Abstract
The coagulation system provides a primitive but effective defense against hemorrhage. Soluble fibrinogen (Fg) monomers, composed of α, β and γ chains, are recruited to provide structural support for the formation of a hemostatic plug. Fg binds to platelets and is processed into a cross-linked fibrin polymer by the enzymatic clotting factors, thrombin and Factor XIII (FXIII). The newly formed fibrin-platelet clot can act as barrier to protect against pathogens from entering the bloodstream. Further, injuries caused by bacterial infections can be confined to the initial wound site. Many pathogenic bacteria have Fg-binding adhesins that can circumvent the coagulation pathway and allow the bacteria to sidestep containment. Fg expression is upregulated during lung infection providing an attachment surface for bacteria with the ability to produce Fg-binding adhesins. Fg binding by leptospira might play a crucial factor in Leptospira-associated pulmonary hemorrhage, the main factor contributing to lethality in severe cases of leptospirosis. The 12th domain of Leptospira immunoglobulin-like protein B (LigB12), a leptospiral adhesin, interacts with the C-terminus of FgαC (FgαCC). In this study, the binding site for LigB12 was mapped to the final 23 amino acids at the C-terminal end of FgαCC (FgαCC8). The association of FgαCC8 with LigB12 (ELISA, KD = 0.76 μM; SPR, KD = 0.96 μM) was reduced by mutations of both charged residues (R608, R611 and H614 from FgαCC8; D1061 from LigB12) and hydrophobic residues (I613 from FgαCC8; F1054 and A1065 from LigB12). Additionally, LigB12 bound strongly to FXIII and also inhibited fibrin formation, suggesting that LigB can disrupt coagulation by suppressing FXIII activity. Here, the detailed binding mechanism of a leptospiral adhesin to a host hemostatic factor is characterized for the first time and should provide better insight into the pathogenesis of leptospirosis.
Highlights
Leptospira spp are pathogenic spirochetes that cause the most widespread zoonotic disease in the world [1,2]
Pulmonary hemorrhage has become one of the major factors leading to fatality
The host coagulation system normally can be activated to confine damage caused by bacteria
Summary
Leptospira spp are pathogenic spirochetes that cause the most widespread zoonotic disease in the world [1,2]. Leptospirosis is reported regularly in tropical nations and is reemerging in the United States [3,4]. Numerous mammalian hosts, including incidental hosts like humans, can be infected by Leptospira at sites of exposed mucous membranes or eroded skin. Direct contact with Leptospira-contaminated water is the main transmission mechanism for endemic leptospirosis associated with flooded areas and populations suffering poor hygienic measures [5,6]. Symptoms vary widely from a mild flu-like syndrome to multiorgan failure such as hepatic dysfunction, interstitial nephritis and pulmonary hemorrhage, known as Weil’s disease. If the infected individual does not receive prompt antibiotic and supportive treatment, fatality may result [7,8]
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