Pulmonary adaptive responses against bacterial pathogens J S Brown Reader 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 % mild - outpatient treatment % admitted % severe / ITU - mortality 5 – 10% (20% UK audit) 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% 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 infections 2nd commonest bacterial cause of death pneumonia 0 to 75 per 100,000 colonisations aspiration nasopharyngeal commensal 10% adults 50% infants Septicaemia 1 in 25 mortality 20% otitis media mortality 0% meningitis mortality 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 Key immune effectors 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-cell Antibody IFN-gamma IL-22 Mucosal repair Antimicrobial peptides Chemokine release Phagocyte recruitment IL-17 Phagocyte CD4 T-cell Th2 CD8 T-cell Cytotoxicity v. intracellular pathogens Hyper IgE syndrome Antibody deficiencies TAP syndrome?

Scavenger Receptors Mannose receptor / lectins Complement Receptors Fc gamma Receptors Toll Like Receptors 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

EFFICIENT BACTERIAL CLEARANCE NO PNEUMONIA / BRONCHITIS low inoculum low virulence strain intact epithelium efficient alveolar macrophages BACTERIAL FACTORSHOST 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 pneumonia after 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