Dataset Information

Genome-Wide Screens Identify Group A Streptococcus Surface Proteins Promoting Female Genital Tract Colonization and Virulence.

ABSTRACT: Group A streptococcus (GAS) is a major pathogen that impacts health and economic affairs worldwide. Although the oropharynx is the primary site of infection, GAS can colonize the female genital tract and cause severe diseases, such as puerperal sepsis, neonatal infections, and necrotizing myometritis. Our understanding of how GAS genes contribute to interaction with the primate female genital tract is limited by the lack of relevant animal models. Using two genome-wide transposon mutagenesis screens, we identified 69 GAS genes required for colonization of the primate vaginal mucosa in vivo and 96 genes required for infection of the uterine wall ex vivo. We discovered a common set of 39 genes important for GAS fitness in both environments. They include genes encoding transporters, surface proteins, transcriptional regulators, and metabolic pathways. Notably, the genes that encode the surface-exclusion protein (SpyAD) and the immunogenic secreted protein 2 (Isp2) were found to be crucial for GAS fitness in the female primate genital tract. Targeted gene deletion confirmed that isogenic mutant strains ΔspyAD and Δisp2 are significantly impaired in ability to colonize the primate genital tract and cause uterine wall pathologic findings. Our studies identified novel GAS genes that contribute to female reproductive tract interaction that warrant translational research investigation.

SUBMITTER: Zhu L

PROVIDER: S-EPMC7184637 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Genome-Wide Screens Identify Group A Streptococcus Surface Proteins Promoting Female Genital Tract Colonization and Virulence.

Zhu Luchang L Olsen Randall J RJ Beres Stephen B SB Ojeda Saavedra Matthew M Kubiak Samantha L SL Cantu Concepcion C CC Jenkins Leslie L Yerramilli Prasanti P Pruitt Layne L Charbonneau Amelia R L ARL Waller Andrew S AS Musser James M JM

The American journal of pathology 20200319 4

Group A streptococcus (GAS) is a major pathogen that impacts health and economic affairs worldwide. Although the oropharynx is the primary site of infection, GAS can colonize the female genital tract and cause severe diseases, such as puerperal sepsis, neonatal infections, and necrotizing myometritis. Our understanding of how GAS genes contribute to interaction with the primate female genital tract is limited by the lack of relevant animal models. Using two genome-wide transposon mutagenesis scr ...[more]

PMID: 32200972

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Project description:Group B Streptococcus (GBS) asymptomatically colonizes the vagina but can opportunistically ascend to the uterus and be transmitted vertically during pregnancy, resulting in neonatal pneumonia, bacteremia, and meningitis. GBS is a leading etiologic agent of neonatal infection and understanding the mechanisms by which GBS persists within the polymicrobial female genital mucosa has the potential to mitigate subsequent transmission and disease. Type VIIb secretion systems (T7SSb) are encoded by Bacillota and often mediate interbacterial competition using LXG toxins that contain conserved N-termini important for secretion and variable C-terminal toxin domains that confer diverse biochemical activities. Our recent work characterized a role for the GBS T7SSb in vaginal colonization and ascending infection but the mechanisms by which the T7SSb promotes GBS persistence in this polymicrobial niche remain unknown. Herein, we investigate the GBS T7SS in interbacterial competition and GBS niche establishment in the female genital tract. We demonstrate GBS T7SS-dependent inhibition of mucosal pathobiont Enterococcus faecalis both in vitro using predator-prey assays and in vivo in the murine genital tract and found that a GBS LXG protein encoded within the T7SS locus (herein named group B streptococcal LXG Toxin A) contributes to these phenotypes. We identify BltA as a T7SS substrate that is toxic to E. coli and S. aureus upon induction of intracellular expression along with associated chaperones. Finally, we show that BltA and its chaperones contribute to GBS vaginal colonization. Altogether, these data reveal a role for a novel T7b-secreted toxin in GBS mucosal persistence and competition.IMPORTANCECompetition between neighboring, non-kin bacteria is essential for microbial niche establishment in mucosal environments. Gram-positive bacteria encoding T7SSb have been shown to engage in competition through the export of LXG-motif-containing toxins, but these have not been characterized in group B Streptococcus (GBS), an opportunistic colonizer of the polymicrobial female genital tract. Here, we show a role for GBS T7SS in competition with mucosal pathobiont Enterococcus faecalis, both in vitro and in vivo. We further find that a GBS LXG protein contributing to this antagonism is exported by the T7SS and is intracellularly toxic to other bacteria; therefore, we have named this protein group B streptococcal LXG Toxin A (BltA). Finally, we show that BltA and its associated chaperones promote persistence within female genital tract tissues, in vivo. These data reveal previously unrecognized mechanisms by which GBS may compete with other mucosal opportunistic pathogens to persist within the female genital tract.

Project description:Various studies have shown Staphylococcus aureus to be one of the most prevalent organism in male and female genital tract but most practitioners dismiss it as mere contamination which is assumed to be of no significance. However, it is now suggested that the presence of this organism should not be ignored, as incubation of spermatozoa with S. aureus results in reduced sperm motility. Although S. aureus has been reported to cause immobilization of spermatozoa, however, its role in infertility has yet to be elucidated. The present study was designed to establish a spermagglutinating strain of S. aureus isolated from the cervix of a woman with unexplained infertility, in mouse and evaluate its effect on fertility outcome. Female Balb/c mice were inoculated intravaginally with different doses of S. aureus (10(4), 10(6) or 10(8)cfu/20 µl) for 10 consecutive days. Microbial colonization monitored every 3(rd) day by vaginal cultures, revealed that strain could efficiently colonize mouse vagina. Mating on day 12, with proven breeder males led to 100% decrease in fertility as compared to control. Even a single dose of 10(6) or 10(8)cfu could lead to vaginal colonization which persisted for 10 days followed by gradual clearing till 21 days, vaginal cultures were negative thereafter. Female mice mated on day 7 (culture positive), were rendered infertile, however, the mice mated on day 22 (culture negative), retained fertility and delivered pups indicating its role in provoking infertility. Further, except infertility, no other clinical manifestation could be seen apparently or histologically. However, when a non-spermagglutinating/immobilizing standard strain of S. aureus MTCC6625 was inoculated intravaginally at 10(8)cfu for 10 days followed by mating on day 12, fertility was observed in all the female mice. This supports the hypothesis that infertility observed in the former groups was as a result of colonization with spermagglutinating strain of S. aureus.

Dataset Information

Genome-Wide Screens Identify Group A Streptococcus Surface Proteins Promoting Female Genital Tract Colonization and Virulence.

Publications

Genome-Wide Screens Identify Group A Streptococcus Surface Proteins Promoting Female Genital Tract Colonization and Virulence.

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