mar 30, 2005 robbins and cotran chapter 7 pp. 343 … · infectious diseases mar 30, 2005 robbins...
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Infectious diseases
Mar 30, 2005Robbins and Cotran Chapter 7
pp. 343-411
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Tumor immunity
• Immune surveillance– Cancer immunoediting
• Tumor-specific antigens• Tumor-associated antigens• Anti-tumor effector mechanisms
– CTL– NK cell– Macrophages– Antibodies
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Examples
Oncogene products: mutated RAS, Bcr/Ablfusion proteins
Normal self proteinsMutated self protein
Overexpressed oraberrantly expressedself protein Oncogenic virus
Product of oncogene or mutated tumor suppressor gene
MHC Class I CD8+ CTL
CD8+ CTL Virus antigen-specificCD8+ CTL
No T cellresponse
Tumor suppressor geneproducts: mutated p53protein
Overexpressed: tyrosinase, gp100, MART in melanomas
Aberrantly expressed:cancer-testis antigens(MAGE, BAGE)
Various mutant proteinsin carcinogen, or radiation, induced animal tumors; variousmutated proteins in melanomas
Human papilloma virus E6, E7 proteins in cervical carcinoma:EBNA proteins in EBVinduced lymphoma
T cell
T cell T cell T cell T cell
Normal host celldisplaying multiple
MHC-associated self antigens
Tumor cells expressing different types of tumor antigens
Figure by MIT OCW.
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Immuno-suppressive cytokines (e.g., TGF-β)
T cell recognition of tumor antigen leading to T cell activation
Lack of T cell recognition of tumor
Lack of T cell recognition of tumor
Inhibition of T cell activation
T cell T cellT cell
Anti-tumor immunity
Immune evasion by tumors
Tumor cell
Tumor antigen
T cell specific for tumor antigen
T cell
MHC molecule
Antigen-loss variant of tumor
cell
Failure to produce tumor antigen
Mutations in MHC genes or genes needed for
antigen processing
Production of immuno-suppressive
protein
Class I MHC-deficient
tumor cell
Figure by MIT OCW.
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Koch’s postulates
1) The organism is found in lesions of the disease
2) The organism can be isolated as single colonies on solid media
3) Inoculation of the organism causes lesions in experimental animals
4) The organism can be recovered from the experimental animal
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Toxin Terminology
• Exotoxin = protein toxins of bacteria, in contrast to endotoxin (LPS)– Not all exotoxins are secreted; some
accumulate inside the bacterium and are released by bacterial lysis
• Cytotoxin = target a wide range of cell types, in contrast to neurotoxins, leukotoxins, hepatotoxins, cardiotoxins
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More Toxin Terminology
• Toxins can be named for the bacterial species that produce them, such as choleratoxin, Shiga toxin, diphtheria toxin and tetanus toxin
• Toxins can be named for their activities, such as adenylate cyclase, lecithinase
• Toxins can be simply given letter designations, such as exotoxin A
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Toxin Classification by Mechanism
• Type I toxins bind to the host cell surface, but they are not translocated into the host cell (i.e. superantigens [Sag])
• Type II toxins disrupt eukaryotic cell membranes (i.e. phospholipases, and pore-forming toxins)
• Type III toxins are A-B toxins, which have a binding (B) component and active (A) component
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Superantigens (Type I) Toxins
• Toxic shock syndrome toxin (TSST) (toxic shock syndrome)
• Streptococcal pyrogenic exotoxin (Spe) (toxic shock-like syndrome and scarlet fever)
• Staphylococcal enterotoxin (food poisoning)
Hormone Analog• STa (heat-stable toxin) (diarrhea)
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Superantigens (Type I Toxins)
APCAPC Helper T cellHelper T cell
Few clonesFew clones
PeptidePeptide
Many clonesMany clones
SAgSAg
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Membrane-Disrupting (Type II) Toxins
• Alpha-toxin (gas gangrene)• Alpha-toxin (necrosis)• Listeriolysin O (LLO) (listeriosis)• Pneumolysin (pneumonia)• Streptolysin O (SLO) (rheumatic fever)• Hemolysin A (Hly A) (urinary tract
infections and peritonitis)
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Membrane-Disrupting (Type II) Toxins
• Two types of membrane-disrupting toxins– Pore-forming toxins insert holes in the
membrane– Enzymes cleave bonds in membrane phopholipids
• Erythrocytes provide a convenient method to assay activity, so these toxins are often called hemolysins
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Role of Membrane Disrupting Toxins
• In some cases, the primary role appears to be killing of professional phagocytes, such as neutrophils and macrophages
• In other cases, they are used by invasive bacteria to escape from a phagosome and enter the host cell cytoplasm
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A-B (Type III) Toxins
• Diphtheria toxin (diphtheria)• Cholera toxin (cholera)• LT (heat-labile toxin) (infant diarrhea and
traveler’s diarrhea)• Shiga toxin (dysentery and hemolytic
uremic syndrome [HUS])• Botulinum toxin (botulism)• Tetanus toxin (tetanus)• Pertussis toxin (whooping cough)
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A-B (Type III) Toxins
• First toxins studied– Historically more interest in A-B toxins than
Type I or type II• Simple A-B toxins are synthesized as a
