Date Published: January 30, 2017
Publisher: Public Library of Science
Author(s): Robert Wilson, Jonathan M. Cohen, Mark Reglinski, Ricardo J. Jose, Win Yan Chan, Helina Marshall, Corné de Vogel, Stephen Gordon, David Goldblatt, Fernanda C. Petersen, Helen Baxendale, Jeremy S. Brown, Timothy J. Mitchell.
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.
Streptococcus pneumoniae is a leading cause of infectious disease related death, responsible annually for up to a million child deaths worldwide . Pneumonia represents the greatest burden of disease caused by S. pneumoniae , and despite current vaccination strategies the burden of pneumococcal pneumonia remains high. 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. Vaccines based on the polysaccharide capsule of S. pneumoniae are highly protective against the capsular serotypes included in the vaccine preparation [3–5], and protection correlates with the level of anti-capsular antibody responses. It has generally been assumed that the type-specific anti-capsular antibodies that can develop in response to colonisation or episodes of infection are also the main mechanism of natural adaptive immunity against IPD [6, 7]. However, there is little good evidence supporting the concept that levels of anti-capsular antibodies predict risk of IPD in unvaccinated individuals.
The bimodal distribution of S. pneumoniae infections in the very young and elderly suggests there is a significant degree of naturally-acquired immunity that evolves in early life and then wanes in later life. This naturally-acquired immunity is probably acquired through multiple episodes of nasopharyngeal colonisation with S. pneumoniae that repeatedly affect all humans rather than solely after disease episodes [16, 18–20, 24, 31]. Human epidemiological and experimental evidence from mouse models of infection suggest naturally-acquired immunity has a serotype-independent component [20, 28, 29, 31], yet the assumption remains that antibody to capsular antigen is the dominant mechanism of protection against IPD [6, 7]. As a consequence, clinical assessment of susceptibility to IPD is dependent on measuring anti-capsular IgG levels.