Plasmin cleaves fibrinogen and the human complement proteins C3b and C5 in the presence of Leptospira interrogans proteins: A new role of LigA and LigB in invasion and complement immune evasion

Castiblanco-Valencia, Mónica Marcela; Fraga, Tatiana R.; Pagotto, Ana Helena; Serrano, Solange M.T.; Abreu, Patrícia Antônia Estima; Barbosa, Angela Silva; Isaac, Lourdes

doi:10.1016/j.imbio.2016.01.001

Cited by 66 publications

(56 citation statements)

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“…Inhibition by antibodies capable of binding to native LigB could explain the protection conferred by vaccination with rLigB(131–645). The N-terminal region of LigB has been shown to bind plasminogen [61], Factor H (FH) and C4b-binding protein (C4BP) [62]. However, recently the LigB binding domains for FH and C4BP were shown to be located towards the C-terminal region of LigB [63].…”

Section: Discussionmentioning

confidence: 99%

LigB subunit vaccine confers sterile immunity against challenge in the hamster model of leptospirosis

et al. 2017

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Neglected tropical diseases, including zoonoses such as leptospirosis, have a major impact on rural and poor urban communities, particularly in developing countries. This has led to major investment in antipoverty vaccines that focus on diseases that influence public health and thereby productivity. While the true, global, impact of leptospirosis is unknown due to the lack of adequate laboratory diagnosis, the WHO estimates that incidence has doubled over the last 15 years to over 1 million cases that require hospitalization every year. Leptospirosis is caused by pathogenic Leptospira spp. and is spread through direct contact with infected animals, their urine or contaminated water and soil. Inactivated leptospirosis vaccines, or bacterins, are approved in only a handful of countries due to the lack of heterologous protection (there are > 250 pathogenic Leptospira serovars) and the serious side-effects associated with vaccination. Currently, research has focused on recombinant vaccines, a possible solution to these problems. However, due to a lack of standardised animal models, rigorous statistical analysis and poor reproducibility, this approach has met with limited success. We evaluated a subunit vaccine preparation, based on a conserved region of the leptospiral immunoglobulin-like B protein (LigB(131–645)) and aluminium hydroxide (AH), in the hamster model of leptospirosis. The vaccine conferred significant protection (80.0–100%, P < 0.05) against mortality in vaccinated animals in seven independent experiments. The efficacy of the LigB(131–645)/AH vaccine ranged from 87.5–100% and we observed sterile immunity (87.5–100%) among the vaccinated survivors. Significant levels of IgM and IgG were induced among vaccinated animals, although they did not correlate with immunity. A mixed IgG1/IgG2 subclass profile was associated with the subunit vaccine, compared to the predominant IgG2 profile seen in bacterin vaccinated hamsters. These findings suggest that LigB(131–645) is a vaccine candidate against leptospirosis with potential ramifications to public and veterinary health.

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Section: Discussionmentioning

confidence: 99%

LigB subunit vaccine confers sterile immunity against challenge in the hamster model of leptospirosis

et al. 2017

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“…(29). LigA and LigB are virulence determinants that are upregulated during infection (30), play a role in host cell adherence (31), prevent blood clotting (32, 33), and inhibit complement (34, 35). However, as seen for LipL32, an L. interrogans ligB knockout mutant remained virulent in the hamster model (36).…”

Section: Experimental Recombinant Vaccinesmentioning

confidence: 99%

A Universal Vaccine against Leptospirosis: Are We Going in the Right Direction?

2017

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Leptospirosis is the most widespread zoonosis in the world and a neglected tropical disease estimated to cause severe infection in more than one million people worldwide every year that can be combated by effective immunization. However, no significant progress has been made on the leptospirosis vaccine since the advent of bacterins over 100 years. Although protective against lethal infection, particularly in animals, bacterin-induced immunity is considered short term, serovar restricted, and the vaccine can cause serious side effects. The urgent need for a new vaccine has motivated several research groups to evaluate the protective immune response induced by recombinant vaccines. Significant protection has been reported with several promising outer membrane proteins, including LipL32 and the leptospiral immunoglobulin-like proteins. However, efficacy was variable and failed to induce a cross-protective response or sterile immunity among vaccinated animals. As hundreds of draft genomes of all known Leptospira species are now available, this should aid novel target discovery through reverse vaccinology (RV) and pangenomic studies. The identification of surface-exposed vaccine candidates that are highly conserved among infectious Leptospira spp. is a requirement for the development of a cross-protective universal vaccine. However, the lack of immune correlates is a major drawback to the application of RV to Leptospira genomes. In addition, as the protective immune response against leptospirosis is not fully understood, the rational use of adjuvants tends to be a process of trial and error. In this perspective, we discuss current advances, the pitfalls, and possible solutions for the development of a universal leptospirosis vaccine.

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“…However, only a few of them were indeed shown to directly interfere with complement activation: the elongation factor Tu [EF-Tu (35)]; LigA and LigB (36) and Leptospira 23 kDa surface adhesion [Lsa23 (34)], whose interactions with PLG resulted in the cleavage of C3b, C4b, and/or C5 (Table 1). …”

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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Plasmin cleaves fibrinogen and the human complement proteins C3b and C5 in the presence of Leptospira interrogans proteins: A new role of LigA and LigB in invasion and complement immune evasion

Cited by 66 publications

References 66 publications

LigB subunit vaccine confers sterile immunity against challenge in the hamster model of leptospirosis

LigB subunit vaccine confers sterile immunity against challenge in the hamster model of leptospirosis

A Universal Vaccine against Leptospirosis: Are We Going in the Right Direction?

Complement Evasion by Pathogenic Leptospira

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