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 1

GAS adheres to the decidua and grows on it using tissue-secreted products.

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GAS adheres to the decidua and grows on it using tissue-secreted product...
(A) Imaris 3D representation of a tissue infected 16 hours and imaged en face. Fibronectin, red; type IV collagen, yellow; GFP-GAS, green; DAPI, blue. Scale bar: 20 μm. Magnification: ×40. (B) Immunofluorescence of a paraffin-embedded tissue transverse slice (24 hpi). Anti-GAS, green; DAPI, blue. Scale bar: 10 μm. Magnification: ×100. (C and E) z-Max intensity projections of GFP signals from live en face acquisition images of GFP-WT at the tissue surface, at indicated time points (hr:min). Scale bars: 10 μm (C) and 20 μm (E). Magnification: ×25. (D) Ratio over time of the area covered by WT GFP-GAS signal area in tissues from 5 samples including those in C. Mean values of 3 to 11 fields for each of the 5 tissues are plotted. (F) Quantification of the surface covered by GFP-GAS from the image in E. Red dotted line, exponential curve fitted starting at 105 minutes; R2 = 0.9948. (G) 3D surface heatmap of the bacterial layer thickness at different time points (hr:min) (live imaging). The x, y, and z axes are scaled, color code in micrometers. Image size: 303 × 190 μm. (H) Quantification of bacterial layer mean thickness; mean values of 2 to 13 fields for each of 5 tissues are plotted. (I) Multiplication factor after GAS incubation for 8 hours in tissue-conditioned medium or RPMI. S# indicates the sample number. (J) Basal levels of accumulation of the indicated antimicrobial peptide in the supernatant of noninfected decidual tissues 8 hours after addition of fresh RPMI. Symbols are the same as in panel I. For all panels, error bars are standard error of the mean. **P < 0.005, ***P < 0.001 by 2-way ANOVA at the initial time points (D and H).