POTERE PATOGENO DEL

MICRORGANISMO :
Capacità di causare malattia o lesioni progressive
nell’ospite.

Un MICRORGANISMO PATOGENO è capace di

invadere e moltiplicarsi in vivo ed è dotato di
potere tossico (virulenza)

La Virulenza indica il grado di patogenicità del

microrganismo
FATTORI CHE CARATTERIZZANO UN
MICRORGANISMO PATOGENO:

- adesività
- capacità di contrastare i meccanismi
difensivi dell’ospite
- capacità di metabolizzare nelle condizioni
nutrizionali fornite dall’ospite
- capacità di penetrare e moltiplicarsi nei
tessuti profondi (invasività)
- produzione di sostanze tossiche
- capacità di resistere agli antibiotici
 ADESIVITA’:
specifica e selettiva per un recettore → tropismo
cellulare e tissutale
1 ADESINA ↔ più recettori
1 recettore ↔ più ADESINE

Examples of mechanisms of bacterial adherence to host-cell surfaces. (a) Pili or fimbriae are organelles
that project from the cell surface. They are made up of a repeating structural subunit and a protein at
their tip that mediates recognition of a specific host-cell glycan motif. (b) Afimbrial adhesins are
integral bacterial cell wall proteins or glycoproteins that directly engage host-cell receptors to promote
colonization.
Molte adesine batteriche sono LECTINE (proteine
altamente specifiche per determinati zuccheri
della superfice cellulare): ↔ glicoproteine,
glicosfingolipidi, glicosaminoglicani

Altre adesine legano glicoproteine della matrice

(fibronectina, collagene, laminina)

Importanti per l’ adesione possono anche essere:

-la capsula
- gli acidi teicoici o lipoteicoici
- il LPS
Microorganism Adhesin Carbohydrate specificity Target tissue

Bordetella filamentous sulfated glycolipids; heparin ciliated epithelium in respiratory tract

pertussis hemag-
glutinin
(FHA)

Borrelia heparan sulfate endothelium, epithelium, extracellular matrix

burgdorferi

Escherichia coli P fimbriae Galα1–4Galβ- urinary tract

Escherichia coli S fimbriae gangliosides GM3, GM2 neural

Escherichia coli Type-1 Manα1–3(Manα6)Man urinary tract

fimbriae

Escherichia coli K99 gangliosides GM3, intestinal cells

fimbriae Neu5Gcα2–3Galβ1–4Glc

Haemophilus Neu5Acα2–3Galβ1– respiratory epithelium

influenzae 4GlcNAcβ-; heparan sulfate

Helicobacter pylori BabA Leb stomach

SabA Neu5Acα2–3Galβ1–
4GlcNAcβ

Mycobacterium Neu5Acα2–3Galβ1– respiratory epithelium

tuberculosis 4GlcNAcβ-; heparan sulfate

Neisseria LacCer; Neu5Acα2–3Galβ1– genital tract

gonorrhoeae 4GlcNAcβ-; heparan sulfate

Propionobacterium LacCer skin, intestine

Pseudomonas type IV pili Asialo GM1 and GM2 respiratory tract

aeruginosa

Staphylococcus heparan sulfate connective tissues, endothelial cells

aureus

Streptococcus Glucans ( Enamel tooth

mutans capsular)

Streptococcus GlcNAcβ1–3Gal- respiratory tract

pneumoniae
Microorganism Adhesin Carbohydrate specificity Target tissue

Streptococcus Prot M + Fibronectin respiratory tract

pyogenes theichoic
acids

Copyright © 2009, The Consortium of Glycobiology Editors, La Jolla, California

IDENTICO DISCORSO VALE PER I VIRUS!!