single polypeptide– Often A and B portions are separated during
processing by proteolytic cleavage• Compound A-B toxins are composed of
multiple B monomers
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S
S
Simple A-B toxinSimple A-B toxin
B portionB portion
A portionA portion
BB
B
BB
Compound A-B toxinCompound A-B toxin
A portionA portion
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AB
BindingBinding
B
A
EndocytosisEndocytosis
B A
TranslocationTranslocation
B
ATranslocationTranslocation
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More About A-B Toxins
• Often the surface receptor for the B subunit is the carbohydrate moiety of a glycoconjugate
• Distribution of receptor determines target cell specificity
• In some cases, the A subunit needs to be enzymatically activated within the cytoplasm, by host cell proteins
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Mechanisms of Action of A-B Toxins
• Although A-B toxins target many different cell types, many of them catalyze the same reaction
• ADP-ribosylation, the transfer of ADP-ribose from NAD to a target protein, changes the behavior of the target protein– Diphtheria toxin inactivates elongation factor-2– Cholera toxin constitutively activates a Gs GTP-
binding protein that regulates adenylate cyclase
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NIAID Category A & B Priority (Bacterial) Pathogens
Category A• Bacillus anthracis• Clostridium botulinum• Yersinia pestis• Francisella tularensis
Category B• Burkholderia
pseudomallei• Coxiella burnetti• Brucella species• Burkholderia mallei
• Rickettsia prowazekii• Ricin toxin• Epsilon toxin of
Clostridium perfringens
• Staphylococcus enterotoxin B
• Food and waterborne bacteria– E. coli, Vibrios, Shigella,
Salmonella, Listeria, Campylobacter jejuni, & Yersinia enterocolitica
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Select Agents (Partial List)
• Rickettsia prowazekii• Rickettsia rickettsii• Yersinia pestis• Ricin toxin• Shiga-like toxins• Bacillus anthracis• Brucella abortus• Brucella melitensis• Brucella suis• Burkholderia mallei
• Burkholderiapseudomallei
• Coxiella burnetii• Francisella tularensis• Botulinum neurotoxin• Clostridium
perfringens epsilon toxin
• Shiga toxin• Staphylococcal
enterotoxin
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Infection and cancer
• During the past 20 years, 4 new infectious causes of cancer have been discovered– Helicobacter pylori, hepatitis C virus (HCV),
papillomavirus, and human herpesvirus 8 (HHV-8)• H. pylori causes gastric cancer (2nd most
important cause of cancer death worldwide)• Papillomavirus causes the vast majority of cervical
cancer (2nd most important cause of cancer in women)
• Liver cancer caused by hepatitis viruses (ranks 6th in worldwide cancer incidence)
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Between 15 and 20% of cancers due to underlying infection
Source:
Parsonnet, Julie. Microbes and Malignancy. 1st ed. Oxford, UK: Oxford University Press, 1999.ISBN: 0195104013.
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Mammalian oncoviruses
• Peyton Rous won a Nobel Prize in 1966 for work he published in 1911
• Dulbecco, Temin, and Baltimore 1975
• Bishop and Varmus1989 for v-src (Roussarcoma virus)
Figure removed for copyright reasons.
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Viruses linked to human neoplasia
Virus Acute infection TumorHuman T lymphotropic virus-1
Smoldering leukemia
Adult T cell leukemia
Epstein-Barr virus Infectious mononucleosis
B cell lymphomasBurkitt’s lymphoma
Hepatitis B virusHepatitis C virus
Hepatitis BHepatitis C
Hepatocellularcarcinoma
Human papillomavirus
Squamous intra-epithelial neoplasia
Cancer of the cervix
Human herpesvirustype 8
? Kaposi’s sarcoma
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Transformation by high-risk HPV
Please see:
Scheffner, M., and NJ. Whitaker. “Human papillomavirus-induced carcinogenesis and the ubiquitin-proteasome system.” Seminars in Cancer Biology 13 (2003): 59 - 67.
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HPV tropism for squamousepithelium
Source: Fehrmann, F. and L.A. Laimins. “Human papillomaviruses: targeting of differentiating epithelia for malignant conversion.” Oncogene 22 (2003): 5201-5207.
Courtesy of L. A. Laimins and F. Fehrmann. Used with permission.
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Infectious group 1 carcinogens
Organism Cancer DistributionHelicobacter pylori
Gastric cancer Worldwide
Schistosomahaematobium
Urinary bladder cancer
Africa and the Middle East
Opisthorchisvivirreni
Bile duct cancer Northeast Thailand
IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Schistosomes, Liver Flukes, and
Helicobacter pylori. Vol 61. Lyon:IARC, 1994
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Geographical distribution of schistosomiasis
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Helicobacter pylori
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Suerbaum S, and P. Michetti. “Helicobacter pyloriinfection.” New England Journal of Medicine 347 (2003):1175.
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Aliment Pharmacology Therapy 18, Supplement 1 (2003): 153.
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Please see:
Haruma, K., and M. Ito. “Review article: clinical significance of mucosal-protective agents: acid, inflammation, carcinogenesis and rebamipide.”
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