Versatile Roles of CspA Orthologs in Complement Inactivation of Serum-Resistant Lyme Disease Spirochetes

Hammerschmidt, Claudia; Koenigs, Arno; Siegel, Corinna; Hallström, Teresia; Skerka, Christine; Wallich, Reinhard; Zipfel, Peter F.; Kraiczy, Peter

doi:10.1128/iai.01094-13

Cited by 55 publications

(100 citation statements)

References 69 publications

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“…4a, b). The spirochaete B. burgdorferi possesses numerous FH-binding proteins to avoid complement killing (Brissette et al, 2009;Hallström et al, 2010;Hammerschmidt et al, 2014;Kraiczy et al, 2003;Siegel et al, 2010). Leptospiral immunoglobulin-like proteins LigA and LigB are also capable of interacting with FH and C4BP (Castiblanco-Valencia et al, 2012), but surface expression of LigB on saprophyte L. biflexa exhibits a partial protection from NHS bactericidal activity (Choy, 2012).…”

Section: Discussionmentioning

confidence: 99%

Leptospira interrogans Lsa23 protein recruits plasminogen, factor H and C4BP from normal human serum and mediates C3b and C4b degradation

et al. 2016

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It has been reported that pathogenic Leptospira are resistant to normal human serum (NHS) due to their ability to evade the complement immune system by interacting with factor H (FH) and C4b-binding protein (C4BP) regulators. Moreover, plasmin generation on the leptospiral surface diminishes C3b and IgG deposition, decreasing opsonophagocytosis by immune competent cells. We have previously reported that Lsa23 (LIC11360) is a multipurpose protein capable of binding purified extracellular matrix molecules, FH, C4BP and plasminogen (PLG)/plasmin in the presence of PLG activators. In this work, we provide further evidence that Lsa23 is located at the bacterial surface by using immunofluorescence microscopy. We show that Lsa23 has the ability to acquire FH, C4BP and PLG from NHS, and use these interactions to evade innate immunity. The binding with the complement regulators FH and C4BP preserves factor I (FI) activity, leading to C3b and C4b degradation products, respectively. C3b and C4b alpha-chain cleavage was also observed when Lsa23 bound to PLG generating plasmin, an effect blocked by the protease inhibitor aprotinin. Lsa23 also inhibited lytic activity by NHS mediated by both classical and alternative complement pathways. Thus, Lsa23 has the ability to block both pathways of the complement system, and may help pathogenic Leptospira to escape complement-mediated clearance in human hosts. Indeed, NHS treated with Lsa23 confers a partial serum resistance phenotype to Leptospira biflexa, whereas blocking this protein with anti-Lsa23 renders pathogenic L. interrogans more susceptible to complement-mediated killing. Thus, Lsa23 is a multifunctional protein involved in many pathways, featuring C4b cleavage by plasmin, knowledge that may help in the development of preventive approaches to intervene with human complement escape by this versatile pathogen.

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Section: Discussionmentioning

confidence: 99%

Leptospira interrogans Lsa23 protein recruits plasminogen, factor H and C4BP from normal human serum and mediates C3b and C4b degradation

et al. 2016

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“…Orthologs of CspA Binding of host-derived proteins and/or direct interaction with the formation of the terminal complement complex [5,6] Extraintestinal Escherichia coli (ExPEC) Exopolysaccharide colanic acid Protection from envelope stress whilst cell wall damage is repaired [15] Yersinia pseudotuberculosis Outer membrane protein Ail Recruitment of regulator of classical and lectin pathway (C4b-binding protein), and regulator of alternate pathway (factor H) [16] inability to regulate the alternative pathway. Mutations in the gene are associated with diseases such as atypical hemolytic uraemic syndrome (aHUS) [17].…”

Section: Acinetobacter Baumanniimentioning

confidence: 99%

“…Borrelia spp. uses CspA for binding of host-derived proteins and/or direct interaction with the formation of the terminal complement complex, as a mechanism for evasion [5] and [6]. These and other examples, including mechanisms used by N. meningitidis, are shown in Table 1 [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16].…”