Mechanisms of viral entry into host cells. (a) Influenza virus initiates host cell contact and entry by binding to cell-
surface sialic acid receptors through its surface glycoprotein hemagglutinin. After intracellular replication, a cell-surface
neuraminidase cleaves sialic acid from the cell membrane allowing viral escape. (b) Herpes simplex virus (HSV) engages
host cells first through a low-affinity engagement of heparan sulfate proteoglycans via its surface glycoproteins gB and
gC. Subsequently, a higher-affinity binding of viral protein gD to a member of the tumor necrosis factor–nerve growth
factor (TNF/NGF) receptor family promotes membrane fusion. (c) Human immunodeficiency virus (HIV) surface
glycoprotein gp120 binds sequentially to the CD4 receptor on T cells and then to a coreceptor such as chemokine
receptor CCR4. The latter interaction triggers a conformational change in gp120, which exposes gp41, the HIV factor
capable of initiating membrane fusion.
BIOFILM: esempio di ADESIONE COMUNITARIA
ad una superficie biologica o inanimata

Esempi di biofilm di importanza medica:

* la placca batterica
* colonizzazione di “cateteri” e “protesi”(S.epidermidis)
* patologie croniche e recidivanti: otiti medie e
croniche, tonsilliti..

NB: i batteri di un biofilm sono molto piu resistenti

all’azione del sist. immunitario e degli antibiotici!!
Biofilm cycle:

1. Free-floating, or planktonic, bacteria encounter a submerged surface

and within minutes can become attached. They begin to produce slimy
extracellular polymeric substances (EPS) and to colonize the surface.

2. EPS production allows the emerging biofilm community to develop a

complex, three-dimensional structure that is influenced by a variety of
environmental factors. Biofilm communities can develop within hours.

3. Biofilms can propagate through detachment of small or large clumps

of cells, or by a type of "seeding dispersal" that releases individual cells.
Either type of detachment allows bacteria to attach to a surface or to a
biofilm downstream of the original community.
 STRATEGIE PER ELUDERE L’AZIONE DEL
SIST. IMMUNE (ANTI-FAGOCITOSI):

1) Prot A di S.aureus

2) Enzimi anti-fagociti ( “leucodine” ) → pori

3) CAPSULA ( S.pneumoniae, P.aeruginosae, H.
influenzae, S. typhi, B. anthracis, E.coli)

la

Classical experiments on the role of the pneumococcal polysaccharide capsule in virulence. Streptococcus
pneumoniae (SPN) strains can be identified with either a “rough” (R) or a “smooth” (S) phenotype, the
latter being due to expression of a thick polysaccharide capsule on their surface. In 1928, Frederick Griffith
found that (R) SPN strains were avirulent for mice, whereas (S) strains were highly lethal. Heat-killed
(S) strains did not produce disease, but when mixed with live (R) bacteria, the mouse died, and the
recovered bacteria expressed the (S) phenotype. Thus, the live (R) strains had been “transformed” to (S)
strains by a factor present in the heat-killed preparation of (S) SPN. The factor later proved to be DNA,
providing the first evidence that DNA was the basis of the genetic code.
NB: La capsula puo favorire il “mimetismo
antigenico”

Es: S. pyogenes ( ac. ialuronico)

N. meningitidis B ( ac. sialico)
4)Capacità di sopravvivere e/o moltiplicarsi
dei macrofagi:

- inibizione della fusione fagolisosomica

Legionella spp., M. tuberculosys, Chlamidia spp.

- Resistenza agli enzimi lisosomiali ( tra cui

catalasi, S.O.D…)
S. typhimuriom, M.leparae, Leishmania spp.

- Adattamento alla replicazione intracellulare

Listeria spp, Rickettsia spp.
5) Produzione di molecole coadiuvanti la
colonizzazione e l’invasione:

- jaluronidasi, collagenasi, proteasi, elastasi,

lipasi…

- coagulasi

- streptocinasi e stafilocinasi (fibrinolisina)

- metaboliti tossici per la cellula eucariotica

(ac.lattico, alcoli, acetone, aldeidi…)
6) produzione di sostaze TOSSICHE →
TOSSINE BATTERICHE:
Fattori di virulenza che mediano l’azione tossica
dei batteri

-ESOTOSSINE: molecole proteiche prodotte da

batteri Gram+ e Gram- SECRETE nell’ambiente
esterno, letali o tossiche per gli organismi
animali.

