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Molecular basis of TMPRSS2 recognition by Paeniclostridium sordellii hemorrhagic toxin.

ABSTRACT: Hemorrhagic toxin (TcsH) is a major virulence factor produced by Paeniclostridium sordellii, which is a non-negligible threat to women undergoing childbirth or abortions. Recently, Transmembrane Serine Protease 2 (TMPRSS2) was identified as a host receptor of TcsH. Here, we show the cryo-EM structures of the TcsH-TMPRSS2 complex and uncover that TcsH binds to the serine protease domain (SPD) of TMPRSS2 through the CROP unit-VI. This receptor binding mode is unique among LCTs. Five top surface loops of TMPRSS2^SPD, which also determine the protease substrate specificity, constitute the structural determinants recognized by TcsH. The binding of TcsH inhibits the proteolytic activity of TMPRSS2, whereas its implication in disease manifestations remains unclear. We further show that mutations selectively disrupting TMPRSS2-binding reduce TcsH toxicity in the intestinal epithelium of the female mice. These findings together shed light on the distinct molecular basis of TcsH-TMPRSS2 interactions, which expands our knowledge of host recognition mechanisms employed by LCTs and provides novel targets for developing therapeutics against P. sordellii infections.

SUBMITTER: Zhou R

PROVIDER: S-EPMC10912200 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature

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Molecular basis of TMPRSS2 recognition by Paeniclostridium sordellii hemorrhagic toxin.

Zhou Ruoyu R He Liuqing L Zhang Jiahao J Zhang Xiaofeng X Li Yanyan Y Zhan Xiechao X Tao Liang L

Nature communications 20240304 1

Hemorrhagic toxin (TcsH) is a major virulence factor produced by Paeniclostridium sordellii, which is a non-negligible threat to women undergoing childbirth or abortions. Recently, Transmembrane Serine Protease 2 (TMPRSS2) was identified as a host receptor of TcsH. Here, we show the cryo-EM structures of the TcsH-TMPRSS2 complex and uncover that TcsH binds to the serine protease domain (SPD) of TMPRSS2 through the CROP unit-VI. This receptor binding mode is unique among LCTs. Five top surface lo ...[more]

PMID: 38438396

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Project description:BackgroundWith the current rise of antibiotic resistance in bacteria, it is important to monitor the efficacy of antimicrobials in clinical use. Paeniclostridium sordellii (previously Clostridium sordellii) is a bacterial pathogen that causes human uterine infection after spontaneous or medically induced abortion, for which mortality rates approach 100%. Prophylactic antibiotics have been recommended for individuals undergoing medically-induced abortion, one of which is doxycycline, a member of the tetracycline antibiotic family. However, tetracycline resistance had not been well characterized in P. sordellii. This study therefore aimed to determine the levels of tetracycline resistance in P. sordellii isolates, and to identify associated loci and their genomic locations.ResultsUsing a MIC assay, five of 24 P. sordellii isolates were found to be resistant to tetracycline, minocycline, and importantly, doxycycline. Analysis of genome sequence data from 46 isolates found that phenotypically resistant isolates encoded a variant of the Clostridium perfringens tetracycline resistance determinant Tet P. Bioinformatic analysis and comparison of the regions surrounding these determinants found variation in the genomic location of Tet P among P. sordellii isolates. The core genome comparison of the 46 isolates revealed genetic diversity and the absence of dominant genetic types among the isolates. There was no strong association between geographic location of isolation, animal host or Tet P carriage with isolate genetic type. Furthermore, the analysis of the Tet P genotype revealed that Tet P is encoded chromosomally, or on one of two, novel, small plasmids, all consistent with multiple acquisition and recombination events. BLAST analysis of Clostridioides difficile draft genome sequences also identified a Tet P locus, the genomic location of which demonstrated an evolutionary relationship with the P. sordellii locus.ConclusionsThe Tet P determinant is found in variable genomic locations within diverse human and animal isolates of P. sordellii and C. difficile, which suggests that it can undergo horizontal transfer, and may disseminate tetracycline resistance between clostridial species. Doxycycline is a suggested prophylactic treatment for P. sordellii infections, however, a small sub-set of the isolates tested are resistant to this antibiotic. Doxycycline may therefore not be an appropriate prophylactic treatment for P. sordellii infections.

Dataset Information

Molecular basis of TMPRSS2 recognition by Paeniclostridium sordellii hemorrhagic toxin.

Publications

Molecular basis of TMPRSS2 recognition by Paeniclostridium sordellii hemorrhagic toxin.

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