Decrease in antithrombin III and prothrombin serum levels contribute to coagulation disorders during leptospirosis

Fernandes, Luis G. V.; Filho, Antônio F. de Souza; Souza, Gisele Oliveira de; Vasconcellos, Sílvio Arruda; Romero, Eliete Caló; Nascimento, Ana L. T. O.

doi:10.1099/mic.0.000318

Cited by 5 publications

(3 citation statements)

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“…Additionally, the degradation of coagulation cascade components by secreted proteases or by acquired surface plasmin could also play a role on reducing clot formation, thereby facilitating dissemination during the establishment of infection. In leptospirosis patients, activated coagulation is observed, with increased levels of fibrin degradation products and plasma fibrinogen and reduced levels of antithrombin, associated with tissue damage and vascular injury (Figure 1) (Oliveira et al, 2013;Fernandes et al, 2015;Fernandes et al, 2016a).…”

Section: Leptospiral Protein Interactions With Fibrinogen and Thrombinmentioning

confidence: 99%

A Review on Host-Leptospira Interactions: What We Know and Future Expectations

Daroz

Fernandes

Cavenague

et al. 2021

Front. Cell. Infect. Microbiol.

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Leptospirosis is a widespread zoonosis caused by pathogenic Leptospira spp. It is considered a neglected infectious disease of human and veterinary concern. Our group has been investigating proteins annotated as hypothetical, predicted to be located on the leptospiral surface. Because of their location, these proteins may have the ability to interact with various host components, which could allow establishment of the infection. These proteins act as adherence factors by binding to host receptor molecules, such as the extracellular matrix (ECM) components laminin and glycosaminoglycans to help bacterial colonization. Leptospira also interacts with the host fibrinolytic system, which has been demonstrated to be a powerful tool for invasion mechanisms. The interaction with fibrinogen and thrombin has been shown to reduce fibrin clot formation. Additionally, the degradation of coagulation cascade components by secreted proteases or by acquired surface plasmin could also play a role in reducing clot formation, hence facilitating dissemination during infection. Interaction with host complement system regulators also plays a role in helping bacteria to evade the immune system, facilitating invasion. Interaction of Leptospira to cell receptors, such as cadherins, can contribute to investigate molecules that participate in virulence. To achieve a better understanding of the host-pathogen interaction, leptospiral mutagenesis tools have been developed and explored. This work presents several proteins that mediate binding to components of the ECM, plasma, components of the complement system and cells, to gather research achievements that can be helpful in better understanding the mechanisms of leptospiral-host interactions and discuss genetic manipulation for Leptospira spp. aimed at protein function validation.

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Section: Leptospiral Protein Interactions With Fibrinogen and Thrombinmentioning

confidence: 99%

A Review on Host-Leptospira Interactions: What We Know and Future Expectations

Daroz

Fernandes

Cavenague

et al. 2021

Front. Cell. Infect. Microbiol.

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“…The mechanism behind this Leptospira -induced hemorrhage is not fully understood. Fernandes et al , [ 51 ] provide evidence that lower serum levels of prothrombin and antithrombin III in patients with the disease is related to the observed hemorrhage. Liver-produced prothrombin remains inactive in circulation until being proteolytically cleaved to form thrombin to start clot formation by converting fibrinogen to fibrin.…”

Section: Discussionmentioning

confidence: 99%

Characterization of the microtranscriptome of macrophages infected with virulent, attenuated and saprophyte strains of Leptospira spp.

et al. 2018

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Leptospirosis is a bacterial zoonosis, caused by Leptospira spp., that leads to significant morbidity and mortality worldwide. Despite considerable advances, much is yet to be discovered about disease pathogenicity. The influence of epigenetic mechanisms, particularly RNA-mediated post-transcriptional regulation of host immune response has been described following a variety of bacterial infections. The current study examined the microtranscriptome of macrophages J774A.1 following an 8h infection with virulent, attenuated and saprophyte strains of Leptospira. Microarray analysis revealed that 29 miRNAs were misregulated following leptospiral infection compared to control macrophages in a strain and virulence-specific manner. Pathway analysis for targets of these differentially expressed miRNAs suggests that several processes involved in immune response could be regulated by miRNAs. Our data provides the first evidence that host miRNAs are regulated by Leptospira infection in macrophages. A number of the identified miRNA targets participate in key immune response processes. We suggest that post-transcriptional regulation by miRNAs may play a role in host response to infection in leptospirosis.

