Infect Disease

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Infectious diseases

Mar 30, 2005

Robbins and Cotran Chapte


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Tumor immunity

Immune surveillance

Cancer immunoediting Tumor-specific antigens Tumor-associated antigens

Anti-tumor effector mechanisms CTL NK cell

Macrophages


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Oncogene products:

Normal self proteinsMutated self protein

Overexpressed or

aberrantly expressed

self protein

Product of oncogene

or mutated tumor

suppressor gene

MHC

Class I CD8+ CTL

CD8+ CTL

No T cell

response

Overexpressed:Various mutant proteins H

T cell

T cell T cell T cell

Normal host cell

displaying multiple

MHC-associatedself antigens

Tumor cells expressing different

types of tumor antigens


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T cell T cellT

Anti-tumor

immunityImmune 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

im

Class I

MHC-deficient

tumor cell


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Kochs postulates

1) The organism is found in lesions o

disease2) The organism can be isolated as scolonies on solid media

3) Inoculation of the organism causein experimental animals4) The organism can be recovered fr

experimental animal


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Toxin Terminology

Exotoxin = protein toxins of bacte

contrast to endotoxin (LPS) Not all exotoxins are secreted; someaccumulate inside the bacterium and a

released by bacterial lysis Cytotoxin = target a wide range of

types, in contrast to neurotoxins,

leukotoxins, hepatotoxins, cardioto


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More Toxin Terminolog

Toxins can be named for the bacte

species that produce them, such astoxin, Shiga toxin, diphtheria toxintetanus toxin

Toxins can be named for their actisuch as adenylate cyclase, lecithina Toxins can be simply given letter

designations, such as exotoxin A


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Toxin Classification by Mech

Type I toxins bind to the host cell

but they are not translocated into cell (i.e. superantigens [Sag]) Type II toxins disrupt eukaryotic c

membranes (i.e. phospholipases, andforming toxins) Type III toxins are A-B toxins, wh

a binding (B) component and activecomponent


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Superantigens (Type I) To

Toxic shock syndrome toxin (TSST) (toxsyndrome)

Streptococcal pyrogenic exotoxin (Spe) shock-like syndrome and scarlet fever)

Staphylococcal enterotoxin (food poison

Hormone Analog

STa (heat-stable toxin) (diarrhea)


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Superantigens (Type I To

APCAPC Helper T cellHelper T cell

FeFe

PeptidePeptide

MM


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Membrane-Disrupting (Typ

Toxins Alpha-toxin (gas gangrene)

Alpha-toxin (necrosis) Listeriolysin O (LLO) (listeriosis)

Pneumolysin (pneumonia)

Streptolysin O (SLO) (rheumatic f

Hemolysin A (Hly A) (urinary tract

infections and peritonitis)


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Membrane-Disrupting (Typ

Toxins Two types of membrane-disrupting

Pore-forming toxins insert holes in thmembrane Enzymes cleave bonds in membrane ph

Erythrocytes provide a convenient to assay activity, so these toxins acalled hemolysins


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Role of Membrane Disrup

Toxins In some cases, the primary role ap

be killing of professional phagocyteas neutrophils and macrophages

In other cases, they are used by in

bacteria to escape from a phagosoenter the host cell cytoplasm


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A-B (Type III) Toxins

Diphtheria toxin (diphtheria)

Cholera toxin (cholera) LT (heat-labile toxin) (infant diarrtravelers diarrhea)

Shiga toxin (dysentery and hemolyuremic syndrome [HUS])

Botulinum toxin (botulism)

Tetanus toxin (tetanus)


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A-B (Type III) Toxins

First toxins studied

Historically more interest in A-B toxiType I or type II

Simple A-B toxins are synthesized single polypeptide Often A and B portions are separated

processing by proteolytic cleavage

Compound A-B toxins are composedmultiple B monomers


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A

B

BindingBinding

B

A

EndocytosisEndocytosis

B

TraTra

B

ATranslocationTranslocation


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More About A-B Toxin

Often the surface receptor for thsubunit is the carbohydrate moietyglycoconjugate

Distribution of receptor determine

cell specificity In some cases, the A subunit needsenzymatically activated within the

cytoplasm by host cell proteins


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Mechanisms of Action of

Toxins Although A-B toxins target many d

cell types, many of them catalyze treaction

ADP-ribosylation, the transfer of A

ribose from NAD to a target protechanges the behavior of the target Diphtheria toxin inactivates elongatio Cholera toxin constitutively activates

binding protein that regulates adenyla


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NIAID Category A & B Pri

(Bacterial) PathogensCategory A

Bacillus anthracis Clostridium botulinum Yersinia pestis Francisella tularensis

Category B Burkholderia

pseudomallei

Coxiella burnetti

Rickettsia pr Ricin toxin Epsilon toxin

Clostridiumperfringens

Staphylococcenterotoxin

Food and wat

bacteria E coli Vibr


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Select Agents (Partial Li

Rickettsia prowazekii

Rickettsia rickettsii

Yersinia pestis

Ricin toxin

Shiga-like toxins Bacillus anthracis

Brucella abortus

Brucella melitensisB ll i

Burkholderiapseudomallei

Coxiella burn Francisella t

Botulinum ne

Clostridiumperfringenstoxin

Shiga toxin


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Infection and cancer

During the past 20 years, 4 new infectioof cancer have been discovered Helicobacter pylori, hepatitis C virus (HCV),

papillomavirus, and human herpesvirus 8 (HHV

H. pyloricauses gastric cancer (2nd most

important cause of cancer death worldwi Papillomavirus causes the vast majority ocancer (2nd most important cause of canwomen)

Liver cancer caused by hepatitis viruses


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Between 15 and 20% of can

due to underlying infect

Source:

Parsonnet, Julie. Microbes and Malignancy. 1st ed. Oxford, UK: Oxford UniveISBN: 0195104013.

Image removed due to copyright reasons.


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Viruses linked to human neo

Virus Acute infection T

Human Tlymphotropic virus-1

Smolderingleukemia

Adult Tleukemi

Epstein-Barr virus Infectious

mononucleosis

B cell ly

Burkitt

Hepatitis B virus

Hepatitis C virus

Hepatitis B

Hepatitis C

Hepatoccarcinom

Human papilloma Squamous intra Cancer


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Transformation by high-ris

Please see:

Scheffner, M., and NJ. Whitaker. Human papillomavirus-induced ca

ubiquitin-proteasome system. Seminars in Cancer Biology 13 (2003)


f


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HPV tropism for squamo

epithelium


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Infectious group 1 carcino

Organism Cancer Dist

Helicobacterpylori

Gastric cancer World

Schistosomahaematobium Urinary bladdercancer AfricaMiddle

Opisthorchis

vivirreni

Bile duct cancer Northe

Thaila

G hi l di ib i


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Geographical distribution

schistosomiasis

Images removed due to copyright reasons.


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Helicobacter pylori



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Aliment Pharmacology Therapy 18, Supplement 1 (200


Please see:

Haruma, K., and M. Ito. Review article: clinical significance of mucosal-protective agen

carcinogenesis and rebamipide.


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