Naturally Acquired Human Immunity to Pneumococcus Is Dependent on Antibody to Protein Antigens

Naturally acquired immunity against invasive pneumococcal disease (IPD) is thought to be dependent on anti-capsular antibody. However nasopharyngeal colonisation by Streptococcus pneumoniae also induces antibody to protein antigens that could be protective. We have used human intravenous immunoglobulin preparation (IVIG), representing natural IgG responses to S. pneumoniae, to identify the classes of antigens that are functionally relevant for immunity to IPD. IgG in IVIG recognised capsular antigen and multiple S. pneumoniae protein antigens, with highly conserved patterns between different geographical sources of pooled human IgG. Incubation of S. pneumoniae in IVIG resulted in IgG binding to the bacteria, formation of bacterial aggregates, and enhanced phagocytosis even for unencapsulated S. pneumoniae strains, demonstrating the capsule was unlikely to be the dominant protective antigen. IgG binding to S. pneumoniae incubated in IVIG was reduced after partial chemical or genetic removal of bacterial surface proteins, and increased against a Streptococcus mitis strain expressing the S. pneumoniae protein PspC. In contrast, depletion of type-specific capsular antibody from IVIG did not affect IgG binding, opsonophagocytosis, or protection by passive vaccination against IPD in murine models. These results demonstrate that naturally acquired protection against IPD largely depends on antibody to protein antigens rather than the capsule.

[1]  D. Goldblatt,et al.  Correction: Naturally Acquired Human Immunity to Pneumococcus Is Dependent on Antibody to Protein Antigens , 2017, PLoS pathogens.

[2]  T. Mitchell,et al.  A dynamic relationship between mucosal T helper type 17 and regulatory T-cell populations in nasopharynx evolves with age and associates with the clearance of pneumococcal carriage in humans. , 2016, Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases.

[3]  R. Edwards,et al.  Identification of the Streptococcus pyogenes surface antigens recognised by pooled human immunoglobulin , 2015, Scientific Reports.

[4]  M. Nahm,et al.  Pneumococcal Capsules and Their Types: Past, Present, and Future , 2015, Clinical Microbiology Reviews.

[5]  R. Chambers,et al.  Regulation of Neutrophilic Inflammation by Proteinase-Activated Receptor 1 during Bacterial Pulmonary Infection , 2015, The Journal of Immunology.

[6]  R. Callard,et al.  Importance of Bacterial Replication and Alveolar Macrophage-Independent Clearance Mechanisms during Early Lung Infection with Streptococcus pneumoniae , 2015, Infection and Immunity.

[7]  R. Wilson,et al.  Protection against Streptococcus pneumoniae lung infection after nasopharyngeal colonization requires both humoral and cellular immune responses , 2014, Mucosal Immunology.

[8]  A. L. Richard,et al.  Antibody blocks acquisition of bacterial colonization through agglutination , 2014, Mucosal Immunology.

[9]  J. Casanova,et al.  Invasive pneumococcal disease in children can reveal a primary immunodeficiency. , 2014, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[10]  U. Repnik,et al.  Protective Role of the Capsule and Impact of Serotype 4 Switching on Streptococcus mitis , 2014, Infection and Immunity.

[11]  Bo Wang,et al.  The Role of Host and Microbial Factors in the Pathogenesis of Pneumococcal Bacteraemia Arising from a Single Bacterial Cell Bottleneck , 2014, PLoS pathogens.

[12]  N. Snowden,et al.  Comprar Essentials Of Clinical Immunology 6th Ed. | Helen Chapel | 9781118472958 | Wiley , 2014 .

[13]  E. Miyaji,et al.  Controlled human infection and rechallenge with Streptococcus pneumoniae reveals the protective efficacy of carriage in healthy adults. , 2013, American journal of respiratory and critical care medicine.

[14]  F. Nimmerjahn,et al.  Intravenous immunoglobulin therapy: how does IgG modulate the immune system? , 2013, Nature Reviews Immunology.

[15]  S. Gordon,et al.  Experimental Human Pneumococcal Carriage Augments IL-17A-dependent T-cell Defence of the Lung , 2013, PLoS pathogens.

[16]  F. Nosten,et al.  Serum antibody responses to pneumococcal colonization in the first 2 years of life: results from an SE Asian longitudinal cohort study. , 2013, Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases.

[17]  T. Vernet,et al.  Effects of Deletion of the Streptococcus pneumoniae Lipoprotein Diacylglyceryl Transferase Gene lgt on ABC Transporter Function and on Growth In Vivo , 2012, PloS one.

[18]  A. van Belkum,et al.  Contributions of capsule, lipoproteins and duration of colonisation towards the protective immunity of prior Streptococcus pneumoniae nasopharyngeal colonisation , 2012, Vaccine.

