Genes de virulence .pdf



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LES GENES DE VIRULENCE
SOIT sur éléments génétiques mobiles : transposons, phages , plasmides
SOIT chromosomique isolé ou groupés
Les plasmides de virulence
Bactérie

Plasmide

E.coli entérotoxinogène

Fonctions de virulence
Enterotoxine LT, ST
K99, K88 , CFA

Shigella flexneri

Invasion des cellules
épithéliale et système de
type III pour la sortie
dans le cytoplasme
Synthèse chaine O

Yersinia pestis,

PYV

Virulon YOP ( Système

Y. enterocolitica,

type III)

Y. pseudotuberculosis

Adhésine YadA

Salmonella thyphimurium

Gènes spv rôle mineur
dans les gastro-entérites

C. tetani
B. anthracis

Toxine tétanique
PXO1

Facteurs LF, EF, PA

PXO2

Capsule

Les phages porteurs de gènes de virulence
Toxine diphtérique
Les souches de C.diphteriae qui produisent la toxine hébergent un
prophage.
Toxine clostridienne
C. botulinum type C, C.botulinum type D et C. Novyi 1type A sont
constituent une même bactérie hébergeant des prophages différents.
Toxine cholerique
Les gènes ctxA et ctxB sont encodés par un bactériophage lysogénique
filamenteux analogue à M13.
Les pili TCP ( toxine co-regulated pili) constituent le récepteur pour le
phage . Ces pili sont encodés par un ilot de pathogénicité et sont
corégulé avec l’expression des gènes phagiens
Les toxines SLT des E. coli enterohemorrhagiques, la cytotoxine de P.
aeruginosa et la toxine érythrogène de la scarlatine sont également
encodées par un phage
Les transposons porteurs de gènes de virulence
Les genes de l’enterotoxine ST d’ E. coli font parties d’un transposon.

Le chromosome et les ilots de pathogénicité
Ces ilots de pathogénicités sont retrouvés chez de nombreuses
bactéries pathogènes
Gram négatives ( E.coli uro- et enteropathogène, S.thyphimurium,
Y.pestis, Y. enterocolitica, H. Pylori, V. cholerae )
Gram positives (L. monocytogenes, S. pyogenes, C. difficile ).

1

C. Novy ne produit pas de neurotoxine mais est un agent de gangrène gazeuse.

Les ilôts de pathogénicité possèdent des caractéristiques communes :
1- encodent souvent de nombreux gènes de virulence
2- présence chez les souches pathogènes et absence chez les souches
moins pathogènes d’une même espèce.
3- contenu en G+C différent du contexte chromosomique
4- souvent d’une taille supérieure à 30 kb
2- Unité génétique compacte souvent bordée de répétitions directes*
3- Association avec des gènes de tRNA *ou des séquences IS à leurs
extrémités
4- Présence souvent cryptique de facteurs de « mobilité » ( IS,
transposase, integrase, origine de réplication plasmidique…)*
Les points marqués d’une * ne concernent pas les IPA des bactéries Gram positives

IPA des bactéries Gram négatives ont une certaine propension à encoder
des système de secrétion de type III

Transfert horizontal de gènes et évolution microbienne
Le transfert horizontal de gène via des phages des plasmides ou des
ilots de pathogénicité (IPA) est un processus d’évolution microbienne
très rapide.
La compétence génétique naturelle ( H.influenzae, S. pneumoniae ) ou
pour les espèces qui en sont dépouvues, un taux plus élevé de
mutation et de recombinaison est un prérequis à cette émergence de
nouveau pathotypes. Ainsi, on a démontré que des souches
pathogènes d’enterobactéries ( Salmonella thyphimurium, E.coli )
possèdent souvent un défaut du gène mutS qui est responsable du
processus de réparation de l’ADN et qui pourrait expliquer
l’acquisition d’IPA par ces souches.
Après le transfert de phages , de plasmide ou d’IPA dans le nouvel hôte,
deux processus génétiques sont cruciaux : la stabilisation de ces exogénotes
et l’expression optimale des gènes qu’ils portent.

