

3. Avoiding phagocytosis

Innate immune cells engulf (phagocytose) and kill microorganisms with degradative enzymes

Can block signaling molecule production or degrade them after production to prevent influx of immune cells
• C5a cleaved by C5a peptidase of Streptococcus pyogenes (strep throat)

Can produce cytotoxins/hemolysins that lyse immune cells

Capsule production on surface of bacteria → C3b inactivation

Blocks engulfment of C3b opsonized bacteria by host complement receptors

M protein of Streptococcus: also inactivates C3b

Bacterial Fc receptors: bind antibodies and orient dangerous end away from bacteria
• Found in Streptococcus pyogenes (Protein G) and
Staphylococcus aureus (Protein A)

bacterial fc receptor protein a

staphylococcus aureus has protein A on its surface which will bing to the FC portion of the antibody → it cannot bind to receptors on the cells

Survival Strategies within Phagocytes: Phagosomal escape

lyse out of vacuole and grow in cytoplasm of host cell
ex: Shigella species + Bacillus anthracis (Anthrax)

Survival Strategies within Phagocytes: Blocking lysosomal fusion

prevent delivery of degradative enzymes to bacterial compartment

Mycobacterium (tuberculosis)

Survival Strategies within Phagocytes: Surviving in phagolysosomes

Surviving in phagolysosomes after lysosomal fusion
ex: Coxiella

avoiding antibodies: igA protease

cleaves Ab’s found in mucosal secretions (Neisseria gonorrhoeae)

Antigenic variation

turning pili On and Off, or switching to new pilus

avoiding antibodies: Mimicking the host

look like self-antigens

Streptococcus pyogenes has capsule of hyaluronic acid, also made by host tissues

avoiding antibodies: bacterial Fc receptors

bind antibodies and orient dangerous end away from bacteria
– Streptococcus pyogenes (Protein G)
– Staphylococcus aureus (Protein A)