title: The immunising effect of pneumococcal nasopharyngeal colonisation; protection against future colonisation and fatal invasive disease.
abstract: The human nasopharynx is an important ecological niche for Streptococcus pneumoniae, and asymptomatic nasopharyngeal carriage is a common precursor to invasive disease. However, knowledge of the immunological events, which occur during carriage, both on a cellular and humoral level, remains limited. Here, we present a long-term stable model of asymptomatic nasopharyngeal carriage using outbred naïve mice, in which we have investigated the effect of previous nasopharyngeal exposure to pneumococci, in the prevention of subsequent carriage and invasive disease. Carriage of D39 wildtype pneumococci restricted to the nasopharynx could be detected for at least 28 days post-infection, whereas nasopharyngeal carriage of a pneumolysin negative isogenic mutant (PLN-A) was cleared in 7-14 days. Both carriage events induced total and capsule specific IgA mucosal antibodies and increased levels of systemic antibodies (IgG against pneumococcal surface protein A (PspA) and IgM capsular polysaccharide), which increased over time and correlated to reduced nasopharyngeal pneumococcal numbers. Prior nasopharyngeal colonisation with PLN-A significantly reduced the duration of subsequent D39 wildtype carriage, and significantly increased survival following invasive pneumococcal challenge. In this case systemic anti-PspA and anti-capsular antibody IgM concentrations showed a strong correlation with reduced bacterial numbers in the lungs and nasopharynx, respectively and also with increased levels of IL17A and CD4+ T cells in lungs of pre-colonised mice. Prior nasopharyngeal colonisation with PLN-A also resulted in significant cross-serotype protection with mice protected from invasive disease with serotype 3 strain (A66) after pre-colonisation with a serotype 2 strain (D39). Our results suggest that both mucosal and systemic antibody as well as cellular host factors have a role in long-term protection against both colonisation and invasive pneumococcal challenge.
authors.affiliation: Department of Infection, Immunity and Inflammation, University of Leicester, Leicester LE19HN, United Kingdom.
authors.forename: Luke
authors.initials: L
authors.lastname: Richards
authors.forename: Daniela M
authors.initials: DM
authors.lastname: Ferreira
authors.forename: Eliane N
authors.initials: EN
authors.lastname: Miyaji
authors.forename: Peter W
authors.initials: PW
authors.lastname: Andrew
authors.forename: Aras
authors.initials: A
authors.lastname: Kadioglu
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood / Q000276:immunology; D016667:Bacterial Capsules / Q000097:blood / Q000276:immunology; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002353:Carrier State / Q000276:immunology* / Q000382:microbiology; D005260:Female; D007070:Immunoglobulin A / Q000032:analysis; D007074:Immunoglobulin G / Q000097:blood; D020381:Interleukin-17 / Q000276:immunology; D008168:Lung / Q000276:immunology; D051379:Mice; D009154:Mutation; D009305:Nasopharynx / Q000276:immunology* / Q000382:microbiology*; D011008:Pneumococcal Infections / Q000276:immunology* / Q000382:microbiology; D013296:Streptococcus pneumoniae / Q000235:genetics / Q000276:immunology*; D013301:Streptolysins / Q000172:deficiency / Q000235:genetics; D014774:Virulence / Q000276:immunology
chemical_list: D000907:Antibodies, Bacterial; D001426:Bacterial Proteins; C098680:Il17a protein, mouse; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D020381:Interleukin-17; D013301:Streptolysins; C032290:plY protein, Streptococcus pneumoniae; C051592:pneumococcal surface protein A