The E. coli genome. The diagram represents an E. coli cell harbouring the K12 chromosome.
Insertion sites for some well-characterised DNA elements and pathogenicity islands
(represented as bars) are shown. These are located at mapped insertion sites with the apex of
the ellipse representing zero minutes on the genome, as designated by Blattner et al. [23].
Hatched bars represent uropathogenic E. coli-associated sequences, whereas black bars
indicate those associated with EHEC or EPEC. The open bars show genetic material
associated with neuroinvasive E. coli and capsule (kps, cps) production. The smaller ellipses
at the bottom of the diagram represent examples of the many E. coli plasmids carrying
determinants not found in K12. These include EAF (which encodes bundle-forming pili from
EPEC), AAF (which encodes adherence fimbriae from enteroaggregative E. coli), Fim (which
encodes colonisation factors such as K88, K99 and human CFs), Ent (which encodes heat-labile
and heat-stable enterotoxins), pCG86 (which encodes antibiotic resistance and enterotoxin
production), ColV (which encodes colicin production and self-immunity to colicin), Hly
(which encodes a haemolysin), pVM01 (which encodes siderophore production) and Vir
(which encodes necrotizing factor 2 and F17b fimbriae). The pentagon-shaped structures show
phage attachment sites. Mins, minutes.

Parallel evolution of virulence in pathogenic Escherichia
coli
SEAN D. REID, CORINNE J. HERBELIN, ALYSSA C. BUMBAUGH, ROBERT K.
SELANDER & THOMAS S. WHITTAM
Nature 2000 406, 64
Phylogenetic analysis of 21 E. coli strains.
, Rooted phylogeny of pathogenic strains. The tree is based on concatenated sequences of 6
loci (a total of 5.0 kb) rooted with homologous sequences from S. enterica Typhimurium. The
phylogeny was constructed with the neighbour-joining algorithm using the synonymous rate
of substitution (dS). The polymorphic codons implicated in recombination of mtlD for strain
E2348/69 were excluded from the analysis. Branch lengths are measured in terms of the
number of synonymous changes per 100 synonymous sites (dS 100) and the numbers at the
nodes are bootstrap confidence values based on 1,000 replicates. Arrows indicate the putative
acquisition events for the mobile elements encoding the virulence factors

La régulation des gènes de virulence
Etant de peu d’utilité en dehors de certaines étapes précises du cycle
infecteux, ces facteurs de virulences sont toujours sujets à un contrôle
étroit et coordonné dépendant des signaux indicatifs de la présence
dans l’hôte.
a- La température :
Les Yersinia n’activent les fonctions virulentes du plasmide PYV qu’à
37°, les Shigella font de même avec leurs fonctions plasmidiques
d’invasion.
Les E.coli entero et uro pathogènes ne synthétisent leurs fimbriae qu’à
37°
b- La carence en Fer
La production de la toxine diphtérique et de la Shiga toxine est sous la
dépendance d’un répresseur fixant le Fer.
c- Le CO2
L’acyivité des plasmides POX1 et POX2 de B. anthacis pour produire
ses toxines et sa capsule depend de la concentration en CO2.
d- Le pH et l’osmolarité
La production de CT par Vibrio cholerae est fortement dépendante du
pH et de l’osmolarité.
e- La concentration en ions Mg++

En intracellulaire, la carence en Mg++ stimule le système PhoP/PhoQ
de Salmonella qui conduit à l’extinction des gènes nécessaires à sa
survie en extracellulaire (SPI-1) et à l’induction des gènes nécessaires à
sa survie en intracellulaire dont le 2° îlot de pathogenicité (SPI-2).

Virulence gene regulation in S. typhimurium
The SirA/HilA regulon, which is expressed primarily when Salmonella are
extracellularly located (i.e. not found in host cells), is shown above the dotted
line. Expression of hilA requires SirA, a possible two-component response
regulator. HilA positively activates the spa, inv and prg operons of the
Salmonella pathogenicity island 1 (SPI1) which encode proteins that form the
Type III secretion apparatus (TIII). The Sip proteins, whose expression is
activated by Inf, are exported through the Type III secretion apparatus and
allow the invasion of epithelial cells by S. typhimurium and the invasion and
induction of apoptosis in macrophages. Below the dotted line, genes expressed
primarily by intracellularly localized Salmonella are shown. PhoP/PhoQ

represses expression of SPI1-encoded genes (bar leading up to dotted line) and
activates expression of genes and operons (i.e. slyA and pag loci) required for
intracellular survival. Other regulons contributing to thephenotypes of
intracellularly located S. typhimurium are also shown. The function of the
Type III secretion system encoded on SPI2 is not known. The bacterial inner
membrane (IM) and outer membrane (OM) are shown.

