Pulmonary adaptive responses
against bacterial pathogens
J S Brown
Reader in Respiratory Infection
Centre for Respiratory Research
Department of Medicine
University College London
Adult community acquired pneumonia: CAP
• 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)
Causes of adult community acquired
pneumonia [CAP] (Lim et al. Thorax 2001)
UK hospitalised patients
influenza
other viruses
13%
4%
Chlamydia
pneumoniae
Mycoplasma
pneumoniae 3%
Legionella 3%
48%
13%
20%
Streptococcus
pneumoniae
7%
Haemophilus influenzae
Unknown
20% no pathogen identified
Staphylococcus aureus 1.5%
Moraxella catarrhalis 2%
Gram negative bacilli 1.4%
Causes of CAP worldwide
(JSBrown Respirology 2009)
Streptococcus pneumoniae infections
2nd commonest bacterial cause of death
nasopharyngeal
commensal
10% adults 50% infants
Septicaemia
1 in 25
aspiration
mortality 20%
otitis media
meningitis
mortality 0% mortality 20%
pneumonia
0 to 75 per 100,000
colonisations
Streptococcus pneumoniae infection epidemiology
- suggests adaptive immunity to colonisation is important?
- waning of adaptive immunity with age?
Health Protection Agency, United Kingdom, 2008
Immune response to S. pneumoniae pneumonia
Key immune
effectors
1. NP
colonisation
1. physical
defences
2. Early lung
infection
1. physical
defences
3. Established
pneumonia 4. Septicaemia
1. inflammatory
exudate
1. Complement
2. RE system
2. mucosal
proteins
2. mucosal
proteins
3. lymphocytes
3. alveolar
macrophages
4. phagocytes
2. phagocytes
3. Circulating
phagocytes
3. CD4 and CD8
lymphocytes?
Mechanisms of adaptive immunity
IFN-gamma
Th1
CD4 T-cell
IL-22
Mucosal repair
Th17 Hyper IgE syndrome
Th2
B-cell
IL-17
Antimicrobial
peptides
Antibody
Antibody
deficiencies
Chemokine release
Phagocyte
recruitment
Phagocyte
CD8 T-cell
Cytotoxicity v.
TAP syndrome?
intracellular pathogens
Alveolar macrophages (AMs)
• First-line phagocyte in lung
• Large range of receptors for
- direct interactions with bacteria
- Indirect interactions
Fc gamma
Receptors
Complement
Receptors
• Airway lining fluid opsonins:
- surfactant
Scavenger
- complement
Receptors
- IgA and IgG
Toll Like
Receptors
Mannose receptor /
lectins
Bacterial phagocytosis by AMs can be saturated
+
+
1 hour
All bacteria killed
1 hour
1 hour
EFFICIENT BACTERIAL
CLEARANCE
NO PNEUMONIA /
BRONCHITIS
• intact epithelium
• efficient alveolar macrophages
Do IgG and IgA improve S.
pneumoniae opsonisation in
airways??
• low inoculum
• low virulence strain
BACTERIAL FACTORS
HOST FACTORS
Antibody and alveolar macrophages:
• 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:
IgG effect
Gordon et al.
Infect Immun 2000
• efficacy of IgA / IgM not clear……
Antibody and prevention pneumonia:
• 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
Anti IgG, alveolar macrophages, and S.
pneumoniae: mouse data
• mice protected v pneumonia
after vaccination with:
- protein antigens
- conjugated capsule antigen
- unconjugated capsule antigen
- dead or live whole cells
Bacterial lung CFU inversely
correlate with Ab level to Cps Ag
• but few data on mechanism(s)
Jakobsen Infect Immun 1999
S. pneumoniae capsular polysaccharide
vaccines and protection against CAP:
• 23 valent unconjugated Pneumovax
- protects against septicaemia
- no evidence protects against pneumonia
• conjugated
vaccine
IgG response
too weak (unconjugated)?
- 7 to
13 valent
Host
response
poor due to comorbidity / age?
- protects
childrentoo
against
pneumonia
(25%:)
Serotype
coverage
restricted
to detect
effects?
directly??
Wrong antigens?
- not used in adults yet
- major issue serotype with coverage:
Failure of clearance of initial S. pneumoniae
infection  neutrophilic consolidation
IL17 dependent immunity
Invading S. pneumoniae
increased mucosal:
- chemokine release
- antimicrobial peptides
- mucosal repair
Neutrophil
recruitment
IL-17
IL-22
Primed Th17 CD4 cells
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
• capsule target for vaccine
adaptive responses
serotype dependent incidence in
children with increasing age
• 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 crossprotective
Lipsitch, Plos Medicine, 2005
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 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
• UCL Institute of Child Health
–
–
–
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Dr Helen Baxendale
Prof David Goldblatt
Prof Nigel Klein
Lindsey Ashton
• UCL Dept Immunology
– Dr Claudia Mauri
– Dr Natalie Carter
• Erasmus Medical Centre, Rotterdam • Intercell AG, Vienna
– Prof Alex van Belkum
– Dr Corné de Vogel
• UCL Biological Services Unit
– Dr Carmen Giefing
– Dr Eszter Nagy