Insight into the Structure, Functions, and Dynamics of the Leptospira Outer Membrane Proteins with the Pathogenicity

Abstract

Leptospirosis is a widespread zoonosis that frequently occurs in tropical and subtropical countries. Leptospira enters the host through wounds or mucous membranes and spreads to the whole body through the blood, causing systemic infection. Kidneys are the preferential site where Leptospira accumulates, especially in the renal interstitium and renal tubule epithelial cells. Clinical symptoms in humans include high fever, jaundice, renal failure, and severe multiple-organ failure (Weil's syndrome). Surface-exposed antigens are located at the outermost layer of Leptospira and these potential virulence factors are likely involved in primary host-pathogen interactions, adhesion, and/or invasion. Using the knockout/knockdown techniques to the evaluation of pathogenicity in the virulence factor are the most direct and effective methods and many virulence factors are evaluated including lipopolysaccharides (LPS), Leptospira lipoprotein 32 (LipL32), Leptospira ompA domain protein 22 (Loa22), LipL41, LipL71, Leptospira immunoglobulin-like repeat A (LigA), LigB, and LipL21. In this review, we will discuss the structure, functions, and dynamics of these virulence factors and the roles of these virulence factors in Leptospira pathogenicity. In addition, a protein family with special Leucine-rich repeat (LRR) will also be discussed for their vital role in Leptospira pathogenicity. Finally, these surface-exposed antigens are discussed in the application of the diagnosis target for leptospirosis and compared with the serum microscope agglutination test (MAT), the gold standard for leptospirosis.

Keywords: Leptospira; Toll-like receptor; outer membrane lipoprotein; peptidoglycan.

Figure 1

Leptospira membrane components. Leptospria membrane is a double membrane structure and it is the first line to contact with the host cell and many outer membrane components may act as virulence factors. The virulence factors evaluated by genes manipulation (including LPS, LipL32, Loa22, LipL41, LruA, LigA, LigB, and LipL21) will be selected to discuss in this review for the virulence mechanism investigation. Blue circle, outer membrane; yellow circle, cell wall; green circle, inner membrane.

Figure 2

The proposed model of LipL32 and TLR2 interactions. Calcium ion-induced conformational changes of LipL32 and regulated the affinity of LipL32 to TLR2. The Ca²⁺ bound LipL32 interacted with TLR2 and the domains and residues involved in the dimer formation were evaluated. The TLR2 LRR domain is shown in cyan and the LipL32 in green as well as the two termini of LipL32 in red.

Figure 3

Crosstalk between E-cadherin/β-catenin and NF-κB signaling pathways under Leptospira LRR20 treatment. rLRR20 protein interacts with E-cadherin through several vital residues and consequently activates β-catenin. The nuclear translocation of activated β-catenin promotes the expression of its target genes, including MMP7. Subsequently, MMP7 is secreted to the extracellular region. The expression and secretion of MMP7 promote the degradation of E-cadherin on the cell surface and downregulate the cell surface levels of E-cadherin. Meanwhile, the degradation of E-cadherin on the cell surface induces the activation of the NF-κB:p65 signal transduction pathway, which subsequently promotes the expression of downstream target gene NGAL.