In Silico Structural and Functional Characterization of HtrA Proteins of Leptospira spp.: Possible Implications in Pathogenesis

Abstract

Leptospirosis is a zoonosis caused by the pathogenic bacteria of the genus Leptospira. The identification of conserved outer membrane proteins among pathogenic strains is a major research target in elucidating mechanisms of pathogenicity. Surface-exposed proteins are most probably the ones involved in the interaction of leptospires with the environment. Some spirochetes use outer membrane proteases as a way to penetrate host tissues. HtrA is a family of proteins found in various cell types, from prokaryotes to primates. They are a set of proteases usually composed of a serine protease and PDZ domains, and they are generally transported to the periplasm. Here, we identified four genes—annotated as HtrA, LIC11111, LIC20143, LIC20144 and LIC11037—and another one annotated as a serine protease, LIC11112. It is believed that the last forms a functional heterodimer with LIC11111, since they are organized in one operon. Our analyses showed that these proteins are highly conserved among pathogenic strains. LIC11112, LIC20143, and LIC11037 have the serine protease domain with the conserved catalytic triad His-Asp-Ser. This is the first bioinformatics analysis of HtrA proteins from Leptospira that suggests their proteolytic activity potential. Experimental studies are warranted to elucidate this possibility.

Disassembly of the apical junctional complex during the transmigration of Leptospira interrogans across polarized renal proximal tubule epithelial cells

“…A number of pathogens have reported to secrete bacterial serine proteases of the HtrA family, which promote the shedding of the S‐E‐cad domain, enabling tissue invasion and transmigration (Backert et al, 2018 ; Devaux et al, 2019 ). Leptospira interrogans encodes Htr‐A homologues (Daroz, Fernandes, Teixeira, & Nascimento, 2020 ; Satou et al, 2015 ) that might play a role in E‐cad cleavage. E‐cad has been reported as a putative leptospiral receptor (Eshghi et al, 2019 ; Kochi et al, 2019 ), but the binding domain of E‐cad has not been determined, and further studies are needed to determine the importance of E‐cad cleavage for the retrieval of host cell binding sites.…”

Degradation of p0071 and p120-catenin during adherens junction disassembly by Leptospira interrogans

“…Bacterial proteases can also directly target AJC proteins for degradation, such as tight junction-membrane protein claudins in Aeromonas and Campylobacter infections ( Sharafutdinov et al., 2020 ; Ueda et al., 2022 ). Several leptospiral proteases capable of degrading extracellular matrix or complement factors were identified by experimental and in silico studies ( Daroz et al., 2020 ; Daroz et al., 2021 ; Courrol et al., 2022 ). However, a specific protease for degrading AJC proteins has not been identified yet.…”