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confidence: 99%

Serum bactericidal antibody assays – The role of complement in infection and immunity

McIntosh

Bröker

Wassil³

et al. 2015

Vaccine

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“…The differentially regulated B. burgdorferi surface protein CspA (32)(33)(34)(35) and some of the OspE-related protein family members, including ErpA (36,37), ErpP (37), and ErpC (38,39), all act similarly by recruitment of complement regulator factor H (FH) and factor H-like protein-1 (FHL-1) or complement factor H-related proteins (CFHR), presumably to the surface of the bacterium, although the majority of studies have been performed using recombinant protein. FH, FHL-1, and the CFHRs inhibit the alternative complement cascade by cleaving C3b.…”

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confidence: 99%

A Short-Term Borrelia burgdorferi Infection Model Identifies Tissue Tropisms and Bloodstream Survival Conferred by Adhesion Proteins

Caine

Coburn

2015

Infect Immun

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Borrelia burgdorferi, the causative agent of Lyme disease in the United States, is able to persist in the joint, heart, skin, and central nervous system for the lifetime of its mammalian host. Borrelia species achieve dissemination to distal sites in part by entry into and travel within the bloodstream. Much work has been performed in vitro describing the roles of many B. burgdorferi outer surface proteins in adhesion to host cell surface proteins and extracellular matrix components, although the biological relevance of these interactions is only beginning to be explored in vivo. A need exists in the field for an in vivo model to define the biological roles of B. burgdorferi adhesins in tissue-specific vascular interactions. We have developed an in vivo model of vascular interaction of B. burgdorferi in which the bacteria are injected intravenously and allowed to circulate for 1 h. This model has shown that the fibronectin binding protein BB0347 has a tropism for joint tissue. We also have shown an importance of the integrin binding protein, P66, in binding to vasculature of the ear and heart. This model also revealed unexpected roles for Borrelia adhesins BBK32 and OspC in bacterial burdens in the bloodstream. The intravenous inoculation model of short-term infection provides new insights into critical B. burgdorferi interactions with the host required for initial survival and tissue colonization. Borrelia burgdorferi, the causative agent of Lyme disease in the United States, is a vector-borne disease transmitted via the bite of an Ixodes scapularis tick (1, 2). Human infection with this bacterium often results in debilitating chronic arthritis, carditis, and/or neurologic symptoms if left untreated (3, 4). Upon entry into the host, Lyme disease Borrelia spirochetes are able to disseminate into the tissues and persist in the joints, heart, skin, and central nervous system (1). It is likely that Borrelia spp. are able to achieve rapid dissemination within the host by entry into and travel within the bloodstream. Colonization of specific host tissues is thought to occur through interactions of the bacteria with host cells of the microvasculature. A large variety of vascular beds are available in the host, determined by the size and type of vessel, as well as the organ with which they are associated (5, 6). One possible mechanism of B. burgdorferi attachment to various vascular beds and bacterial extravasation at particular tissue sites is through preferential interactions of various adhesive outer surface proteins on the bacterial surface with different types of endothelial cell surface proteins, carbohydrates, and/or extracellular matrix components. It has been shown that adhesion of B. burgdorferi to the vasculature occurs in a series of interactions (7). We hypothesize that the action of vascular binding and tissue colonization is not a random event but rather is determined by adhesion of B. burgdorferi surface proteins to tissue bed-specific endothelial cell (EC) surface receptors, such as VCAM1 on liver ECs,...

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Versatile Roles of CspA Orthologs in Complement Inactivation of Serum-Resistant Lyme Disease Spirochetes

Abstract: CspA of the Lyme disease spirochete

Cited by 55 publications

References 69 publications

Leptospira interrogans Lsa23 protein recruits plasminogen, factor H and C4BP from normal human serum and mediates C3b and C4b degradation

Leptospira interrogans Lsa23 protein recruits plasminogen, factor H and C4BP from normal human serum and mediates C3b and C4b degradation

Serum bactericidal antibody assays – The role of complement in infection and immunity

A Short-Term Borrelia burgdorferi Infection Model Identifies Tissue Tropisms and Bloodstream Survival Conferred by Adhesion Proteins

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