M16-Type Metallopeptidases Are Involved in Virulence for Invasiveness and Diffusion of Leptospira interrogans and Transmission of Leptospirosis

Yu, Ge; Sun, Ai Hua; Ojcius, David M.; Li, Shi Jun; Hu, Wei Lin; Lin, Xiaojie; Yan, Jie

doi:10.1093/infdis/jiaa176

Cited by 4 publications

(3 citation statements)

References 48 publications

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“…Upon inhibition and genedepletion of ITGB1/CAV-1, the transcytosis efficiency of L. interrogans was reduced (Fig 6B and 6D). In human enteric, renal, and umbilical vein endothelial cell lines, L. interrogans was shown to use M16-Type metallopeptidases to hydrolyze extracellular matrix proteins and disassemble cell apical junctional complexes (AJCs), which may enhance transmigration through cell monolayers [61,62].…”

Section: Discussionmentioning

confidence: 99%

Internalization of Leptospira interrogans via diverse endocytosis mechanisms in human macrophages and vascular endothelial cells

et al. 2022

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Leptospirosis, one of the leading global causes of morbidity and mortality, is an emerging public health problem, particularly in large urban centers of developing countries. Leptospirosis results from infection with an organism belonging to the Leptospira genus L. interrogans. The extensive invasive ability has previously been documented, however a mechanism that describes how the organism is internalized by human macrophages and transmigrates through human blood vessel remains poorly understood. In the present study, we utilized a human macrophage and vascular endothelial cell line to study the diverse invasive mechanisms by which L. interrogans infections occur. We found that THP-1 and HUVEC had a diverse expression of cell receptors and L. interrogans entered THP-1 and HUVEC by different pathways. In the macrophage model cell line, ITGB1/FAK-signaling mediated microfilament dependent endocytosis with lysosome fusion, whereas ITGB1/CAV-1/PI3K-signaling mediated microfilament dependent endocytosis and transcytosis without lysosome fusion in the endothelial cell model. Shedding of pathogenic leptospires from HUVEC displayed higher viability than those from THP-1. The monolayer of HUVEC maintained integrity during the infection, while 3D imaging showed that leptospires were transmigrated both intra- and intercellularly. These results indicate that endocytosis of leptospires in human macrophages and human vascular endothelial cells are quite different, macrophages are responsible for eliminating leptospires in the human body during the infection while vascular endothelial cells facilitate dissemination of leptospires from blood vessels into target organs where they cause injury.

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Section: Discussionmentioning

confidence: 99%

Internalization of Leptospira interrogans via diverse endocytosis mechanisms in human macrophages and vascular endothelial cells

et al. 2022

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“…An example is the thermolysin encoded by LIC13322 , which presents proteolytic activity against complement components C3 and C6 ( Amamura et al., 2017 ; Chura-Chambi et al., 2018 ). In addition, M16-type metallopeptidases are involved in Leptospira invasiveness and transmission ( Ge et al., 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Leptolysin, a Leptospira secreted metalloprotease of the pappalysin family with broad-spectrum activity

Silva

Prado

Chura-Chambi

et al. 2022

Front. Cell. Infect. Microbiol.

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Extracellular proteolytic enzymes are produced by a variety of pathogenic microorganisms, and contribute to host colonization by modulating virulence. Here, we present a first characterization of leptolysin, a Leptospira metalloprotease of the pappalysin family identified in a previous exoproteomic study. Comparative molecular analysis of leptolysin with two other pappalysins from prokaryotes, ulilysin and mirolysin, reveals similarities regarding calcium, zinc, and arginine -binding sites conservation within the catalytic domain, but also discloses peculiarities. Variations observed in the primary and tertiary structures may reflect differences in primary specificities. Purified recombinant leptolysin of L. interrogans was obtained as a ~50 kDa protein. The protease exhibited maximal activity at pH 8.0 and 37°C, and hydrolytic activity was observed in the presence of different salts with maximum efficiency in NaCl. Substrate specificity was assessed using a small number of FRET peptides, and showed a marked preference for arginine residues at the P1 position. L. interrogans leptolysin proteolytic activity on proteinaceous substrates such as proteoglycans and plasma fibronectin was also evaluated. All proteins tested were efficiently degraded over time, confirming the protease´s broad-spectrum activity in vitro. In addition, leptolysin induced morphological alterations on HK-2 cells, which may be partially attributed to extracellular matrix (ECM) degradation. Hemorrhagic foci were observed in the dorsal skin of mice intradermally injected with leptolysin, as a plausible consequence of ECM disarray and vascular endothelium glycocalyx damage. Assuming that leptospiral proteases play an important role in all stages of the infectious process, characterizing their functional properties, substrates and mechanisms of action is of great importance for therapeutic purposes.

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“…Na Tabela 9, mostra-se uma relação das proteínas com domínios Peptidase (2 cisteíno-, 15 metalo-e 2 serino-peptidases) que foram identificadas por espectrometria de massas e selecionadas como potenciais alvos envolvidos na virulência da L. interrogans. Na espécie patogênica, L. interrogans, temos algumas metalo-proteases com capacidades proteolíticas confirmadas experimentalmente contendo os domínios Peptidase_M23 (Hashimoto et al, 2013), Peptidase_M4 (Chura-Chambi et al, 2018 e Peptidase_M16 (Ge et al, 2020).…”

Section: Proteínas Com Domínios Peptidaseunclassified

Identificação dos fatores de virulência da Leptospira interrogans através de análises proteômicas comparativas

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M16-Type Metallopeptidases Are Involved in Virulence for Invasiveness and Diffusion of Leptospira interrogans and Transmission of Leptospirosis

Cited by 4 publications

References 48 publications

Internalization of Leptospira interrogans via diverse endocytosis mechanisms in human macrophages and vascular endothelial cells

Internalization of Leptospira interrogans via diverse endocytosis mechanisms in human macrophages and vascular endothelial cells

Leptolysin, a Leptospira secreted metalloprotease of the pappalysin family with broad-spectrum activity

Identificação dos fatores de virulência da Leptospira interrogans através de análises proteômicas comparativas

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