Pulmonary adaptive responses against bacterial pathogens

1. Pulmonary adaptive responses against bacterial pathogens J S Brown Reader in Respiratory Infection Centre for Respiratory Research Department of Medicine University College London

2. 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 / diabetesCNSdisease)

3. Causes of adult community acquired pneumonia [CAP] (Lim et al. Thorax 2001)UK hospitalised patients influenza 13% other viruses 4% Streptococcus pneumoniae Chlamydia pneumoniae 48% 13% Mycoplasma pneumoniae 3% Legionella 3% 20% 7% Haemophilus influenzae Unknown Staphylococcus aureus 1.5% Moraxella catarrhalis 2% 20% no pathogen identified Gram negative bacilli 1.4%

4. Causes of CAP worldwide (JSBrownRespirology 2009)

5. Streptococcus pneumoniae infections2nd commonest bacterial cause of death nasopharyngeal commensal 10% adults 50% infants Septicaemia 1 in 25 mortality 20% aspiration meningitis mortality 20% pneumonia 0 to 75 per 100,000 colonisations otitis media mortality 0%

6. Streptococcus pneumoniae infection epidemiology • suggests adaptive immunity to colonisation is important? • waning of adaptive immunity with age? Health Protection Agency, United Kingdom, 2008

7. Immune response to S. pneumoniae pneumonia 3. Established pneumonia 2. Early lung infection 1. NP colonisation 4. Septicaemia • physical • defences • 2. mucosal • proteins • 3. lymphocytes • 4. phagocytes • physical • defences • 2. mucosal • proteins • 3.alveolar • macrophages 1. Complement 2. RE system 3. Circulating phagocytes 1. inflammatory exudate 2. phagocytes 3. CD4 and CD8 lymphocytes? Key immune effectors

8. Mechanisms of adaptive immunity Hyper IgE syndrome IFN-gamma Th1 CD4 T-cell Mucosal repair IL-22 Th17 Antimicrobial peptides Antibody deficiencies Th2 IL-17 Antibody Chemokine release B-cell Phagocyte recruitment Phagocyte CD8 T-cell Cytotoxicity v. intracellular pathogens TAP syndrome?

9. Alveolar macrophages (AMs) • 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 Fc gamma Receptors Complement Receptors Scavenger Receptors Toll Like Receptors Mannose receptor / lectins

10. Bacterial phagocytosis by AMs can be saturated 1 hour + All bacteria killed 1 hour 1 hour +

11. EFFICIENT BACTERIAL CLEARANCE NO PNEUMONIA / BRONCHITIS • intact epithelium • efficient alveolar macrophages Do IgG and IgA improve S. pneumoniaeopsonisation in airways?? • low inoculum • low virulence strain BACTERIAL FACTORS HOST FACTORS

12. 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: IgG effect Gordon et al. Infect Immun 2000

13. 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

14. Anti IgG, alveolar macrophages, and S. pneumoniae: mouse data Bacterial lung CFU inversely correlate with Ab level to Cps Ag • mice protected v pneumonia • after vaccination with: • protein antigens • conjugated capsule antigen • unconjugated capsule antigen • dead or live whole cells • but few data on mechanism(s) Jakobsen Infect Immun 1999

15. S. pneumoniae capsular polysaccharide vaccines and protection against CAP: • 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? IgG response too weak (unconjugated)? Host response poor due to comorbidity / age? Serotype coverage too restricted to detect effects? Wrong antigens?

16. Failure of clearance of initial S. pneumoniae infection  neutrophilic consolidation

17. IL17 dependent immunity Invading S. pneumoniae increased mucosal: - chemokine release - antimicrobial peptides - mucosal repair Neutrophil recruitment IL-22 IL-17 Primed Th17 CD4 cells

18. 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

19. 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?)

20. Target antigens for natural adaptive responses to S. pneumoniae 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 Lipsitch, Plos Medicine, 2005

21. Summary and conclusions re. lung adaptive immunity v. S.pneumoniae • Antibody via improved alveolar macrophage and neutrophilphagocytosisv. 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. pneumoniaeclearance from the lungs • therefore alveolar macrophage efficacy key • can protect against wide-range of strains • protein antigens need to be considered

22. 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 • Erasmus Medical Centre, Rotterdam • Prof Alex van Belkum • Dr Corné de Vogel • UCL Biological Services Unit • UCL Institute of Child Health • Dr Helen Baxendale • Prof David Goldblatt • Prof Nigel Klein • Lindsey Ashton • UCL Dept Immunology • Dr Claudia Mauri • Dr Natalie Carter • Intercell AG, Vienna • Dr Carmen Giefing • Dr Eszter Nagy