Abstract
The virulence mechanisms required for infection and evasion of immunity by pathogenic Leptospira species remain poorly understood. A number of L. interrogans surface proteins have been discovered, lying at the interface between the pathogen and host. Among these proteins, the functional properties of the Lig (leptospiral immunoglobulin-like domain) proteins have been examined most thoroughly. LigA, LigB, and LigC contain a series of, 13, 12, and 12 closely related domains, respectively, each containing a bacterial immunoglobulin (Big) -like fold. The multidomain region forms a mostly elongated structure that exposes a large surface area. Leptospires wield the Lig proteins to promote interactions with a range of specific host proteins, including those that aid evasion of innate immune mechanisms. These diverse binding events mediate adhesion of L. interrogans to the extracellular matrix, inhibit hemostasis, and inactivate key complement proteins. These interactions may help L. interrogans overcome the physical, hematological, and immunological barriers that would otherwise prevent the spirochete from establishing a systemic infection. Despite significant differences in the affinities of the LigA and LigB proteins for host targets, their functions overlap during lethal infection of hamsters; virulence is lost only when both ligA and ligB transcription is knocked down simultaneously. Lig proteins have been shown to be promising vaccine antigens through evaluation of a variety of different adjuvant strategies. This review serves to summarize current knowledge of Lig protein roles in virulence and immunity and to identify directions needed to better understand the precise functions of the Lig proteins during infection.
Highlights
Leptospiral immunoglobulin-like (Lig) domain proteins play key roles in the pathogenesis mechanisms of the spirochetes responsible for leptospirosis, an infectious disease that is reemerging worldwide
LigBCen and LigBctv (Figure 1) attached to MDCK cells in a dose-dependent manner, binding of LigBctv was weaker. This result is consistent with the stronger affinity of LigBCen over LigBctv for fibronectin. Binding of both LigBCen and LigBctv were reduced in MDCK cells in which fibronectin expression was knocked down with siRNA, further supporting the notion that fibronectin serves a receptor for LigB-mediated adhesion of L. interrogans to MDCK cells
It is likely that the LigB proteins prebound to MDCK cells block other fibronectinbinding adhesins expressed by L. interrogans, such as LigA
Summary
Leptospiral immunoglobulin-like (Lig) domain proteins play key roles in the pathogenesis mechanisms of the spirochetes responsible for leptospirosis, an infectious disease that is reemerging worldwide. By the time the humoral immune response produces antibodies targeting L. interrogans, the spirochetes have disseminated to various organs including the kidneys, liver, and other organs and triggered the release of proinflammatory cytokines [5]. Some of the host ligands targeted by the Lig proteins indicate a role for the Lig proteins in evasion of innate immunity. We present an integrated model of the role of Lig proteins in leptospiral virulence and immunity. This is the first focused review on the Lig proteins that we are aware of
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