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C-di-GMP is responsible for several behaviors in bacteria, such as biofilm production, cell cycle, motility, chemotaxis, quorum sensing, virulence, and may the action of regular riboswitches <ref name="nimbus7">DOI 10.1128/MMBR.00043-12</ref>. Despite the efforts of different mechanisms of the immune system to eliminate infection by leptospires, these bacteria are able to evade the immune system and survive. A possible evasion mechanism is the production of biofilms, which helps bacteria to organize a physical-chemical barrier against the immune system and against antimicrobial agents <ref name="nimbus8">PMID: 23102459</ref>. Therefore, an elucidation of the c-di-GMP mechanism produced by ''L. interrogans'' helps to understand the bacteria's virulence.
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C-di-GMP is responsible for several behaviors in bacteria, such as [https://en.wikipedia.org/wiki/Biofilm biofilm], cell cycle, motility, chemotaxis,[https://en.wikipedia.org/wiki/Quorum_sensing quorum sensing], virulence, and may the action of regular [https://en.wikipedia.org/wiki/Riboswitch riboswitches] <ref name="nimbus7">DOI 10.1128/MMBR.00043-12</ref>. Despite the efforts of different mechanisms of the immune system to eliminate infection by leptospires, these bacteria are able to evade the immune system and survive. A possible evasion mechanism is the production of biofilms, which helps bacteria to organize a physical-chemical barrier against the immune system and against antimicrobial agents <ref name="nimbus8">PMID: 23102459</ref>. Therefore, an elucidation of the c-di-GMP mechanism produced by ''L. interrogans'' helps to understand the bacteria's virulence.

Revision as of 02:33, 8 December 2021

Contents

Leptospira cAMP-dependent DGC 1 (Lcd1)

Lcd1 GAF domain in complex with cAMP ligand. Method: X-Ray Diffraction. Resolution: 2.15 Å

Drag the structure with the mouse to rotate

The leptospirosis is caused by spirochaetes of pathogenic species of genus Leptospira and is a emerging zoonotic disease worldwide [1] [2]. According to the World Health Organization (WHO), approximately 1 million people become infected with leptospiras per year and 60,000 die from the disease worldwide [3].The ability of some Leptospira species to grow in different conditions, such as in soil, water and in different mammalian organs and in the bloodstream, suggests that the bacteria must have different signaling pathways to detect the external environment and modulate its gene expression. One way to respond to environmental changes and modulate gene expression is through the production of bis (3 ′, 5 ′) - cyclic diguanylic acid, known as cyclic di-GMP (c-di-GMP) [1]. However, to date, almost nothing is known about c-di-GMP signaling in Leptospira[1] [4][5][6].


C-di-GMP is responsible for several behaviors in bacteria, such as biofilm, cell cycle, motility, chemotaxis,quorum sensing, virulence, and may the action of regular riboswitches [7]. Despite the efforts of different mechanisms of the immune system to eliminate infection by leptospires, these bacteria are able to evade the immune system and survive. A possible evasion mechanism is the production of biofilms, which helps bacteria to organize a physical-chemical barrier against the immune system and against antimicrobial agents [8]. Therefore, an elucidation of the c-di-GMP mechanism produced by L. interrogans helps to understand the bacteria's virulence.


Structure of VlsE

exists as a molecule in its natural form, comprised of two identical molecules bonded together through weak ionic interactions. The surface area interactions caused by dimerization, along with the variable and invariable , are central to understanding vlsE.

