Pathogenic Leptospira Species Acquire Factor H and Vitronectin via the Surface Protein LcpA

Silva, Ludmila Bezerra da; Miragaia, Lidia dos Santos; Breda, Leandro Carvalho Dantas; Abe, Cecília M.; Schmidt, Mariana Costa Braga; Moro, Ana Maria; Monaris, Denize; Conde, Jonas Nascimento; Józsi, Mihály; Isaac, Lourdes; Abreu, Patrícia Antônia Estima; Barbosa, Angela Silva

doi:10.1128/iai.02844-14

Cited by 60 publications

(70 citation statements)

References 35 publications

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“…ing VN to their membranes, they avoid lysis through inhibition of C5b9 complex formation (14,18). Whereas the majority of the described interactions are for bacterial proteins, there are a few viral proteins that have been shown to interact with human VN, including the HIV gp120/160 protein (34,35) and the hepatitis C virus (HCV) F protein (36).…”

Section: Discussionmentioning

confidence: 99%

“…The MAC-inhibitory activity of NS1 and VN was analyzed in a hemolytic assay using sheep erythrocytes and purified complement proteins (18). Erythrocytes were resuspended to 1 ϫ 10 8 cells/ml in Veronal-buffered saline (VBS) and preincubated with 1 g/ml C5b6 for 1 h at room temperature.…”

Section: Proteins and Antibodies Human Vitronectin (Vn)mentioning

confidence: 99%

“…Furthermore, VN limits ongoing membrane-associated pore formation by inhibiting C9 polymerization (15)(16)(17). Acquisition of soluble human VN on the surfaces of microbial pathogens is a common complement evasion strategy that has been described for many bacterial pathogens (14,18); however, this particular evasion mechanism has never been evaluated in viral pathogens.…”

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confidence: 99%

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Inhibition of the Membrane Attack Complex by Dengue Virus NS1 through Interaction with Vitronectin and Terminal Complement Proteins

Conde

Silva

Allonso

et al. 2016

J Virol

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Dengue virus (DENV) infects millions of people worldwide and is a major public health problem. DENV nonstructural protein 1 (NS1) is a conserved glycoprotein that associates with membranes and is also secreted into the plasma in DENV-infected patients. The present study describes a novel mechanism by which NS1 inhibits the terminal complement pathway. We first identified the terminal complement regulator vitronectin (VN) as a novel DENV2 NS1 binding partner by using a yeast two-hybrid system. This interaction was further assessed by enzyme-linked immunosorbent assay (ELISA) and surface plasmon resonance (SPR) assay. The NS1-VN complex was also detected in plasmas from DENV-infected patients, suggesting that this interaction occurs during DENV infection. We also demonstrated that the DENV2 NS1 protein, either by itself or by interacting with VN, hinders the formation of the membrane attack complex (MAC) and C9 polymerization. Finally, we showed that DENV2, West Nile virus (WNV), and Zika virus (ZIKV) NS1 proteins produced in mammalian cells inhibited C9 polymerization. Taken together, our results points to a role for NS1 as a terminal pathway inhibitor of the complement system. IMPORTANCE Dengue is the most important arthropod-borne viral disease nowadays and is caused by dengue virus (DENV).The flavivirus NS1 glycoprotein has been characterized functionally as a complement evasion protein that can attenuate the activation of the classical, lectin, and alternative pathways. The present study describes a novel mechanism by which DENV NS1 inhibits the terminal complement pathway. We identified the terminal complement regulator vitronectin (VN) as a novel DENV NS1 binding partner, and the NS1-VN complex was detected in plasmas from DENV-infected patients, suggesting that this interaction occurs during DENV infection. We also demonstrated that the NS1-VN complex inhibited membrane attack complex (MAC) formation, thus interfering with the complement terminal pathway. Interestingly, NS1 itself also inhibited MAC activity, suggesting a direct role of this protein in the inhibition process. Our findings imply a role for NS1 as a terminal pathway inhibitor of the complement system. D engue constitutes a major public health problem in tropical and subtropical countries. According to current estimates, at least 390 million cases of dengue occur annually, of which approximately 100 million are symptomatic (1). The infection is caused by dengue virus (DENV), a member of the Flaviviridae family that cocirculates in nature as four distinct antigenic serotypes (DENV1 to -4). DENV infection in humans is generally asymptomatic, but symptomatic cases can vary from a mild and self-limited fever to a potentially fatal hemorrhagic syndrome (2). The DENV genome is composed of a single positive-sense RNA that encodes a single viral polyprotein that is further processed by viral and host proteases into three structural proteins (C, prM/M, and E) and seven nonstructural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5) (3).NS1 ...

