Abstract
Leptospirosis, an emerging zoonotic disease with worldwide distribution, is caused by spirochetes belonging to the genus Leptospira. More than 500,000 cases of severe leptospirosis are reported annually, with >10% of these being fatal. Leptospires can survive for weeks in suitably moist conditions before encountering a new host. Reservoir hosts, typically rodents, exhibit little to no signs of disease but shed large numbers of organisms in their urine. Transmission occurs when mucosal surfaces or abraded skin come into contact with infected urine or urine-contaminated water or soil. In humans, leptospires can cause a variety of clinical manifestations, ranging from asymptomatic or mild fever to severe icteric (Weil's) disease and pulmonary haemorrhage. Currently, little is known about how Leptospira persist within a reservoir host. Prior in vitro studies have suggested that leptospires alter their transcriptomic and proteomic profiles in response to environmental signals encountered during mammalian infection. However, no study has examined gene expression by leptospires within a mammalian host-adapted state. To obtain a more faithful representation of how leptospires respond to host-derived signals, we used RNA-Seq to compare the transcriptome of L. interrogans cultivated within dialysis membrane chambers (DMCs) implanted into the peritoneal cavities of rats with that of organisms grown in vitro. In addition to determining the relative expression levels of “core” housekeeping genes under both growth conditions, we identified 166 genes that are differentially-expressed by L. interrogans in vivo. Our analyses highlight physiological aspects of host adaptation by leptospires relating to heme uptake and utilization. We also identified 11 novel non-coding transcripts that are candidate small regulatory RNAs. The DMC model provides a facile system for studying the transcriptional and antigenic changes associated with mammalian host-adaption, selection of targets for mutagenesis, and the identification of previously unrecognized virulence determinants.
Highlights
Leptospirosis is a neglected disease of global significance [1,2]
We know very little about the regulatory pathways and gene products that promote mammalian host adaptation and enable leptospires to establish infection
We used a novel system whereby leptospires are cultivated in dialysis membrane chambers implanted into the peritoneal cavities of rats to compare the gene expression profiles of mammalian hostadapted and in vitro-cultivated organisms
Summary
Leptospirosis is a neglected disease of global significance [1,2]. Pathogenic leptospires, shed in animal urine or free-living within contaminated water, enter the host through small abrasions in the skin or contact with mucous membranes of the eyes, nose or throat. Organisms disseminate almost immediately following acquisition, travelling via the bloodstream to multiple tissues [3]. L. interrogans, an extracellular pathogen, is thought to penetrate host tissues by intercellular migration [4]. The majority of leptospires are thought to be cleared by opsonophagocytosis following the appearance of specific antibodies [5]. Organisms that reach the kidneys, an immunoprivileged site [1], adhere to and colonize the proximal convoluted renal tubules, where they replicate exponentially. The majority of human disease is caused by Leptospira interrogans serovar
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