Streptococcus pyogenes infects human endometrium by limiting the innate immune response
Antonin Weckel, … , Céline Méhats, Agnès Fouet
Antonin Weckel, … , Céline Méhats, Agnès Fouet
Published December 15, 2020
Citation Information: J Clin Invest. 2021;131(4):e130746. https://doi.org/10.1172/JCI130746.
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Research Article Infectious disease Microbiology

Streptococcus pyogenes infects human endometrium by limiting the innate immune response

Abstract

Group A Streptococcus (GAS), a Gram-positive human-specific pathogen, yields 517,000 deaths annually worldwide, including 163,000 due to invasive infections and among them puerperal fever. Before efficient prophylactic measures were introduced, the mortality rate for mothers during childbirth was approximately 10%; puerperal fever still accounts for over 75,000 maternal deaths annually. Yet, little is known regarding the factors and mechanisms of GAS invasion and establishment in postpartum infection. We characterized the early steps of infection in an ex vivo infection model of the human decidua, the puerperal fever portal of entry. Coordinate analysis of GAS behavior and the immune response led us to demonstrate that (a) GAS growth was stimulated by tissue products; (b) GAS invaded tissue and killed approximately 50% of host cells within 2 hours, and these processes required SpeB protease and streptolysin O (SLO) activities, respectively; and (c) GAS impaired the tissue immune response. Immune impairment occurred both at the RNA level, with only partial induction of the innate immune response, and protein level, in an SLO- and SpeB-dependent manner. Our study indicates that efficient GAS invasion of the decidua and the restricted host immune response favored its propensity to develop rapid invasive infections in a gynecological-obstetrical context.

Authors

Antonin Weckel, Thomas Guilbert, Clara Lambert, Céline Plainvert, François Goffinet, Claire Poyart, Céline Méhats, Agnès Fouet

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Figure 3

GAS induces stromal and immune cell death via processes involving SLO and other secreted factors.

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GAS induces stromal and immune cell death via processes involving SLO an...
(A) Orthogonal view of a sample 5 hpi under static conditions prestained with anti-fibronectin (red), anti-CD45 (yellow), WT-GFP bacteria (green), and DAPI (gray). Scale bar: 10 μm. Magnification: ×40. (B) Immunofluorescence of the decidua 16 hpi under static conditions. DAPI, gray; TUNEL, green. Scale bar: 10 μm. Magnification: ×63. (C) Immunofluorescence of a sample 16 hpi under static conditions. Stromal cells are vimentin+CD45– and immune cells are CD45+. Vimentin, red; DAPI, gray; CD45, yellow; TUNEL, green. Scale bar: 10 μm. Magnification: ×40. (D) Immunofluorescence of a sample 4 hpi under static conditions with the indicated strains. N.I., not infected. DAPI, gray; TUNEL, green. Scale bar: 40 μm. Magnification: ×20. (E–G) Quantification of cytotoxicity by determination of the percentage of dead cells (E) on decidua with 3 samples, in the absence, contact (+), or the presence, contact (–), of a Transwell insert at indicated times; (F) on primary decidual cells from 3 different samples with indicated strains 4 hpi; and (G) on decidua with 4 samples with indicated strains, at indicated times. *P < 0.05; **P < 0.005; ***P < 0.001 by 2-way ANOVA with Bonferroni’s post hoc test (E and G) or paired 1-way ANOVA (F).