Transcript Lec 8 Microbial mechanisms of pathogenicity

Lecture 8: Microbial mechanisms of pathogenicity
Edith Porter, M.D.
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 Important definitions
 The infection cycle
 Bacterial pathogenesis
▪ How bacteria enter and invade a host
▪ How bacteria circumvent host defenses
▪ How bacteria damage host cells
 Pathogenic properties of viruses
 Pathogenic properties of fungi, protozoa, and
helminths
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Pathogenicity
 The ability to cause disease
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Virulence
 The extent or degree of pathogenicity
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Obligate pathogen (pathogen)
 Causes disease in the healthy adult by means of specific pathogenic
factors
 Typically not part of the normal microbiota
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Opportunist
 Causes disease only in individuals with locally or systemically
compromised immune function
 Often part of the normal microbiota
ID50: Infectious dose for 50% of the test population
 LD50: Lethal dose for 50% of the test population
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Disease
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Disease
Health
Health
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Disease
Health
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Mucous membranes
Parenteral route
Skin
Penetration through
intact skin
Schistosoma mansoni
Trematode (Fluke), with male and
female worms, live in blood vessels
Bacillus anthracis
Portal of entry
ID50
Skin
10-50 endospores
Inhalation
10,000-20,000 endospores
Ingestion
250,000-1,000,000 endospores
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Respiratory tract
 Coughing, sneezing
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Gastrointestinal tract
 Feces, saliva
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Genitourinary tract
 Urine, semen, vaginal secretions
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Skin
Blood
 Biting arthropods, needles/syringes
Exit route is typically the same as entry route
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Entry
 Adherence
 Penetration
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Enzyme and toxin production
 Direct damage to host
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Evasion of host defense
 Resistance to uptake by phagocytes
 Change of surface molecule expression
 Latency (hiding in host cells)
 Degradation of host defense molecules

Adhesins bind to specific receptors on host cells
Adhesin
Bacterial strain
Glycocalyx
Streptococcus mutans (plaque)
Fimbriae (pili)
Escherichia coli (UTI)
M protein
Streptococcus pyogenes
Opa protein
Neisseria gonorrhoeae (transcytosis)
Neisseria gonorrhoeae
initiates receptor
mediated uptake by
urethral or cervical
epithelial cells
 Salmonella typhimurium
invades intestinal
epithelial cells using their
cell surface protein invasin
(rearranges the
cytoskeleton)
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Coagulase
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Kinases
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Streptokinase*
Digest fibrin clots
Hyaluronidase*
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Coagulates blood (S. aureus, thick pus)
Hydrolyses hyaluronic acid
Facilitate tissue
degradation
and spreading
Collagenase
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Hydrolyzes collagen
* Therapeutic use!
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Toxin
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 Poisonous substance
 Presence of toxin the host's
 Molecule that contributes to
pathogenicity
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Toxigenicity
blood
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Toxicity
 Ability to induce toxic reactions in
host
Toxoid
 Inactivated toxin used in a
 Capacity of a microbe to produce
toxin
 Toxigenic strains: strains producing
toxins
Toxemia
vaccine
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Antitoxin
 Neutralizing antibodies
against a specific toxin
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Secreted by the microbe
Act locally and in a distance
Typically proteins
 AB toxins: inactivate essential cell functions
 Membrane disrupting toxins
 Toxins overstimulating immune system
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C. diphteriae
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Toxins with 2 sub units:
 A: Active component, mediates
toxicity
 B: Binding component, guides
toxin to the target cell
 Example: Diptheria toxin
▪ Inhibits elongation factor II in
ribosomes, inhibits protein synthesis
▪ 0.01 mg can kill a 200 lb person
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http://www.sumanasinc.com/webcontent/ani
mations/content/diphtheria.html
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Diphteria
Membrane
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Disrupt host cell plasma
membrane
Depending on target:
 Hemolysins: erythrocytes
 Leukocidins: phagocytes
 Some destroy also other cell types
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SLO-Pores
(Bhakdi et al)
Examples:
 Pore forming
▪ S. aureus alpha toxin
▪ S. pyogenes streptolysin -O and -S
 Enzymatic
▪ C. perfringens phospholipase C
Gas Gangrene
Producer
Exotoxin
S. pyogenes
Streptolysins (membrane-disrupting)
Erythrogenic toxin* (scarlet fever)
S. aureus
TSST (hyperstimulate immune system)
Enterotoxins* (similar to V. cholerae toxin)
C. diphtheriae
Diphteria toxin* (A-B toxin, inhibits protein
synthesis)
C. botulinum
Neurotoxin (A-B toxin, flaccid paralysis)
C. tetani
Neurotoxin (A-B toxin, muscle contractions)
V. cholerae
Enterotoxin (A-B toxin, diarrhea)
*phage coded
LPS (lipopolysaccharide)
Component of outer membrane of gramnegative bacteria
 Triggers fever!
 Pyrogen
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Capsules
M-protein in Streptococci
Intracellular survival
 Escape into cytoplasma
▪ Rickettsia
 Resistance against
antimicrobial factors
▪ M. tuberculosis with lipids
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Trypanosoma
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Assume host molecules
Shedding of surface
N. gonorrhoeae
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Undulating Membrane
Schistosoma
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Vary surface glycoprotein
1 of 1000 genes expressed at a time
Genes randomly switched on and off
Vary outer membrane
protein (opa)
Influenza virus
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Changes in spikes
Trypanosome cruzi
Microbial agent (virus) retreats in
host cells
 HIV in Lymphocytes
 Herpes viridae in Nerve cells
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 Herpes simplex
▪ Fever blister
 Varizella Zoster Virus
▪ Chicken pox
▪ Latency in dorsal root ganglion
▪ Recurrence: zoster in skin cells
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Many mucosal
pathogens produce IgAproteases
 Degrade antibody type A
Negri bodies in rabies
Inclusion bodies
Cell rounding
Cell aggregation
Syncytium: multinucleated
cells
 Inactivation of host defense
cells (HIV)
 Down regulation of host
defense
 Transformation: loss of contact
inhibition, uninhibited growth
 Cancerogenic
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 oncogens
Transformed cells in culture
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Chronic infections provoke an allergic
response
Toxins
 Ergot toxin: Claviceps, Hallucinations,
LSD like, abortions
 Aflatoxin: Primary liver cancer
 Mycotoxin: amanitin, neurotoxin, death
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Presence of protozoa
Protozoan waste products and products
released from damaged tissue may cause
symptoms
Avoid host defenses by
 Growing in phagocytes
 Antigenic variation
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Helminth body mass can block host liquid movement
 Ileus with Ascaris infection
 Elephantiasis (Filaria infection blockage of lymph vessels)
Elephantiasis
Filaria
Adult
Can survive for 5 – 10 y
Virulence determined by invading
microorganism and host defense
 Entry route is typically same as exit route
 Main pathogenic factors:
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 Promote entry
 Damage host
▪ Enzyme and toxin production
▪ Toxins often phage coded
 Evasion of host defense
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Disease is a combination of direct cell damage
and host defense response

http://www.doctorfungus.com/thefungi/Cryptococcus.htm
 http://www.geo.ucalgary.ca/~macrae/palynology/dinoflagellates/din
oflagellates.html
• http://www.mikrobiologie.medizin.uni-mainz.de/de/index.html
 Primary Literature available on request