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Section: Discussionmentioning

confidence: 99%

Section: Proteins and Antibodies Human Vitronectin (Vn)mentioning

confidence: 99%

mentioning

confidence: 99%

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Inhibition of the Membrane Attack Complex by Dengue Virus NS1 through Interaction with Vitronectin and Terminal Complement Proteins

Conde

Silva

Allonso

et al. 2016

J Virol

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“…It is known that pathogenic leptospires are resistant to the bactericidal activity of normal human sera (NHS) (Johnson & Muschel, 1965) and can spread through the circulation of susceptible hosts until reaching target tissues. The resistance of leptospires to the innate immunity response is attributed to their ability of binding the soluble complement regulators factor H (FH), C4b binding protein (C4BP) and, more recently, vitronectin (Barbosa et al, 2009;da Silva et al, 2015;Meri et al, 2005;Verma et al, 2006). Another suggested strategy for leptospiral immune evasion is the recruitment of plasminogen (PLG) to the bacterial surface and plasmin generation.…”

Section: Introductionmentioning

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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“…As expected, C4b is more efficiently cleaved by FI in the presence of C4BP bound to Leptospira interrogans virulent strains, which may probably explain their higher survival rate in normal human serum as compared to culture-attenuated strains (10). Leptospires also acquire vitronectin (Vn) on their surfaces (20). Vn is a glycoprotein that circulates in the bloodstream as a monomer [65–75 kDa, 104 ± 25 μg/mL (12)] or is deposited in the extracellular matrix (ECM) as a multimer that interacts with several macromolecular components, including glycosaminoglycans and collagens (21, 22).…”

Section: Complement Evasion Strategies By Leptospiramentioning

confidence: 99%

Complement Evasion by Pathogenic Leptospira

2016

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Leptospirosis is a neglected infectious disease caused by spirochetes from the genus Leptospira. Pathogenic microorganisms, notably those which reach the blood circulation such as Leptospira, have evolved multiple strategies to escape the host complement system, which is important for innate and acquired immunity. Leptospira avoid complement-mediated killing through: (i) recruitment of host complement regulators; (ii) acquisition of host proteases that cleave complement proteins on the bacterial surface; and, (iii) secretion of proteases that inactivate complement proteins in the Leptospira surroundings. The recruitment of host soluble complement regulatory proteins includes the acquisition of Factor H (FH) and FH-like-1 (alternative pathway), C4b-binding protein (C4BP) (classical and lectin pathways), and vitronectin (Vn) (terminal pathway). Once bound to the leptospiral surface, FH and C4BP retain cofactor activity of Factor I in the cleavage of C3b and C4b, respectively. Vn acquisition by leptospires may result in terminal pathway inhibition by blocking C9 polymerization. The second evasion mechanism lies in plasminogen (PLG) binding to the leptospiral surface. In the presence of host activators, PLG is converted to enzymatically active plasmin, which is able to degrade C3b, C4b, and C5 at the surface of the pathogen. A third strategy used by leptospires to escape from complement system is the active secretion of proteases. Pathogenic, but not saprophytic leptospires, are able to secrete metalloproteases that cleave C3 (central complement molecule), Factor B (alternative pathway), and C4 and C2 (classical and lectin pathways). The purpose of this review is to fully explore these complement evasion mechanisms, which act together to favor Leptospira survival and multiplication in the host.

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Pathogenic Leptospira Species Acquire Factor H and Vitronectin via the Surface Protein LcpA

Cited by 60 publications

References 35 publications

Inhibition of the Membrane Attack Complex by Dengue Virus NS1 through Interaction with Vitronectin and Terminal Complement Proteins

Inhibition of the Membrane Attack Complex by Dengue Virus NS1 through Interaction with Vitronectin and Terminal Complement Proteins

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

Complement Evasion by Pathogenic Leptospira

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