-ENDOTOSSINE: lipide A dei batteri Gram-

(COMPONENTI STRUTTURALI)

Spesso agiscono nelle vicinanze della cellula

batteriche che le ha rilasciate
 Characteristics of bacterial endotoxins and classic exotoxin

PROPERTY ENDOTOXIN EXOTOXIN

Protein
Lipopolysaccharide
CHEMICAL NATURE (mw = 50-
(mw = 10kDa)
1000kDa)
RELATIONSHIP TO Part of outer Extracellular,
CELL membrane diffusible
DENATURED BY
No Usually
BOILING
ANTIGENIC Yes Yes
FORM TOXOID No Yes
Relatively low Relatively high (1
POTENCY
(>100ug) ug)
SPECIFICITY Low degree High degree
ENZYMATIC
No Often
ACTIVITY
PYROGENICITY Yes Occasionally
 Neutralization of Exotoxins

The Fab portion of the antibodies made against epitopes of the binding site of an
exotoxin blocks the exotoxin from binding to the exotoxin receptor on the host cell
membrane. As a result, the toxin can not enter the cell and cause harm.
 Esotossine: struttura molecolare

1) MONOMERICHE: (tossine citolitiche)

* ATT. ENZIMATICA ( fosfolipasi C)sui
lipidi di membrana:

- α-tossina di C.perfringens
- emolisina tremolabile di P aeruginosae
- tossina β di S.aureus
* formazione di PORI o CANALI: polipeptidi
amfifilici che si inseriscono nello spessore della
membrane cellulare alterandone la funzionalità

- streptolisina O di S. pyogenes (colest-dip)

- α e δ tossina di S. aureus

- emolisine di E.coli e B.pertussis

SOME PORE-FORMING BACTERIAL TOXINS
Toxin Bacterial source Target Disease
perfringiolysin C. perfringens cholesterol gas gangrene
O
hemolysin E. coli cell membrane Urinary Tract
Infections
listeriolysin L. monocytogenes cholesterol systemic; meningitis

anthrax EF B. anthracis cell membrane anthrax (edema)

alpha toxin S. aureus cell membrane abcesses
pneumolysin S. pneumoniae cholesterol pneumonia; otitis
media
streptolysin O S. pyogenes cholesterol strep throat

leukocidin S. aureus phagocyte pyogenic infections

membrane
2) DIMERICHE: A + B
Subunità B (“binding”-legante): si lega ai
recettori cellulari

Subunità A (“active”- tossica):

si trasferisce all’interno della cellula e induce il
danno cellulare. Da sola è atossica (non penetra)

Le due subunità sono unite da ponti SH e in genere sono separate da proteasi dell’ospite (Tox difterica e tetanica)
 - MULTIMERICHE:

1 subunità A + varie subunità B

- tossina di B. pertussis
- enterotossina colerica
 -MULTIFATTORIALI:
monomeri diversi (tossina di B. anthracis)
EF + LF + AP
BIOLOGICAL EFFECTS IN HUMANS OF SOME BACTERIAL EXOTOXINS
WITH ENZYMATIC ACTIVITY

TOXIN (subunit arr)* ENZYMATIC ACTIVITY BIOLOGICAL EFFECTS

ADP ribosylates eucaryotic Activates adenylate cyclase; increased level of intracellular
Cholera toxin (A-5B) adenylate cyclase Gs regulatory cAMP promote secretion of fluid and electrolytes in intestinal
protein epithelium leading to diarrhea
Diphtheria toxin
ADP ribosylates elongation factor 2 Inhibits protein synthesis in animal cells resulting in death of
(A/B)
the cells
ADP ribosylates adenylate cyclase
Pertussis toxin (A-5B) Blocks inhibition of adenylate cyclase; increased levels of
Gi regulatory protein
cAMP affect hormone activity and reduce phagocytic activity
E. coli heat-labile ADP ribosylates adenylate cyclase
Similar or identical to cholera toxin
toxin LT (A-5B) Gs regulatory protein

