Introduction to microbes and infectious disease

Most microbes do NOT cause disease (what’s the difference, i.e., what is a virulencefactor?)

Microbes cause different diseases (why?)

How do microbes get into the body (portals ofentry) and spread (portals of exit)?

Why do some organisms cause disease whileothers do not?

Pathogens cause diseaseevade immune systemcause tissue damage

Other organisms harmlessly colonize the body

(Ch. 22-28; why do organisms cause disease ina particular part of the body?)

p. 460

p. 461; locations for normal flora

Resident?Transient?

Pathogenesis of infectious disease

How does an organism cause disease?(impairment of function)

What is the course of disease?How is disease spread?

How is the organism shown to be pathogenic?

Is it always pathogenic (primary pathogen) oronly is susceptible people (opportunistic)

How virulent is the infectious organism?

Contagious (communicable) diseases are easilyspread

Sometimes the infectious dose is very low (therefore easier to spread)

Example: dose is high for Salmonellalow for Shigella (both cause diarrhea)

Infectious dose can be calculated

General sequence of events in infectiousdisease

p. 463Infection may be localized or systemicTime course can be short or long

Koch’s postulates- classical way to determineif a particular organism causes disease

1. Microbe is present in all affected individuals2. Organism is isolated from a sick individual3. When organism is introduced into new hosts,

they get sick, too- and same organism is isolated from them.

Not all organism can be grown in pure cultureor tested

Postulates are applied on molecular level(what microbial product causes disease)

Mechanisms of pathogenicity

Toxin production (endotoxin or exotoxin)toxins can be produced in body oringested

Colonization (usually GI or respiratory tract)acquire food, overcome normal flora

Invasion of tissues (avoid immune system)

Or some combination!

How do bacteria establish infections?

Adhesion (adherence) is often a necessaryfirst step

Adhesins bind to specific molecules on cellsurface- contributes to tissue specificity

i.e., E.coli in urinary tract; Neisseria in repro-ductive tract

How do microbes invade body

Skin- through lesions or vectors (bites)

Many bacteria have developed ways to getthrough innate immune barriers or bycrossing epithelia (cells specialized forengulfment and/or transport)

Some bacteria hide inside host cells(e.g., Listeria)

Avoiding immune mechanisms

Gram-positive organisms are not sensitive tocomplement-mediated lysis

Some Gram-negatives use complement receptors or special glycosylation

Avoiding phagocytosiscapsules; complement inactivation

streptococci, staphylococci

Surviving phagocytosisListeria, Shigella get out of phagosome

Salmonella- prevent fusion with lysosome

IgA proteases

Antigenic variation; mimicking host molecules(streptococci good at this)

Pathogenic mechanisms

• Toxins– “A-B” (“B” attaches to cell (specificity); “A” part is the toxin– Cytotoxins damage cells membranes– Superantigens aggravate immune

response– Other damage specific tissues

How do toxins damage host? (see p. 473)

A-B toxins: examples

I. Neurotoxins- interfere with transmission of nervous signal

C. botulinum- prevents release of acetylcholine(flaccid)

C. tetani- blocks inhibitory neuronsspastic

II. Enterotoxins- oversecretion of fluids intointestine- E. coli; V. cholerae

III. Cytotoxins

B. anthracis, B. pertussis- oversecretion

C. diphtheriae, E. coli O157:H7, S. dysenteriaeinhibit protein synthesis

Membrane-damaging toxins have differentstructure, directly attacking cell membranes

(Have different structure than A-B toxins)

Example: hemolytic bacteria (can lyse other membranes beside RBC membranes)

Superantigens break the rules of antigenspecificity (also act differently than otherexotoxins)

Recall that T cells recognize antigen “presented”to them by MHC Class II on APCs (see p. 475)

Superantigens bind differently; can activatemay different T cells simultaneously

Excess stimulation can cause nausea, vomitingand sometimes shock

S. aureus toxin is well characterized (TSS)

Most exotoxins are not heat-stable (exceptS. aureus superantigen)

Many exotoxins have been isolated and areused (as toxoids) for vaccines

See p. 477 for comparison with endotoxin

Endotoxin is actually component of Gram-negatives (LPS), so cannot be isolatedlike an exotoxin can

Damage is due to inflammatory response to itcan be fatal (septic shock)

Heat-stable; not autoclavable

Limulus amoebocyte assay is used to test forendotoxins

Thus immune response itself can contributeto disease

Inflammation

Hypersensitivity

Autoimmune disease (cross-reactive antibodies)

“Immune complex disease” can lead to kidneydamage

Viral pathogenesis

All viruses must live within cell; some can causechronic or latent infections

Viruses bind to specific receptors on cells and(in animals) are endocytosed

May stick to one type of tissue or spread

Many viruses have evolved mechanisms thatneutralize specific immune functions

Influenza, HIV- avoid interferons(HIV-infects regulatory T cells!)

Block MHC Class I expression

Form syncytia (cells fuse together)

Antigenic variation

How do viruses damage cells?

Burst cellsApoptosis (avoids inflammatory response, too)Inflammatory response

(Most, but not, rashes associated with infectiousdisease are caused by viruses)

Fungal infections

Remember how fungi eat!

Fungi can damage living tissue, too

Effect is strong in immunocompromisedpatients

Toxins

Hypersensitivities

Helminths and protozoa

Depends on organism and host tissue

Malnutrition

Damage to colonized tissue; dysfunctionassociated with that

Can suppress immune response

Study of pathogenesis involves:

Identification of virulence factors

Understanding host range of organisms

Normal host response to organism and howpathogen deals with it

Strategies for prevention and treatment