Quorum sensing in S. aureus
The agrBDCA locus encodes the AgrC/AgrA two-component regulatory
system that controls expression of rnaiii and the agrBDCA loci in response to
the presence of peptide pheromones. In many cases, post-translationally
processed peptide pheromones are secreted by ATP-binding cassette exporter
proteins; however, such a factor has not been described for the agr system.
RNAIII, either directly or indirectly, activates expression of capsule, toxic shock
syndrome toxin (TSST), -hemolysin and exotoxin B, and represses expression of
protein A, coagulase and fibronectin-binding protein (FBP). Peptide
pheromones which activate the agr regulon in strains producing them can in
some cases inhibit agr in other strains and cause 'interference' .

The V. cholerae ToxR/ToxS regulon.
ToxR and ToxS are cytoplasmic membrane proteins. ToxR/ToxS activates
expression of ompU and represses expression of ompT. ToxR/ToxS controls
expression of the cholera toxin genes (ctxA and ctxB) encoded on the
bacteriophage CTX and activates the expression of genes on the TCP–ACF
pathogenicity island, including genes encoding the toxin co-regulated pilus (tcp
genes). ToxR/ToxS may control expression of accessory colonization factors (acf
genes) indirectly via ToxT. It appears that TcpP/TcpH, which are also predicted
to be cytoplasmic membrane proteins, activates expression of toxT, and ToxT
activates tcp, acf, and ctx loci [20] [21]. For simplicity, regulatory functions of
tcp loci are not shown.

Regulation of B. pertussis virulence

B. pertussis virulence factors can be modulated by changes in the environment . In addition,
B. pertussis can undergo phase variation and lose or (rarely) regain virulence determinants
[5]. Both phenotypic modulation and phase variation depend on a two-

component phosphorelay system encoded by the bvgA/S operon [6].
BvgS is an inner membrane protein that senses changes in the environment. It

contains a large periplasmic domain attached to a cytoplasmic domain via a transmembrane
segment and a cytoplasmic linker. Compared to most other two-component systems, the
cytoplasmic domain is unusually large and contains several distinguishable modules that
participate in the phosphorylation cascade. At 37°C and in the absence of

modulators, BvgS undergoes autophosphorylation. After several
intramolecular phosphorylation steps, the phosphate group is finally
transferred to the amino-terminal domain of the second component, BvgA, a
transcriptional activator. Phosphorylation activates BvgA and increases its
affinity for the promoter regions of B. pertussis virulence-activated genes (vag)
[7]. This triggers the transcription of these genes through the interaction of the
extreme carboxyl terminus of BvgA with the subunit of RNA polymerase [8].
This interaction probably involves the carboxy-terminal domain of the subunit [9].
However, the BvgA‹RNA polymerase contacts may vary, depending on the promoter
context, and the vag genes are differentially expressed. Some are expressed almost
immediately after stimulation of BvgA, whereas others are expressed only after several
hours, depending on the nature of DNA binding and RNA polymerase interaction of BvgA
[10]. At low temperatures or in the presence of nicotinic acid or sulfate ions, the

phosphorelay is interrupted and the vag genes are silent. This is called
phenotypic modulation. Essentially irreversible repression of the vag genes can also
occur by mutations in the bvgA/S operon during phase variation [5]. Although in the
absence of functional BvgA, the vag genes remain silent, another set of genes,
referred to as the virulence-repressed genes (vrg), are derepressed. BvgA
regulation of the vrg genes is indirect and involves a repressor named BvgR
[11]. The gene encoding BvgR maps to a location immediately downstream of
bvgAS and is activated by BvgA. BvgR then most likely binds to conserved
operator sequences of the vrg genes. The function of these genes and their role
in virulence are not yet known; however, mouse aerosol challenge studies
have indicated that bvgR-mediated regulation of B. pertussis gene expression
contributes to respiratory infection [12]. A bvgR deletion mutant is much less
virulent than the wild-type parent strain, whereas constitutive expression of
bvgR is not detrimental to virulence, consistent with the notion that vrg genes
are not required for infection in the mouse model [13]. Rather, the
inappropriate expression of vrg genes may interfere with the ability of B.
pertussis to cause disease. However, this does not preclude that vrg genes may
be required at later stages of the infectious cycle. Interestingly, at least one vrg
gene is strongly induced at high growth density by a quorum-sensing system
[14], suggesting that BvgR regulation may perhaps serve to alert the bacteria
that a sufficiently high cell density has been reached to initiate the next step of
the infectious cycle. Alternatively, since B. pertussis has the ability to invade
and survive within a variety of eukaryotic cells, and since vrg genes are
expressed intracellularly, BvgR-regulated quorum sensing has been suggested

to sense the transition of the bacteria from the extracellular milieu to a more
confined intracellular environment.




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