Glycosidase cleavage of ribosomal Inactivates the mammalian 60S ribosomal subunit and leads to
Shiga toxin (A/5B RNA (cleaves a single Adenine inhibition of protein synthesis and death of the susceptible
base from the 28S rRNA) cells; pathology is diarrhea, hemorrhagic colitis (HC) and/or
hemolytic uremic syndrome (HUS)
Pseudomonas ADP ribosylates elongation factor-
Inhibits protein synthesis in susceptible cells, resulting in death
Exotoxin A (A/B) 2 analogous to diphtheria toxin
of the cells
Zn++ dependent protease acts on
Botulinum toxin
synaptobrevin at motor neuron Inhibits presynaptic acetylycholine release from peripheral
(A/B)
ganglioside cholinergic neurons resulting in flaccid paralysis
Zn++ dependent protease acts on
Tetanus toxin (A/B) synaptobrevin in central nervous Inhibits neurotransmitter release from inhibitory neurons in the
system CNS resulting in spastic paralysis

Metallo protease that cleaves

Anthrax toxin LF
MAPKK (mitogen-activated Combined with the B subunit (PA), LF induces cytokine
(A2+B)
protein kinase kinase) enzymes release and death of target cells or experimental animals

Calmodulin-regulated adenylate
Bordetella pertussis
cyclases that catalyze the formation Increases cAMP in phagocytes leading to inhibition of
AC toxin (A/B) and
of cyclic AMP from ATP in phagocytosis by neutrophils and macrophages; also causes
Bacillus anthracis EF
susceptible cells, as well as the hemolysis and leukolysis
(A1+B)
formation of ion-permeable pores
in cell membranes
Cleaves desmoglein 1, a cadherin
Staphylococcus found in desmosomes in the
Separation of the stratum granulosum of the epidermis,
aureus Exfoliatin B epidermis
between the living layers and the superficial dead layers.
(also a superantigen)

* toxin subunit arrangements: A-B or A-5B indicates subunits synthesized separately and associated by noncovalent bonds;
A/B denotes subunit domains of a single protein that may be separated by proteolytic cleavage; A+B indicates subunits
synthesized and secreted as separate protein subunits that interact at the target cell surface; 5B indicates that the binding
domain is composed of 5 identical subunits.
ACTIVITIES OF EXTRACELLULAR BACTERIAL TOXINS
BACTERIA
NAME OF TOXIN ACTIVITY
INVOLVED
An adenylate cyclase enzyme that increases levels in intracellular cyclic AMP in phagocytes and
Anthrax toxin B. anthracis formation of ion-permeable pores in cell membrane. Leads to edema and decreased phagocytic
(EF) responses

Adenylate Acts locally to increase levels of cyclic AMP in phagocytes and formation of ion-permeable pores
cyclase toxin B. pertussis
in cell membranes
(pertussis AC)

Alpha toxin S.aureus Protein subunits assemble into an oligomeric structure that forms an ion channel (pore) in the cell
plasma membrane
Cholera
enterotoxin V. cholerae ADP ribosylation of G proteins stimulates adenlyate cyclase and increases cAMP in cells of the
(Ctx) GI tract, causing secretion of water and electrolytes leading to diarrhea

E. coli LT toxin E. coli Similar to cholera toxin

Binding of the heat-stable enterotoxins (ST) to a guanylate cyclase receptor results in an increase
E. coli ST toxins E. coli in cyclic GMP (cGMP) that adversely effects electrolyte flux. Promotes secretion of water and
electrolytes from intestinal epithelium leading to diarrhea.

Enzymatically cleaves eucaryotic 28S rRNA resulting in inhibition of protein synthesis in

Shiga toxin S. dysenteriae
susceptible cells. Results in diarrhea, hemorrhagic colitis (HC) and hemolytic uremic syndrome
E. coli O157:H7
(HUS)
Perfringens
enterotoxin C.perfringens Stimulates adenylate cyclase leading to increased cAMP in epithelial cells. Result is diarrhea

Modifies Rho, a subfamily of small GTP-binding proteins that are regulators of the actin
C. difficile cytoskeleton. Deamidation of the glutamine residue at position 63 of Rho to a glutamic acid
ToxinA/ToxinB produces a dominant active Rho protein unable to hydrolyze bound GTP. Pathological result is
cell necrosis and bloody diarrhea associated with colitis

Botulinum toxin C. botulinum Zn++ dependent protease that inhibits neurotransmission at neuromuscular synapses resulting in
flaccid paralysis