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“…When reaching the bloodstream for dissemination, leptospires need to overcome host natural defenses, such as the complement system and oxidative stress, and several research groups have elucidated the role of surface-exposed proteins in leptospiral immune evasion mechanisms by in vitro assays with recombinant proteins (Verma et al, 2006;Vieira et al, 2010aVieira et al, , 2018Castiblanco-Valencia et al, 2012Siqueira et al, 2016;Cavenague et al, 2019). Rapid tissue dissemination can also be related to the ability of pathogenic leptospires to impair the host coagulation cascade (Oliveira et al, 2013;Fernandes et al, 2015Fernandes et al, , 2016a.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Leptospira interrogans knockdown mutants for LipL32, LipL41, LipL21, and OmpL1 proteins

2023

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IntroductionLeptospirosis is a worldwide zoonosis caused by pathogenic and virulent species of the genus Leptospira, whose pathophysiology and virulence factors remain widely unexplored. Recently, the application of CRISPR interference (CRISPRi) has allowed the specific and rapid gene silencing of major leptospiral proteins, favoring the elucidation of their role in bacterial basic biology, host-pathogen interaction and virulence. Episomally expressed dead Cas9 from the Streptococcus pyogenes CRISPR/Cas system (dCas9) and single-guide RNA recognize and block transcription of the target gene by base pairing, dictated by the sequence contained in the 5′ 20-nt sequence of the sgRNA.MethodsIn this work, we tailored plasmids for silencing the major proteins of L. interrogans serovar Copenhageni strain Fiocruz L1-130, namely LipL32, LipL41, LipL21 and OmpL1. Double- and triple-gene silencing by in tandem sgRNA cassettes were also achieved, despite plasmid instability.ResultsOmpL1 silencing resulted in a lethal phenotype, in both L. interrogans and saprophyte L. biflexa, suggesting its essential role in leptospiral biology. Mutants were confirmed and evaluated regarding interaction with host molecules, including extracellular matrix (ECM) and plasma components, and despite the dominant abundance of the studied proteins in the leptospiral membrane, protein silencing mostly resulted in unaltered interactions, either because they intrinsically display low affinity to the molecules assayed or by a compensation mechanism, where other proteins could be upregulated to fill the niche left by protein silencing, a feature previously described for the LipL32 mutant. Evaluation of the mutants in the hamster model confirms the augmented virulence of the LipL32 mutant, as hinted previously. The essential role of LipL21 in acute disease was demonstrated, since the LipL21 knockdown mutants were avirulent in the animal model, and even though mutants could still colonize the kidneys, they were found in markedly lower numbers in the animals' liver. Taking advantage of higher bacterial burden in LipL32 mutant-infected organs, protein silencing was demonstrated in vivo directly in leptospires present in organ homogenates.DiscussionCRISPRi is now a well-established, attractive genetic tool that can be applied for exploring leptospiral virulence factors, leading to the rational for designing more effective subunit or even chimeric recombinant vaccines.

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Decrease in antithrombin III and prothrombin serum levels contribute to coagulation disorders during leptospirosis

Cited by 5 publications

References 55 publications

A Review on Host-Leptospira Interactions: What We Know and Future Expectations

A Review on Host-Leptospira Interactions: What We Know and Future Expectations

Characterization of the microtranscriptome of macrophages infected with virulent, attenuated and saprophyte strains of Leptospira spp.

Evaluation of Leptospira interrogans knockdown mutants for LipL32, LipL41, LipL21, and OmpL1 proteins

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