VlsE contains N and C terminus, which correspond to the start of the amino acid sequence to the end, respectively. Unlike other proteins, the N and C terminus regions are neighbored and very flexible. Due to the fact that these regions do not change sequence, they are heavily used for diagnostic tests and vaccination experiments. There is little information on the antigenicity of the N-terminal, however, the C-terminal region is found to be highly immunogenic. Experiments involving treatment with antisera have shown the alpha structure of the C-terminal region associated with the immunogenicity to vary among Lyme disease Borrelia [9]. The peptide associated with this immunogenicity is membrane proximal and surface exposed, although crowding of vlsE proteins or bonding to other proteins may block exposure.[10]

Burgdorferi uses antigenic variation to evade the host immune system. It uses genetic recombination as its antigenic variation strategy. The genes coding for vlsE’s variable regions are replaced by replicated vls silent cassette sequences on the B-31 locus, just upstream form the vlsE expression site, that are up to 92% similar to the corresponding vlsE sequences. This gene recombination results in many slightly varied versions of the vlsE antigen.

Variable Domain

consists of one central which is comprised of six invariable regions (IR1 to IR6), and six variable regions (VR1 to VR6). These variable regions are highly immunogenic; they stimulate an immune response in the body and they serves as a major target of the host immune response. Most of the membrane-distal surface, which covers the α-helix, is made up of coiled forms of the VRs. The placement of these segments on the surface protects the hidden regions from coming into contact with antibodies and therefore serves as the immune evasion from antibody binding. The structure of vlsE indicates that the surface of the protein consists mainly of the variable regions, which go through rapid sequence changes at a high rate during the early stages of an infection. The variable regions on the surface cover the invariable regions of the protein. The exposed variable regions attract the antibodies and turn the immune system away from the invariable regions, leading to an evasion of the immune system.

The invariable regions (IR) are important in maintaining the structure of the molecule, although some of the invariable regions also trigger . In humans, only IR6 does so, whereas in mice there is an immune response to IR6, IR2 and sometimes IR4.[10] These responses only apply to vlsE that is non-dimerized and detached from the membrane. However, when the antigenicity of IRs was tested on the vlsE of an intact B. burgdorferi, no detectable binding was found. When entering the amino acid sequence into an algorithm that calculates antigenicity, it is found that IR6 has a very high antigenic index.[11] This helps to explain why it elicites antibody response across all three species. IR2 and IR4 also have relatively high antigenic index as well, though not as high as IR6. The reason for the limited antigenic properties of these IRs in the natural form is because the dimer interactions between two molecules of vlsE greatly reduce the surface area to residue ratio, especially for IR4. Hindrance from other surface membranes may also affect the antigenicity.

Relation to Lyme Disease

The more serious prolonged symptoms of Lyme Disease, known as post-Lyme disease syndrome, are attributed to the highly variable antigenic properties of vlsE. These symptoms include pain, fatigue and neurocognitive impairment and may occur in patients despite antibiotic treatment. (Chandra et. al). In addition to its successful antigenic variation strategy, these prolonged side effects may be due to targeted epitopes that have not yet been found. Recent studies using epitope mapping have shown sequences for targeted epitopes on the N and C terminus regions of the invariable domains in addition to the IR6 region. VlsE may contain many more epitope sequences than was previously thought.

Future Directions

Further research must be done to determine why some immunodominant regions are not accessible to the antibody on the surface of spirochetes. For instance, IR6 is highly antigenic, but only accessible in the non-dimerized form (Liang & Philipp, 1999). Understanding this will allow us to find possible ways to vaccinate against Borrelia, and would be another step in finding a cure to Lyme disease.