Tetanus toxin C. tetani Zn++ dependent protease that Inhibits neurotransmission at inhibitory synapses resulting in spastic
paralysis
Diphtheria toxin
(Dtx) C. diphtheriae ADP ribosylation of elongation factor 2 leads to inhibition of protein synthesis in target cells

Exotoxin A P. aeruginosa
Inhibits protein synthesis; similar to diphtheria toxin

Anthrax toxin B. anthracis Lethal Factor (LF) is a Zn++ dependent protease that induces cytokine release and is cytotoxic to
(LF) cells by an unknown mechanism
Pertussis toxin
(Ptx) B. pertussis ADP ribosylation of G proteins blocks inhibition of adenylate cyclase in susceptible cells
S.s aureus
Exfoliatin toxin* Cleavage within epidermal cells (intraepidermal separation); also acts as a superantigen
Staphylococcus
Staphylococcus aureus Superantigen causes massive activation of the immune system, including lymphocytes and
enterotoxins* macrophages; exact role in in emesis not not known

Toxic shock
syndrome toxin S. aureus Superantigen acts on the vascular system causing inflammation, fever and shock
(TSST-1)*

streptococcal S. pyogenes
Super antigen same as TSST - inflammation, fever and shock; can cause localized erythematous
pyrogenic reactions (scarlet fever)
exotoxin (SPE)*

* The pyrogenic exotoxins produced by Staphylococcus aureus and Streptococcus pyogenes have been designated as
superantigens. They represent a family of molecules with the ability to elicit massive activation of the immune system. These
proteins share the ability to stimulate T cell proliferation by interaction with Class II MHC molecules on APCs and specific V
beta chains of the T-cell receptor. The important feature of this interaction is the resultant production of IL-1, TNF, and other
lymphokines which appear to be the principal mediators of disease processes associated with these toxins.
 Cell recognition (with a specific receptor) and
intracellular trafficking of bacterial toxins

The Figure shows toxin recognition and interaction with a specific receptor on the cell surface. A large variety Commento [1]:

of compounds (lipids or lipid derivatives, transmembrane proteins or glycoproteins) can be use as toxin Commento [2]: FigurLegend --->

receptors. These first steps direct the subsequent intoxication steps, such as pore formation at the cell
surface, internalization and subsequent intracellular trafficking and translocation of active domains into the
cytosol.
I recettori (prevalentemente lipidici o derivati
lipidici) per le tox. batteriche determinano la
sensibilità della cellula alla tossina
(TROPISMO)
Microorganism Toxin Proposed receptor sequence Target tissue

B. thuringiensis crystal toxins Galβ1–3/6Galα/β1–3(±Glcβ1–6)GalNAcβ GlcNAcβ1– intestinal epithelia of

3Manβ1–4GlcβCer insects

C. botulinum botulinum toxins gangliosides GT1b, GQ1b nerve membrane

(A–E)

C.difficile toxin A GalNAcβ1–3Galβ1–4GlcNAcβ1–3Galβ1–4GlcβCer large intestine

C. tetani tetanus toxin ganglioside GT1b nerve membrane

Escherichia coli heat-labile toxin GM1 intestine

S.dysenteriae Shiga toxin Galα1–4GalβCer Galα1–4Galβ1–4GlcβCer large intestine

V. cholerae cholera toxin GM1 small intestine

Sono lipidi, glicolipidi, gangliosidi,

(glicoproteine) che hanno diversi ruoli
fisiologici nella cellula.
Fondamentale è anche la localizzazione in
ambiente lipidico del recttore
INGRESSO DELLA TOX NELLA C. BERSAGLIO

- “ingresso diretto”(raro):la sub B lega il

recettore cellulare → poro → ingresso sub A
es: B.pertussis

- “endocitosi mediata da recettori” (frequente)

la tossina ha 3 domini funzionali:
B: lega il recettore, T: traslocazione, A: att.enzimatica

via di rilascio breve o lunga

Si distinguono esotossine:

extracellulari
citolitiche
ciliostatiche
neurotrope
ADP-ribosilanti
enterotossiche
pantrope
superantigeni
 T. EXTRACELLULARI:
Tossina epidermiolitica / esfoliativa di alcuni
stipiti di S. aureus → “sindrome della cute
ustionata” o di Ritter

meccanismo d’azione non ancora ben definito

 CITOLITICHE (emolisine)