[19]  G. Rajam,et al.  P4-mediated antibody therapy in an acute model of invasive pneumococcal disease. , 2012, The Journal of infectious diseases.

[20]  M. Pichichero,et al.  Reduced serum IgG responses to pneumococcal antigens in otitis-prone children may be due to poor memory B-cell generation. , 2012, The Journal of infectious diseases.

[21]  R. Veenhoven,et al.  Nasopharyngeal Colonization Elicits Antibody Responses to Staphylococcal and Pneumococcal Proteins That Are Not Associated with a Reduced Risk of Subsequent Carriage , 2012, Infection and Immunity.

[22]  T. Vernet,et al.  Zinc uptake by Streptococcus pneumoniae depends on both AdcA and AdcAII and is essential for normal bacterial morphology and virulence , 2011, Molecular microbiology.

[23]  Jeremy S. Brown,et al.  Protective Contributions against Invasive Streptococcus pneumoniae Pneumonia of Antibody and Th17-Cell Responses to Nasopharyngeal Colonisation , 2011, PloS one.

[24]  A. van Belkum,et al.  Infection with Conditionally Virulent Streptococcus pneumoniae Δpab Strains Induces Antibody to Conserved Protein Antigens but Does Not Protect against Systemic Infection with Heterologous Strains , 2011, Infection and Immunity.

[25]  D. Goldblatt,et al.  Comparison of a New Multiplex Binding Assay versus the Enzyme-Linked Immunosorbent Assay for Measurement of Serotype-Specific Pneumococcal Capsular Polysaccharide IgG , 2011, Clinical and Vaccine Immunology.

[26]  M. Pichichero,et al.  Serum Antibody Response to Five Streptococcus pneumoniae Proteins During Acute Otitis Media in Otitis-prone and Non–otitis-prone Children , 2011, The Pediatric infectious disease journal.

[27]  C. Bougault,et al.  Biochemical characterization of the histidine triad protein PhtD as a cell surface zinc-binding protein of pneumococcus. , 2011, Biochemistry.

[28]  Aaron A King,et al.  Natural immune boosting in pertussis dynamics and the potential for long-term vaccine failure , 2011, Proceedings of the National Academy of Sciences.

[29]  A. Plebani,et al.  Effectiveness of Immunoglobulin Replacement Therapy on Clinical Outcome in Patients with Primary Antibody Deficiencies: Results from a Multicenter Prospective Cohort Study , 2011, Journal of Clinical Immunology.

[30]  Todd M. Gierahn,et al.  T(H)17-based vaccine design for prevention of Streptococcus pneumoniae colonization. , 2011, Cell host & microbe.

[31]  A. Hofman,et al.  Natural Antibodies against Several Pneumococcal Virulence Proteins in Children during the Pre-Pneumococcal-Vaccine Era: the Generation R Study , 2011, Infection and Immunity.

[32]  Alimuddin Zumla.  Mandell, Douglas, and Bennett's principles and practice of infectious diseases , 2010, The Lancet Infectious Diseases.

[33]  P. Andrew,et al.  The immunising effect of pneumococcal nasopharyngeal colonisation; protection against future colonisation and fatal invasive disease. , 2010, Immunobiology.

[34]  J. Weiser,et al.  Identification of the Targets of Cross-Reactive Antibodies Induced by Streptococcus pneumoniae Colonization , 2010, Infection and Immunity.

[35]  L. Notarangelo,et al.  Primary immunodeficiencies. , 2010, The Journal of allergy and clinical immunology.

[36]  Jeremy S. Brown,et al.  The Streptococcuspneumoniae Capsule Inhibits Complement Activity and Neutrophil Phagocytosis by Multiple Mechanisms , 2009, Infection and Immunity.

[37]  J. Weiser,et al.  Streptococcus pneumoniae Resistance to Complement-Mediated Immunity Is Dependent on the Capsular Serotype , 2009, Infection and Immunity.

[38]  T. Cherian,et al.  Burden of disease caused by Streptococcus pneumoniae in children younger than 5 years: global estimates , 2009, The Lancet.

[39]  R. Adegbola,et al.  T cell memory response to pneumococcal protein antigens in an area of high pneumococcal carriage and disease. , 2009, The Journal of infectious diseases.

[40]  Thomas B. Clarke,et al.  Cellular effectors mediating Th17-dependent clearance of pneumococcal colonization in mice. , 2009, The Journal of clinical investigation.

[41]  A. Reunanen,et al.  Effects of Ageing and Gender on Naturally Acquired Antibodies to Pneumococcal Capsular Polysaccharides and Virulence-Associated Proteins , 2008, Clinical and Vaccine Immunology.

