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

Robert Wilson,Jonathan M Cohen,Win Yan Chan,Mark Reglinski,Ricardo J Jose,Jeremy S Brown,Helen Baxendale,Corné De Vogel,Fernanda C Petersen,David Goldblatt,Helina Marshall,Stephen Gordon

doi:10.1371/journal.ppat.1006137

Abstract

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.

Highlights

Streptococcus pneumoniae is a leading cause of infectious disease related death, responsible annually for up to a million child deaths worldwide [1]
ELISAs using the whole S. pneumoniae cell as the antigenic target confirmed that intravenous immunoglobulin preparation (IVIG) contained significant titres of immunoglobulin G (IgG) that recognised S. pneumoniae (Table 1)
Polysaccharide-specific ELISAs demonstrated that IVIG contained IgG that recognised common S. pneumoniae capsular serotypes and cell wall polysaccharide (CWPS) (Table 1)

Summary

Introduction

Streptococcus pneumoniae is a leading cause of infectious disease related death, responsible annually for up to a million child deaths worldwide [1]. Invasive pneumococcal disease (IPD) is the most severe form of S. pneumoniae infection and mainly affects very young children and older adults. This is attributed to an underdeveloped adaptive immune system in infants, and to waning natural immunity combined with co-morbidities in the older adult. A clear understanding of the mechanisms of natural-acquired adaptive immunity to S. pneumoniae is essential to characterise why both the young and elderly are at high risk of disease and for the development of effective preventative strategies. It has generally been assumed that the type-specific anti-capsular antibodies that can develop in response to colonisation or episodes of infection are the main mechanism of natural adaptive immunity against IPD [6, 7]. There is little good evidence supporting the concept that levels of anti-capsular antibodies predict risk of IPD in unvaccinated individuals

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Discussion

Conclusion