The Molecular Basis of Leptospiral Pathogenesis

Abstract

The mechanisms of disease pathogenesis in leptospirosis are poorly defined. Recent developments in the application of genetic tools in the study of Leptospira have advanced our understanding by allowing the assessment of mutants in animal models. As a result, a small number of essential virulence factors have been identified, though most do not have a clearly defined function. Significant advances have also been made in the in vitro characterization of leptospiral interaction with host structures, including extracellular matrix proteins (such as laminin, elastin, fibronectin, collagens), proteins related to hemostasis (fibrinogen, plasmin), and soluble mediators of complement resistance (factor H, C4b-binding protein), although none of these in vitro findings has been translated to the host animal. Binding to host structures may permit colonization of the host, prevention of blood clotting may contribute to hemorrhage, while interaction with complement resistance mediators may contribute to survival in serum. While not a classical intracellular pathogen, the interaction of leptospires and phagocytic cells appears complex, with bacteria surviving uptake and promoting apoptosis; mutants relating to these processes (such as cell invasion and oxidative stress resistance) are attenuated in vivo. Another feature of leptospiral biology is the high degree of functional redundancy and the surprising lack of attenuation of mutants in what appear to be certain virulence factors, such as LipL32 and LigB. While many advances have been made, there remains a lack of understanding of how Leptospira causes tissue pathology. It is likely that leptospires have many novel pathogenesis mechanisms that are yet to be identified.

Control of Gene Expression in Leptospira spp. by Transcription Activator-Like Effectors Demonstrates a Potential Role for LigA and LigB in Leptospira interrogans Virulence

“…This is mainly due to the lack of adequate and efficient genetic tools (2). Genetic modifications of the pathogen are limited primarily to random transposon mutagenesis, and there are only a few examples of mutants obtained by targeted mutagenesis (3). Thus, there is a clear need for additional tools to develop genetic studies of Leptospira spp.…”

Pathogenic Leptospira interrogans Exoproteins Are Primarily Involved in Heterotrophic Processes

“…The bacteria are highly motile, and previous studies have demonstrated that both full motility (11,12) and an intact LPS (13) are required for successful colonization of the host. Unlike the majority of other pathogenic Gram-negative bacteria, Leptospira genomes lack the genes encoding delivery systems, such as type III and IV secretion systems, and classical virulence proteins, such as toxins and effectors (14).…”

Pathogenic <i>Leptospira</i>: Advances in understanding the molecular pathogenesis and virulence

“…Recent review articles have attempted to describe the genetic mechanisms of virulence genes of Leptospira species (Adler et al, 2011;Murray, 2015). However, a recent genome-wide analysis of 20 species of Leptospira observed only three types of alternative sigma (σ) factors (σ54, σF, σE), a number that was much less than that in E. coli genome (Fouts et al, 2016).…”

“…Recent studies (Xue et al, 2013;Iraola et al, 2016;Schons-Fonseca et al, 2016) and reviews (Murray, 2015;Picardeau, 2015) have described the application of transcriptomic technologies to decipher mechanisms of Leptospira pathogenesis (Zhukova et al, 2017). Reports from the RNA-sequence technology that enabled the generation of the first transcriptome (Iraola et al, 2016) facilitated the investigation of changes in the transcript turnover that were associated with the biofilm growth and description of the functional Leptospira pathways (Ko et al, 2009).…”