Immune exclusion by naturally acquired secretory IgA against pneumococcal pilus-1
Ulrike Binsker, … , Alexandria J. Hammond, Jeffrey N. Weiser
Ulrike Binsker, … , Alexandria J. Hammond, Jeffrey N. Weiser
Published February 3, 2020; First published November 5, 2019
Citation Information: J Clin Invest. 2020;130(2):927-941. https://doi.org/10.1172/JCI132005.
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Research Article Microbiology

Immune exclusion by naturally acquired secretory IgA against pneumococcal pilus-1

Abstract

Successful infection by mucosal pathogens requires overcoming the mucus barrier. To better understand this key step, we performed a survey of the interactions between human respiratory mucus and the human pathogen Streptococcus pneumoniae. Pneumococcal adherence to adult human nasal fluid was seen only by isolates expressing pilus-1. Robust binding was independent of pilus-1 adhesive properties but required Fab-dependent recognition of RrgB, the pilus shaft protein, by naturally acquired secretory IgA (sIgA). Pilus-1 binding by specific sIgA led to bacterial agglutination, but adherence required interaction of agglutinated pneumococci and entrapment in mucus particles. To test the effect of these interactions in vivo, pneumococci were preincubated with human sIgA before intranasal challenge in a mouse model of colonization. sIgA treatment resulted in rapid immune exclusion of pilus-expressing pneumococci. Our findings predict that immune exclusion would select for nonpiliated isolates in individuals who acquired RrgB-specific sIgA from prior episodes of colonization with piliated strains. Accordingly, genomic data comparing isolates carried by mothers and their children showed that mothers are less likely to be colonized with pilus-expressing strains. Our study provides a specific example of immune exclusion involving naturally acquired antibody in the human host, a major factor driving pneumococcal adaptation.

Authors

Ulrike Binsker, John A. Lees, Alexandria J. Hammond, Jeffrey N. Weiser

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Figure 8

Immune exclusion by pilus-1–specific sIgA.

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Immune exclusion by pilus-1–specific sIgA. (A–C) Adult mice were intrana...
(A–C) Adult mice were intranasally infected with a suspension containing equal amounts of TIGR4 and isogenic pilus-1–deficient mutant. Before administration, bacteria were preincubated with either sIgA, serum IgA (equal anti-RrgB titer compared with sIgA), cleaved sIgA, or PBS. Colonization density and competitive index (CI) were assessed 4 hours (A) and 22 hours (C) after infection by culture of upper respiratory tract lavages followed by colony immunoblot using an anti-RrgB antibody. n = 5–13. (B) Before administration, sIgA was cleaved with recombinant IgA1 protease for 20 hours at 37°C. Cleavage was visualized on a denaturing and nonreducing SDS-PAGE and Western blot. Solid arrow indicates uncleaved sIgA (400 kDa), and dotted arrows indicate cleaved sIgA1 (200 kDa and 50 kDa). (D) Adherence of Spn TIGR4 and isogenic iga-deficient mutant to hNF was analyzed in a solid-phase assay as described before. Results are shown as mean values of 3 independent experiments with error bars corresponding to SD. *P < 0.05 by 2-tailed unpaired t test, n = 6. (E) Adult mice were challenged intranasally with mutants lacking the IgA1 protease. CI was determined as described in C. n = 8–9. (A, C, and E) Experiments were repeated twice, and groups represent n = 5–13 animals with median ± IQR. Dashed lines represent CI = 1. Group medians were compared with a CI = 1 by Wilcoxon signed rank test, and resulting P values are indicated.