CILIOSTATICHE:
Agiscono sugli epiteli ciliati delle mucose,
bloccandone il movimento e facilitando la
colonizzazione batterica
Es: tossina di B.pertussis (ADP ribosilante)
 NEUROTROPE:

* TOSSINA BOTULINICA→ botulismo

- Uno dei piu potenti veleni naturali (70-90 ng)

- Esistono 7 sierotipi di tossina (tipi A - G)
A, B ed E (talvolta F) → malattia umana.
C → botulismo aviario
D → botulismo nei mammiferi.
Distribuzione: A (USA); B (Europa)
La tox. non è inattivata da acidità gastrica.
Si lega alla superficie apicale delle cellule epiteliali intestinali e tramite
endocitosi e transcitosi è trasportata e rilasciata dalla superficie
basolaterale delle cellule stesse → circolazione generale →migrazione ai
neuroni colinergici presinaptici nelle giunzioni neuromuscolari
 La tossina è una endoproteasi zinco-dipendente.
Sierotipi A-E → SNAP-25
Sierotipo C → Sintaxina e SNAP-25
Sierotipi B-D-F-G → sinaptobrevina
* TOSSINA TETANICA → TETANO
C. tetani produce 2 tossine (PLASMIDICHE):

1) Tetanolisina: emolisina ossigeno labile (?)

2) Tetanospasmina: neurotossina termolabile

A-B sintetizzata come un unico peptide di 150Kda
successivamente tagliato da una endonucleasi
endogena quando la cellula rilascia la neurotossina.
 → migrazione della tossina dalle terminazioni periferiche verso il SNC
mediante trasporto assonico regtrogrado

E’ rilasciata dai dendriti post sinaptici, attraversa le giunzioni sinaptiche e si

localizza nelle vescicole delle terminazioni nervose pre-sinaptiche.
→ nelle sinapsi inibitorie agisce bloccando il rilascio*
dei neurotrasmettitori GABA e glicina
→ PARALISI SPASTICA

*degrada la sinaptobrevina

NB: Il legame della tossina è irreversibile per cui la guarigione

dipende dal tempo necessario per la formazione di nuove
terminazioni assoniche
 TOSSINE ADP-RIBOSILANTI:

Le tossine batteriche mono-ADP -ribosilano!

E’ diversa dalla fisiologica poli-ADP-ribosilazione che avviene nella cellula eucariotica.

Spesso la loro attività è associata ad una G-protein e

la loro azione produce una disregolazione della
concentrazione di cAMP cellulare →
disfunzionamento cellulare
 Esempi di tossine ADP-ribosilanti:

* TOSSINA COLERICA (V.cholerae)

Lega il ganglioside GM1 sull’epitelio dell’intestino tenue

ADP-ribosila (= attiva irreversibilmente) la

subunità αs della G-protein che stimola l’attività
dell’Adenilato ciclasi
→ Aumento del livello di cAMP intracellulare
→ Alterazione dell’equilibrio idrico ed elettrolitico
della cellula → diarrea
* TOSSINA PERTOSSICA (B.bertussis)
ADP-ribosila (= inattiva irreversibilmente) la
subunità αi della G-protein che inibisce l’attività
dell’Adenilato ciclasi → Aumento del livello di cAMP
intracellulare → Blocco alfa-adrenergico →
vasodilatazione, ipoglicemia, ipopotassemia…
*TOSSINA DIFTERICA (C.difteriae)
ADP-ribosila il fattore EF2
→ Inibizione della sintesi proteica.

* Tossina A di P. aeruginosae
* Enterotossina termolabile di E. coli
* varie tossine di clostridi ..e altre ancora….
 ENTEROTOSSINE:
Causano tipicamente vomito e/o diarrea

V. cholerae
E. coli O157:H7
E. coli enteroemorragico
C. perfringens
S. aureus
Y. enterocolitica
S. dysenteriae (Shiga toxin)

PANTROPE:
Inibiscono le sintesi proteiche di diversi tipi
cellulari (tossina difterica)
 TOSSINA DELL’ANTRACE

Fully virulent B. anthracis produce an antiphagocytic capsule as well as toxins.