References

  1. ↑ 1.0 1.1 1.2 da Costa Vasconcelos FN, Maciel NK, Favaro DC, de Oliveira LC, Barbosa AS, Salinas RK, de Souza RF, Farah CS, Guzzo CR. Structural and Enzymatic Characterization of a cAMP-Dependent Diguanylate Cyclase from Pathogenic Leptospira Species. J Mol Biol. 2017 Jul 21;429(15):2337-2352. doi: 10.1016/j.jmb.2017.06.002. Epub, 2017 Jun 7. PMID:28601495 doi:http://dx.doi.org/10.1016/j.jmb.2017.06.002
  2. ↑ Vincent AT, Schiettekatte O, Goarant C, Neela VK, Bernet E, Thibeaux R, Ismail N, Mohd Khalid MKN, Amran F, Masuzawa T, Nakao R, Amara Korba A, Bourhy P, Veyrier FJ, Picardeau M. Revisiting the taxonomy and evolution of pathogenicity of the genus Leptospira through the prism of genomics. PLoS Negl Trop Dis. 2019 May 23;13(5):e0007270. doi:, 10.1371/journal.pntd.0007270. eCollection 2019 May. PMID:31120895 doi:http://dx.doi.org/10.1371/journal.pntd.0007270
  3. ↑ Costa F, Hagan JE, Calcagno J, Kane M, Torgerson P, Martinez-Silveira MS, Stein C, Abela-Ridder B, Ko AI. Global Morbidity and Mortality of Leptospirosis: A Systematic Review. PLoS Negl Trop Dis. 2015 Sep 17;9(9):e0003898. doi: 10.1371/journal.pntd.0003898., eCollection 2015. PMID:26379143 doi:http://dx.doi.org/10.1371/journal.pntd.0003898
  4. ↑ Xiao G, Kong L, Che R, Yi Y, Zhang Q, Yan J, Lin X. Identification and Characterization of c-di-GMP Metabolic Enzymes of Leptospira interrogans and c-di-GMP Fluctuations After Thermal Shift and Infection. Front Microbiol. 2018 Apr 20;9:764. doi: 10.3389/fmicb.2018.00764. eCollection, 2018. PMID:29755425 doi:http://dx.doi.org/10.3389/fmicb.2018.00764
  5. ↑ Thibeaux R, Soupe-Gilbert ME, Kainiu M, Girault D, Bierque E, Fernandes J, Bahre H, Douyere A, Eskenazi N, Vinh J, Picardeau M, Goarant C. The zoonotic pathogen Leptospira interrogans mitigates environmental stress through cyclic-di-GMP-controlled biofilm production. NPJ Biofilms Microbiomes. 2020 Jun 12;6(1):24. doi: 10.1038/s41522-020-0134-1. PMID:32532998 doi:http://dx.doi.org/10.1038/s41522-020-0134-1
  6. ↑ Teixeira RD, Holzschuh F, Schirmer T. Activation mechanism of a small prototypic Rec-GGDEF diguanylate cyclase. Nat Commun. 2021 Apr 12;12(1):2162. doi: 10.1038/s41467-021-22492-7. PMID:33846343 doi:http://dx.doi.org/10.1038/s41467-021-22492-7
  7. ↑ Romling U, Galperin MY, Gomelsky M. Cyclic di-GMP: the first 25 years of a universal bacterial second messenger. Microbiol Mol Biol Rev. 2013 Mar;77(1):1-52. doi: 10.1128/MMBR.00043-12. PMID:23471616 doi:http://dx.doi.org/10.1128/MMBR.00043-12
  8. ↑ Brihuega B, Samartino L, Auteri C, Venzano A, Caimi K. In vivo cell aggregations of a recent swine biofilm-forming isolate of Leptospira interrogans strain from Argentina. Rev Argent Microbiol. 2012 Jul-Sep;44(3):138-43. PMID:23102459
  9. ↑ Chandra A,Latov N, Wormser GP, Marques AR, Alaedini A. 2011.Epitope Mapping of Antibodies to VlsE Protein of Borrelia burgdorferi in Post-Lyme Disease Syndrome. Clinical Immunology.141(1): 103–110.
  10. ↑ 10.0 10.1 Liang FT, Philipp MT. Analysis of Antibody Response to Invariable Regions of VlsE, the Variable Surface Antigen of Borrelia burgdorferi. 1999. American Society for Microbiology Journal. 67(12): 6702–6706.
  11. ↑ Toldo, Luca IG. "Antigenicity Plot." Bioinformatics. Bioinformatics Organization, 28 Feb. 1997. Web. 15 Apr. 2013. <http://www.bioinformatics.org/JaMBW/3/1/7/>.

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