Abstract
BackgroundLeptospira interrogans is a pathogenic, spirochetal bacterium that is responsible for leptospirosis, an emerging worldwide zoonosis. Leptospires colonize the renal proximal tubules and chronically infect the kidney. Live bacteria are excreted into urine, contaminating the environment. While it is well known that leptospires can persist in the kidneys without signs of disease for several months, the interactions of leptospires with the proximal renal epithelial tubule cells that allow the chronic renal colonization have not been elucidated yet. In the present study, we compared the interactions between a virulent, low passage (LP) strain and a cultured-attenuated, high passage (HP) strain with renal proximal tubule epithelial cells (RPTECs) to elucidate the strategies used by Leptospira to colonize the kidney.ResultsKinetics analysis of kidney colonization in a mouse model of chronic infection performed by quantitative real-time PCR and immunofluorescence, showed that the LP strain reached the kidney by 3 days post infection (pi) and attached to the basal membrane side of the renal epithelial cells. At 10 days pi, some leptospires were attached to the luminal side of the tubular epithelia and the number of colonizing leptospires gradually increased. On the other hand, the HP strain was cleared during hematogenous dissemination and did not colonize the kidney. Transmission electron microscopy analysis of LP-infected kidneys at 25 days pi showed aggregated leptospires and membrane vesicles attached to the epithelial brush border. Leptospiral kidney colonization altered the organization of the RPTEC brush border. An in vitro model of infection using TCMK-1 cells, showed that leptospiral infection induced a host stress response, which is delayed in LP-infected cells.ConclusionsAfter hematogenous dissemination, leptospires create protective and replicative niches in the base membrane and luminal sides of the RPTECs. During the long-term colonization, leptospires attached to the RPTEC brush borders and membrane vesicles might be involved in the formation of a biofilm-like structure in vivo. Our results also suggested that the virulent strain is able to manipulate host cell stress responses to promote renal colonization.
Highlights
Leptospira interrogans is a pathogenic, spirochetal bacterium that is responsible for leptospirosis, an emerging worldwide zoonosis
Kinetics of leptospiral dissemination in mouse infected with low-passage number (LP) virulent or high-passagenumber (HP) attenuated Leptospira interrogans strains The kinetics of leptospiral dissemination was studied in C57BL/6 mice after intraperitoneal (IP) injection of a sublethal dose of low passage (LP) or high passage (HP) L. interrogans strains [17]
A hamster model of infection showed that IP injection of an HP L. interrogans strain resulted in the dissemination of leptospires to the kidney and colonization by 7 days pi [11], our results suggested that the HP strain was almost completely cleared during hematogenous dissemination in the mouse model of chronic infection (Fig. 1a)
Summary
Leptospira interrogans is a pathogenic, spirochetal bacterium that is responsible for leptospirosis, an emerging worldwide zoonosis. While it is well known that leptospires can persist in the kidneys without signs of disease for several months, the interactions of leptospires with the proximal renal epithelial tubule cells that allow the chronic renal colonization have not been elucidated yet. Leptospires enter the host through the skin or mucous membranes, disseminate hematogenously, and reach target organs, such as the liver, lungs and, mainly, the renal proximal tubules (RPTs) in the kidneys, where they can survive for several months [3]. In vivo imaging systems were used to analyze the distribution of leptospires in the whole bodies of infected animals during the early stages of infection as well as in late colonization. Live imaging of bioluminescent bacteria and quantitative real-time PCR have been used to characterize the kinetics of kidney colonization in various animal infection models [9, 11, 12], the kinetics of proximal renal tubule colonization and the mechanisms that allow the long-term persistence of bacteria in the tubules remains poorly understood
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