The protective antigen (PA) of the anthrax toxin binds to the ATR on the host
cell surface. The 83-kDa form of PA is cleaved by the cell surface protease furin
and produces a 63-kDa monomer. Heptamerization of PA induces clustering of
the ATRs, association of the complex with lipid rafts, and exposure of binding
domains to the edema factor (EF) or the lethal factor (LF). The heptamer, and
bound EF or LF, are then endocytosed. EF, an adenylate cyclase, and LF, a
Zn2+ metalloprotease, translocate to the cytosol through a pore created in the
membrane and act on host cytosolic targets to induce edema, necrosis, and
hypoxia.
 Tossine batteriche “superantigeni” (SAgs):

Proteine non processate che legano specifiche sequenze della regione

dell’MHCII sulle APC e del TCR (Vß) fuori dalla tasca di legame per
l’Ag. Bastano concentrazioni di nano o pico grammi per indurre un
intensa risposta policlonale (10-30%) linfocitaria (CD4(+), CD8(+)
e a volte γδ). La normale risposta dei linfociti T è 0.01-0.0001%!

Massiccio rilascio di citochine da parte di linfociti e

monociti (IL-1,Il-2, IL-6, TNFa TNFb INFγ) →
ipotensione, febbre, eritema diffuso… tipici delle shock
tossico

ES: Tossina eritrogenica di S.pyogenes, tossine pirogene di

S.aureus, enterotossine stafilococciche, tossina dello shock
tossico di S.aureus, enterotossina di C.perfingens
 ENDOTTOSSINE: (lipide A)

The lysis of gram-negative bacteria causes them to release lipopolysaccharide (LPS; endotoxin) from
the outer membrane of their cell wall. The LPS binds to a LPS-binding protein circulating in the blood
and this complex, in turn, binds to a receptor molecule (CD14) found on the surface of body defense
cells called macrophages. This is thought to promote the ability of the toll-like receptor TLR-4 to
respond to the LPS, triggering the macrophage to release various defense regulatory chemicals
called cytokines, including IL-1, IL-6, IL-8, TNF-alpha, and PAF. The cytokines then bind to cytokine
receptors on target cells and initiate inflammation and activate both the complement pathways and
the coagulation pathway. (LPS, lipopolysaccharide; IL-1, interleukin-1; IL-6, interleukin-6; IL-8,
interleukin-8, TNF-alpha, tumor necrosis factor-alpha; PAF, platelet-activating factor.)
The mechanism is complex. In monocytes and macrophages, three types of events are triggered during their interaction with LPS:

1. Production of cytokines, including IL-1, IL-6, IL-8, tumor necrosis factor (TNF) and platelet-activating factor. These, in turn, stimulate
production of prostaglandins and leukotrienes. These are powerful mediators of inflammation and septic shock that accompanies endotoxin
toxemia. LPS activates macrophages to enhanced phagocytosis and cytotoxicity. Macrophages are stimulated to produce and release
lysosomal enzymes, IL-1 ("endogenous pyrogen"), and tumor necrosis factor (TNFalpha), as well as other cytokines and mediators.

2. Activation of the complement cascade. C3a and C5a cause histamine release (leading to vasodilation) and affect neutrophil chemotaxis
and accumulation. The result is inflammation.

3. Activation of the coagulation cascade. Initial activation of Hageman factor (blood-clotting Factor XII) can activate several humoral
systems resulting in
a. coagulation: a blood clotting cascade that leads to coagulation, thrombosis, acute disseminated intravascular coagulation, which depletes
platelets and various clotting factors resulting in internal bleeding.
b. activation of the complement alternative pathway (as above, which leads to inflammation)
c. plasmin activation which leads to fibrinolysis and hemorrhaging.
d. kinin activation releases bradykinins and other vasoactive peptides which causes hypotension.

The net effect is to induce inflammation, intravascular coagulation, hemorrhage and shock.