[42]  G. Jönsson,et al.  Impaired Opsonization with C3b and Phagocytosis of Streptococcus pneumoniae in Sera from Subjects with Defects in the Classical Complement Pathway , 2008, Infection and Immunity.

[43]  M. Lipsitch,et al.  Epidemiologic evidence for serotype-specific acquired immunity to pneumococcal carriage. , 2008, The Journal of infectious diseases.

[44]  T. Mitchell,et al.  Maturation of Streptococcus pneumoniae lipoproteins by a type II signal peptidase is required for ABC transporter function and full virulence , 2007, Molecular microbiology.

[45]  J. Weiser,et al.  Live Attenuated Streptococcus pneumoniae Strains Induce Serotype-Independent Mucosal and Systemic Protection in Mice , 2007, Infection and Immunity.

[46]  D. Lehmann,et al.  Pneumococcal vaccination in developing countries , 2006, The Lancet.

[47]  N. Rezaei,et al.  Effect of regular intravenous immunoglobulin therapy on prevention of pneumonia in patients with common variable immunodeficiency. , 2006, Journal of microbiology, immunology, and infection = Wei mian yu gan ran za zhi.

[48]  A. Pollard,et al.  Serum and mucosal antibody responses to pneumococcal protein antigens in children:relationships with carriage status , 2006, European journal of immunology.

[49]  S. S. Tai.  Streptococcus pneumoniae Protein Vaccine Candidates: Properties, Activities and Animal Studies , 2006, Critical reviews in microbiology.

[50]  J. Weiser,et al.  Host and Bacterial Factors Contributing to the Clearance of Colonization by Streptococcus pneumoniae in a Murine Model , 2005, Infection and Immunity.

[51]  G. Dougan,et al.  Antibodies to the Iron Uptake ABC Transporter Lipoproteins PiaA and PiuA Promote Opsonophagocytosis of Streptococcus pneumoniae , 2005, Infection and Immunity.

[52]  A. Melegaro,et al.  Antibody responses to nasopharyngeal carriage of Streptococcus pneumoniae in adults: a longitudinal household study. , 2005, The Journal of infectious diseases.

[53]  Jeremy S. Brown,et al.  Additive Inhibition of Complement Deposition by Pneumolysin and PspA Facilitates Streptococcus pneumoniae Septicemia 1 , 2005, The Journal of Immunology.

[54]  A. Melegaro,et al.  A longitudinal household study of Streptococcus pneumoniae nasopharyngeal carriage in a UK setting , 2005, Epidemiology and Infection.

[55]  M. Lipsitch,et al.  Are Anticapsular Antibodies the Primary Mechanism of Protection against Invasive Pneumococcal Disease? , 2005, PLoS medicine.

[56]  M. Lipsitch,et al.  Construction of Otherwise Isogenic Serotype 6B, 7F, 14, and 19F Capsular Variants of Streptococcus pneumoniae Strain TIGR4 , 2003, Applied and Environmental Microbiology.

[57]  T. Cate,et al.  The Immune Response to Pneumococcal Proteins during Experimental Human Carriage , 2002, The Journal of experimental medicine.

[58]  Jeremy S. Brown,et al.  A Streptococcus pneumoniae pathogenicity island encoding an ABC transporter involved in iron uptake and virulence , 2001, Molecular microbiology.

[59]  F. Ramisse,et al.  Effective Combination Therapy for Invasive Pneumococcal Pneumonia with Ampicillin and Intravenous Immunoglobulins in a Mouse Model , 2001, Antimicrobial Agents and Chemotherapy.

[60]  E. Lewis,et al.  Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children , 2000, The Pediatric infectious disease journal.

[61]  E. Swiatlo,et al.  Intranasal Immunization of Mice with a Mixture of the Pneumococcal Proteins PsaA and PspA Is Highly Protective against Nasopharyngeal Carriage of Streptococcus pneumoniae , 2000, Infection and Immunity.

[62]  T Nagatake,et al.  Streptococcus pneumoniae , 2020, Methods in Molecular Biology.

[63]  I. Furuta,et al.  Bacterial Infection , 2020, Definitions.

[64]  M. Hilleman,et al.  Protective efficacy of pneumococcal polysaccharide vaccines. , 1977, JAMA.

[65]  M. Heidelberger,et al.  PREVENTION OF PNEUMOCOCCAL PNEUMONIA BY IMMUNIZATION WITH SPECIFIC CAPSULAR POLYSACCHARIDES , 1945, The Journal of experimental medicine.

[66]  D. Tayloe,et al.  Pediatrics , 1927, The Indian Medical Gazette.