Miscellaneous Bacterial Moonlighting Virulence Proteins

Unexpected Interactions of Leptospiral Ef-Tu and Enolase

Natalia Salazar and Angela Barbosa

Laboratorio de Bacteriologia, Instituto Butantan, Sao Paulo, Brazil

Leptospira -Host Interactions

Spirochaetes of the genus Leptospira may cause leptospirosis, a zoonosis of worldwide distribution. Highly frequent in tropical and subtropical areas, the disease represents an important public health problem. The Leptospira genus includes pathogenic and saprophytic species, which are classified into more than 300 serovars (Hartskeerl et al. 2011). Pathogenic leptospires have evolved virulence strategies to successfully colonize a variety of hosts. During infection, they express a number of surface-exposed proteins capable of binding to ECM molecules, including laminin and type IV collagen, the major constituents of the basement membrane, as well as cellular and plasma fibronectin, type I collagen, elastin, tropoelastin, and proteoglycans (Barbosa et al. 2006; Choy et al. 2007; Breiner et al. 2009; Lin et al. 2009). Binding to host cells has also been reported, notably to kidney epithelial cells, macrophages, fibroblasts, and endothelial cells (Thomas and Higbie 1990; Liu et al. 2007). Resistance to the bactericidal effect of host serum is another important attribute of virulent Leptospira strains. The ability to escape the natural defense mechanisms of the body relies mainly on their capacity to overcome complement-mediated killing (reviewed in Fraga et al. 2011). Among these mechanisms are the acquisition of factor H (FH) and C4b Binding Protein (C4BP), the soluble regulators of the classical, alternative, and lectin pathways of complement (Meri et al. 2005; Barbosa et al. 2009). Binding to human vitronectin, a negative regulator of the terminal pathway of complement, has recently been reported, indicating that leptospires are able to control both the early and late steps of the complement cascade (Silva et al. 2014). Moreover, the secretion of proteases capable of cleaving key complement molecules also contributes to Leptospira immune evasion (Fraga et al. 2014). By possessing multiple complement escape strategies, pathogenic Leptospira efficiently circumvent the host's innate immune responses. Leptospires are also capable of binding plasminogen on their surfaces (Vieira et al. 2009; Verma

Moonlighting Proteins: Novel Virulence Factors in Bacterial Infections, First Edition. Edited by Brian Henderson.

© 2017 John Wiley & Sons, Inc. Published 2017 by John Wiley & Sons, Inc.

Table 19.1 Leptospira proteins exhibiting moonlighting activities.



Function associated with cytosolic localization

Glycolytic enzyme: catalysis of 2- phosphoglycerate to phosphoenolpyruvate

Protein synthesis

Functions associated with surface localization

Interaction with plasminogen

Interaction with: ECM components and coagulation cascade molecules; complement FH (bound-FH displays cofactor activity mediating C3b degradation by FI); and plasminogen (bound-plasmin(ogen) cleaves C3b and fibrinogen)

et al. 2010). In the presence of host-specific activators, bound plasminogen is converted to plasmin. This key enzyme of the coagulation system may contribute to bacterial invasion and immune evasion by degrading ECM molecules (Ponting et al. 1992), and also by cleaving the central complement components C3b and C5 (Barthel et al. 2012).

Various Leptospira surface-exposed molecules, most of them lipoproteins, have been shown to have a considerable significance in virulence by playing key roles in adhesion, invasion, and immune evasion of the host complement pathways (reviewed in Fraga et al. 2011). As such, some of them seem to be potential vaccine candidates (Silva et al. 2007; Faisal et al. 2008, 2009; Yan et al. 2009). In addition to the panoply of “classical” outer membrane proteins having a presumed role in Leptospira pathogenesis described to date, recent studies have reported the involvement of leptospiral Ef-Tu and enolase in plasminogen recruitment and/or adhesion to host ECM and immune evasion (Table 19.1). The moonlighting activities of such proteins are addressed in the following sections.

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