Pulmonary adaptive responses against bacterial pathogens

J S BrownReader in Respiratory Infection

Centre for Respiratory Research

Department of Medicine

University College London

• incidence: overall 0.25%? admissions 50/100,000 per year > 65 years

• 50 - 80% mild - outpatient treatment

• 50 - 20% admitted - 10 - 20% severe / ITU- mortality 5 – 10% (20% UK audit)- 65000 deaths per year in UK

• who gets CAP?- elderly: but only 50% cases >65 years- smokers: attributable risk 51%- comorbidities: attributable risk 14%(lung /cirrhosis / renal disease / diabetes CNS

disease)

Adult community acquired pneumonia: CAP

Causes of adult community acquired pneumonia [CAP] (Lim et al. Thorax 2001)

UK hospitalised patients

Unknown

48%

13%

13%

20%

Haemophilus influenzae

Gram negative bacilli 1.4%

Staphylococcus aureus 1.5%

Moraxella catarrhalis 2%

7%

4%

Legionella 3%

Mycoplasma pneumoniae 3%

Chlamydia pneumoniae

other viruses

influenza

Streptococcus pneumoniae

20% no pathogen identified

Causes of CAP worldwide (JSBrown Respirology 2009)

Streptococcus pneumoniae infections2nd commonest bacterial cause of death

pneumonia0 to 75 per 100,000

colonisations

aspiration

nasopharyngeal commensal

10% adults 50% infants

Septicaemia1 in 25

mortality 20%

otitis mediamortality 0%

meningitismortality 20%

Health Protection Agency, United Kingdom, 2008

Streptococcus pneumoniae infection epidemiology- suggests adaptive immunity to colonisation is important?- waning of adaptive immunity with age?

Immune response to S. pneumoniae pneumonia

2. Early lung infection

3. Established pneumonia

1. NP colonisation 4. Septicaemia

Ke

y im

mu

ne

eff

ect

ors

1. inflammatory exudate 2. phagocytes

3. CD4 and CD8 lymphocytes?

1. physical defences

2. mucosal proteins

3. alveolar macrophages

1. Complement

2. RE system

3. Circulating phagocytes

1. physical defences

2. mucosal proteins

3. lymphocytes

4. phagocytes

Mechanisms of adaptive immunity

Th1

Th17

B-cellAntibody

IFN-gamma

IL-22Mucosal repair

Antimicrobial peptides

Chemokine release

Phagocyterecruitment

IL-17

Phagocyte

CD4 T-cell

Th2

CD8 T-cell Cytotoxicity v. intracellular pathogens

Hyper IgE syndrome

Antibody deficiencies

TAP syndrome?

ScavengerReceptors

Mannose receptor / lectins

ComplementReceptors

Fc gamma Receptors

Toll LikeReceptors

• First-line phagocyte in lung

• Large range of receptors for - direct interactions with bacteria- Indirect interactions

• Airway lining fluid opsonins:- surfactant - complement - IgA and IgG

Alveolar macrophages (AMs)

+

+

All bacteria killed

Bacterial phagocytosis by AMs can be saturated

1 hour

1 hour 1 hour

EFFICIENT BACTERIAL CLEARANCE

NO PNEUMONIA / BRONCHITIS

• low inoculum• low virulence strain

• intact epithelium• efficient alveolar macrophages

BACTERIAL FACTORS HOST FACTORS

Do IgG and IgA improve S. pneumoniae opsonisation in

airways??

• significant levels in IgG, IgA and IgM in airway lining fluid

• IgG predominant x5 that of IgA

• efficacy of IgG at promoting alveolar macrophage activity:

• efficacy of IgA / IgM not clear……

Antibody and alveolar macrophages:

Gordon et al.Infect Immun 2000

IgG effect

• 1er and 2er IgG deficiency recurrent lung infections

• therefore IgG essential for preventing lung infection

• role of IgA unclear - IgA deficiency 1 in 400, only a subset

develop recurrent lung infections

• deficiency IgM also only sometimes associated with

recurrent lung infection

Antibody and prevention pneumonia:

• mice protected v pneumoniaafter vaccination with:- protein antigens- conjugated capsule antigen- unconjugated capsule antigen- dead or live whole cells

• but few data on mechanism(s)

Anti IgG, alveolar macrophages, and S. pneumoniae: mouse data

Bacterial lung CFU inversely correlate with Ab level to Cps Ag

Jakobsen Infect Immun 1999

• 23 valent unconjugated Pneumovax

- protects against septicaemia

- no evidence protects against pneumonia

• conjugated vaccine

- 7 to 13 valent

- protects children against pneumonia (25%:)

directly??

- not used in adults yet

- major issue serotype with coverage:

<30% CAP strains covered by Prevenar?

S. pneumoniae capsular polysaccharide vaccines and protection against CAP:

IgG response too weak (unconjugated)?

Host response poor due to comorbidity / age?

Serotype coverage too restricted to detect effects?

Wrong antigens?

Failure of clearance of initial S. pneumoniae infection neutrophilic consolidation

IL17 dependent immunity

IL-22

Invading S. pneumoniae

increased mucosal:- chemokine release- antimicrobial peptides- mucosal repair

IL-17

Primed Th17 CD4 cells

Neutrophil recruitment

Hyper IgE (Job’s) syndrome and pneumonia

• triad of: raised IgE, abscesses, and pneumonia

• infections with S. pneumoniae

• mutations of STAT3, regulates cytokine responses

• specifically causes a defect in CD4 Th17 response

• demonstrates probable role for Th17 v. lung infection

Milner Nature 2008

IL-17 dependent adaptive immunity and S. pneumoniae

• required for immunity v. nasopharyngeal colonisation:- after colonisation (Zhang J Clin Inv 2009)

- after vaccination with whole cell vaccine (Lu PLoS Pathogens)

• mechanism: - neutrophil-dependent- increases neutrophil recruitment and efficacy

• We don’t know whether protects against pneumonia….

• Antigen targets unknown…… (lipoprotein?)

Target antigens for natural adaptive responses to S. pneumoniae

Lipsitch, Plos Medicine, 2005

serotype dependent incidence in children with increasing age• capsule target for vaccine

adaptive responses

• may not be for natural responses:- wide range protein antigens- acquired immunity seems

independent of capsule serotype- anti-protein response to

colonisation often dominant

• protein antigens maybe cross-protective

Summary and conclusions re. lung adaptive immunity v. S.pneumoniae

• Antibody via improved alveolar macrophage and neutrophil phagocytosis v. important

• Th-17 mechanisms also could be helpful

• Natural adaptive immune responses can be directed against protein antigens

• Need to aim for vaccination strategy that:- boosts S. pneumoniae clearance from the lungs therefore alveolar macrophage efficacy key- can protect against wide-range of strains protein antigens need to be considered

Acknowledgments• UCL Institute of Child Health

– Dr Helen Baxendale– Prof David Goldblatt– Prof Nigel Klein– Lindsey Ashton

• UCL Centre for Respiratory Research

– Dr Jonathan Cohen– Dr Suneeta Khandavilli– Dr Catherine Hyams– Dr Emilie Camberlein– Dr Jose Yuste– Dr Alejandro Ortiz Stern – Steve Bottoms

• Erasmus Medical Centre, Rotterdam– Prof Alex van Belkum– Dr Corné de Vogel

• UCL Biological Services Unit

• UCL Dept Immunology– Dr Claudia Mauri– Dr Natalie Carter

• Intercell AG, Vienna– Dr Carmen Giefing– Dr Eszter Nagy