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Metabolites from plasma-like medium fuel nitrogen metabolism and influence proliferation in Leptospira interrogans

ABSTRACT: The adaptation and survival of bacterial pathogens in a host involves a complex series of processes, with bacterial metabolism as a critical checkpoint and facilitator of infection. The pathogen Leptospira interrogans expands from a small inoculum to reach high bloodstream titers before colonizing host kidneys; however the supporting metabolic programs and the role of the host environment are largely unknown, and tools to investigate these host-pathogen metabolic interactions in a controlled in vitro setting are in their infancy. Here, we built upon the concept of human plasma-like medium (HPLM) to develop a more physiological system for L. interrogans culture. This supplemented HPLM (sHPLM) supported robust growth, and we used RNA-sequencing analyses to demonstrate the fidelity of the transcriptome of sHPLM cultures to in vivo models. Through the use of sHPLM, we identified the amino acid glutamine as a major nitrogen source supplying the biosynthetic activities of L. interrogans. Further study of the role of glutamine revealed that exposure altered the proliferative behavior and biofilm formation of L. interrogans, although RNA-sequencing revealed few strong transcriptional consequences of this environmental signal. This work adds to our understanding of the metabolic mechanisms supporting L. interrogans infection which could be targeted for new anti-leptospiral therapies. We propose a dual, pathogen-supporting role for glutamine: as a metabolic fuel for continued biosynthesis and replication, and as a metabolite signal to inform pathogen adaptation in the process of host infection.

ORGANISM(S): Leptospira interrogans

PROVIDER: GSE316384 | GEO | 2026/03/17

REPOSITORIES: GEO

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Project description: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. Transcriptome analysis of L. interrogans Copenhageni FIOCRUZ L1-130 using RNA from 2 different conditions using RNA-seq. Also, the reproducibility and robustness of data is ensured by three biological replicates from each condition.

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Metabolites from plasma-like medium fuel nitrogen metabolism and influence proliferation in Leptospira interrogans

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