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S. aureus - GLOBE Network

Staphylococcus aureus: where do

we stand in our understanding of

virulence and immunity?

Bachra ROKBI

Annecy. September 28, 2011

| 1


Presentation outline

● Pathogen, general features

● Innate and adaptive host response to S. aureus

● S. aureus virulence factors and their role in

circumventing host immune response

● Conclusion

| 2


Switching from asymptomatic carriage to deep

metastic infections

Broughan et al., Expert Rev Vaccines 10(5) 2011

SSI: Surgical-site infection

| 3


S. aureus: the changing epidemiology (San Francisco

data)

All S. aureus

all MRSA

CA -MRSA

USA300

HA- MRSA

Although steady growth is observed in HA-MRSA infections, CA-

MRSA increased dramatically since 2001

Liu et al., CID 2008, 46, 752-760

| 4


Presentation outline

● Pathogen, general features

● Innate and adaptive immunity to S. aureus

● S. aureus virulence factors and their role in

circumventing host immune response

● Conclusion

| 5


Commensal

S. aureus- commensal and pathogen

The carrier paradox

25% of healthy adults: permanent symptom-free

carriers of S. aureus 1

Pathogen

S. aureus: second most

common causative agent of

HA infections in the

industrialized world: mild skin

infection to severe deepinvasive

diseases

S. aureus carriers :4-fold higher risk for an S.

aureus bacteremia, when hospitalized 3,4

1

Heiman et al., PLos Med 2008

2

Heiman et al., The Lancet Infectious

Diseases2005; Lebon et al., JCM 2008

3

Wertheim et al., Lancet 2004

4

Wertheim et al., Lancet Infect. Dis, 2005

In case of an S. aureus

bacteremia: much better

prognosis for carriers than

non-carriers 3, 4

Hypothesis: Colonization

with S. aureus tunes the

adaptive system, which

results in (partial) protection

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Role of antibodies and neutrophils in protection against

S. aureus: human natural immunity

Antibodies 1

‣More pronounced serum

response in infected individuals

‣Hypo and agammaglobulinemic

patients, more susceptible to S.

aureus infections

‣S. aureus bacteremia more

frequent in carriers but better

survival rate than in non-carriers.

Critical role of neutrophils in S. aureus

infections

‣Chronic neutropenia (Lakshamn,2001; J. Clin.

Pathol)

‣Leucocytes adhesion deficiency (Abramson et

al.,1981, J. Pedriat.)

‣Disorders of intracellular killing

*Patients with chronic granulomatous

disease/defective assembly of NADPH oxydase

complex (Segal et al. 2000, Pediatr Clin North

Am. Liese et al. 2000, J Pediatr. 2000 )

*Chediak and Higashi patients: degranulation

impaired (Lakshamn, 2001,J. Clin. Pathol )

1

For review see Van Belkum 2011, Adv Exp Med Biol. 2011

| 7


Role of T-cell in protection against S. aureus:

human natural immunity and mouse studies

MOUSE DATA 1 HUMAN DATA 2

‣Partial protection with Novadigm

candida adhesin against MRSA

bacteremia in mice.

•Th1/Th17 cells and not B-cells

responsible for the protection

‣Protective role of IL17 in

protection against cutaneous S.

aureus infections

‣Recurrent severe S. aureus

infections in patients deficient in

Th17 (Job’s syndrome)

‣Human IL17A and IL17F essential

for protective immunity to C. albicans

and S. aureus in mucosae

1

Lin et al. 2009, PLOS Pathogens 2009; Ishigame et al. 2009, Immunity; Cho et al. 2010; J. clin. Invest.

2

Minigashi et al. 2009, J. Exp. Med; Puel et al., 2011,Science.

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Presentation outline

● Pathogen, general features

● Innate and adaptive immunity to S. aureus

● S. aureus virulence factors and their role in

circumventing host immune response

● Conclusion

| 9


A large set of virulence factors able to interact

with the host immune response

Broughan et al., 2011; Expert Rev Vaccines

| 10


Interference with innate response: subverting

complement activation

Adapted from Laarman et al., 2010.J. Mol. Med.

•ProtA

•Sbi

•SAK

•SCIN-A/B/C

•Efb/Ecb

•Sbi

CHIPS

CHIPS

•SCIN-

A/B/C

SSL7

Efb/Ecb

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S. aureus virulence factors interfering with bacterial

killing after uptake by neutrophils

S. aureus virulence factors

• S. aureus survival after

phagocytosis by neutrophils

shown repeatedly 1

•Survival of S. aureus in

phagocytes is a way to

disseminate and to cause

recurrent infections 2,3

1

Van de Velde et al., 1894, La cellule 10; Rogers et al., 1952, J. Exp

Med 95; Voyish et al., 2005 J. Immunol 175

2

Gresham et al., 2000.J. immunol. 164; Rogers et al., 1956 J. Exp.

Med. 103.

3

Velasco et al.2006, J.Clin.Microbiol.Infect 25; Venditi et al., 2003.

Haematologica88.

From Thwaites et Gant, Nature Reviews Microbiology, Vol9,2011

| 12


Adhesins, invasins and toxins also associated

with S. aureus dissemination

Effector

FnBPA

2

ClfA

ClfA and ClfB

WTA

5

4

1

LTA

EDIN (A, B and C)

3

6

Function

Adhesin, invasin

Adhesin, platelet activation,

3

immune evasion

Cell wall component

Cell wall component

Toxin

1

Edwards et al., 2010 PLoS Pathog. 6

2

Josefsson et al. 2008, PLoS one 3

3

Chavakis 2002 et al., Nat. Med. 8

4

Weidenmaier 2008 et al., J. Infect. Dis, 191

5

Sheen 2010 et al., J. Mol. Med 88

6

Boyer et al., 2006. J. Cell. Biol 173; Franke et al., 2010. Microbiology 156; Munro et al., 2010. Infect. Immun 78

| 13


Conclusions and challenges for vaccine

development

● Over 50 virulence factors described for S. aureus

● Adaptation to a variety of host niches

● Large spectrum of diverse infections

● Variation in patterns of expression of virulence factors

● Among individual clinical isolates

● According to disease state

● Role of virulence factors in immune evasion

● Impact on bacterial clearance

● Impact on dessimination

● Intracellular persistence in different cell types

● Recurrent infections

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