Mast cell–derived factor XIIIA contributes to sexual dimorphic defense against group B streptococcal infections
Adrian M. Piliponsky, … , Adam J. Moeser, Lakshmi Rajagopal
Adrian M. Piliponsky, … , Adam J. Moeser, Lakshmi Rajagopal
Published August 25, 2022
Citation Information: J Clin Invest. 2022;132(20):e157999. https://doi.org/10.1172/JCI157999.
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Mast cell–derived factor XIIIA contributes to sexual dimorphic defense against group B streptococcal infections

Abstract

Invasive bacterial infections remain a major cause of human morbidity. Group B streptococcus (GBS) are Gram-positive bacteria that cause invasive infections in humans. Here, we show that factor XIIIA–deficient (FXIIIA-deficient) female mice exhibited significantly increased susceptibility to GBS infections. Additionally, female WT mice had increased levels of FXIIIA and were more resistant to GBS infection compared with isogenic male mice. We observed that administration of exogenous FXIIIA to male mice increased host resistance to GBS infection. Conversely, administration of a FXIIIA transglutaminase inhibitor to female mice decreased host resistance to GBS infection. Interestingly, male gonadectomized mice exhibited decreased sensitivity to GBS infection, suggesting a role for gonadal androgens in host susceptibility. FXIIIA promoted GBS entrapment within fibrin clots by crosslinking fibronectin with ScpB, a fibronectin-binding GBS surface protein. Thus, ScpB-deficient GBS exhibited decreased entrapment within fibrin clots in vitro and increased dissemination during systemic infections. Finally, using mice in which FXIIIA expression was depleted in mast cells, we observed that mast cell–derived FXIIIA contributes to host defense against GBS infection. Our studies provide insights into the effects of sexual dimorphism and mast cells on FXIIIA expression and its interactions with GBS adhesins that mediate bacterial dissemination and pathogenesis.

Authors

Adrian M. Piliponsky, Kavita Sharma, Phoenicia Quach, Alyssa Brokaw, Shayla Nguyen, Austyn Orvis, Siddhartha S. Saha, Nyssa Becker Samanas, Ravin Seepersaud, Yu Ping Tang, Emily Mackey, Gauri Bhise, Claire Gendrin, Anna Furuta, Albert J. Seo, Eric Guga, Irina Miralda, Michelle Coleman, Erin L. Sweeney, Charlotte A. Bäuml, Diana Imhof, Jessica M. Snyder, Adam J. Moeser, Lakshmi Rajagopal

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Figure 3

Increased FXIIIA levels promote resistance to GBS infection.

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Increased FXIIIA levels promote resistance to GBS infection. (A) FXIIIA ...
(A) FXIIIA activity in plasma from uninfected male and female B6 mice (n = 4–5/group). Data are represented as mean ± SD with individual values. *P < 0.05, unpaired Student’s t test. (B) Bleeding time tests on uninfected or GBS-infected B6 male and female mice at 24 hours after infection (n = 7–10/group). Data are represented as mean ± SEM with individual values. *P < 0.05; **P < 0.01; ****P < 0.0001, Tukey’s multiple-comparison test following 1-way ANOVA. (C) Male and female B6 mice (n = 8–9/group) were infected i.p. with 0.5 to 1 × 108 of WT GBS A909. Bacterial burden in blood, peritoneal fluids, spleen, and lungs at 24 hours after infection. Data are represented as median with individual values. *P < 0.05; **P < 0.01, Mann-Whitney U test. (D) Exogenous FXIIIA (1 unit/mouse) or control PBS was administered i.v. to male B6 mice (n = 8 mice/group) 2 hours after GBS infection as above. Bacterial burden in blood, peritoneal fluids, spleen, and lungs at 24 hours after infection. Data are represented as medians with individual values. *P < 0.05; **P < 0.01, Mann-Whitney U test. (E) GDX and control (sham operated) male B6 mice (n = 4-5/group) were infected with WT GBS, and bacterial burden was evaluated in the peritoneal fluids, spleen, and lungs as above. Data are represented as median with individual values. *P < 0.05, Mann-Whitney U test. Many of the infected mice in the control group were morbid and hence blood could not be collected. (F) Bleeding time tests were performed on GBS-infected male GDX or control (sham operated) B6 mice at 24 hours after infection (n = 5/group). Data are represented as mean ± SEM with individual mouse values. ***P < 0.001, unpaired t test.