Adhesion of Bartonella henselae to Fibronectin Is Mediated via Repetitive Motifs Present in the Stalk of
            <i>Bartonella</i>
            Adhesin A

Thibau, Arno; Vaca, Diana J.; Bagowski, Marlene; Hipp, Katharina; Bender, Daniela; Ballhorn, Wibke; Linke, Dirk; Kempf, Volkhard A. J.

doi:10.1128/spectrum.02117-22

Cited by 6 publications

(16 citation statements)

References 50 publications

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“…Additionally, as inter-protein interactions were scarce in the analysis, the occurrence of other interactions not detected by the XL-MS analysis can not be ruled out. In line with the previous, a recent research used a mutant B. henselae producing a truncated BadA containing domain 16 and proved to recover Fn binding [137], this domain was not identified in the XL-MS analysis. Furthermore, protein glycosylation has been described to play a significant role in host-pathogen interaction, and a vast majority of membrane proteins are glycosylated [139].…”

Section: Further Exploration Of So Far Unidentified Bada-fn Interactionssupporting

confidence: 64%

“…By rendering the predicted domain 27 structure next to the FnI 5 structures, the feasibility of the crosslinked interaction was theoretically confirmed (see Figure 36). Additionally, the importance of domains 19 and 25 for B. henselae adherence to Fn was confirmed by recent research using B. henselae mutants producing truncated BadA proteins [137]. 24), and the identified crosslink between one of the BadA monomers and the Fn fragment is indicated as a black dotted line drawn between the lysine (K) residues.…”

Section: Fnmentioning

confidence: 68%

“…In the XL-MS analysis, the BadA interactions happening with the heparin-binding domains in Fn were distributed along [47]. Recent research suggested that a peptide in the DALL motif of domain 27 could be responsible for Fn binding [137]; this peptide includes the sequence identified in the XL-MS analysis interacting with FnI 5 domain.…”

Section: Fnmentioning

confidence: 99%

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The role of Bartonella adhesin A and fibronectin in adherence of Bartonella henselae to endothelial cells

Vaca Llerena

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The capacity of pathogenic bacteria to adhere to host cells and to avoid subsequent clearance by the host´s immune response is the initial and most decisive step leading to infections. Human pathogenic bacteria circulating in the bloodstream need to find ways to interact with endothelial cells (ECs) lining the blood vessels to infect and colonise the host. The extracellular matrix (ECM) of ECs might represent an attractive initial target for bacterial interaction, as many bacterial adhesins have reported affinities to ECM proteins, particularly fibronectin (Fn). Trimeric autotransporter adhesins (TAA) have been described as important pathogenicity factors of Gram-negative bacteria. The TAA from human pathogenic Bartonella henselae, Bartonella adhesin A (BadA), is one of the longest and best characterised adhesin and represents a prototypic TAA due to its domain architecture. B. henselae, the causative agent of cat scratch disease, endocarditis, and bacillary angiomatosis, adheres to ECs and ECM proteins via BadA interaction. In this research, it was determined that the interaction between BadA and Fn is essential for B. henselae host cell adhesion. BadA interactions were identified within the heparin-binding domains of Fn, and the exact binding sites were revealed by mass spectrometry analysis of chemically crosslinked whole-cell bacteria and Fn. It turned out that specific BadA interactions with defined Fn regions represent the molecular basis for bacterial adhesion to ECs. These data were confirmed by using BadA-deficient bacteria and CRISPR-Cas FN1 knockout ECs. It was also identified that BadA binds to Fn from both cellular and plasma origin, suggesting that B. henselae binding to Fn might possibly take part in other infection processes apart from bacterial adherence, e.g. evasion from the host cell immune system. Interactions between TAAs and Fn represent a key step for adherence of B. henselae to ECs. Still, Fn-mediated binding is of more significant importance for pathogenic bacteria than broadly recognised. Fn removal from the ECM environment of ECs, also reduced adherence of Staphylococcus aureus, Borrelia burgdorferi, and Acinetobacter baumannii to host cells Interactions between adhesins and Fn might therefore represent a crucial step for the adhesion of human-pathogenic Gram-negative and Gram-positive bacteria targeting the ECs as a niche of infection or as means for persistence. This research demonstrated that combining large-scale analysis approaches to describe protein-protein interactions with supportive functional readouts (binding assays) allows for the discrimination of crucial interactions involved in bacterial adhesion to the host. The herein-described experimental approaches and tools might guide future research for other pathogenic bacteria and represent an initial point for the future generation of anti-virulence strategies to inhibit bacterial binding to host cells.

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Section: Further Exploration Of So Far Unidentified Bada-fn Interactionssupporting

confidence: 64%

Section: Fnmentioning

confidence: 68%

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The role of Bartonella adhesin A and fibronectin in adherence of Bartonella henselae to endothelial cells

Vaca Llerena

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“…In certain conditions, such as those observed with B. bacilliformis , the absence of VirB/D4-T4SS does not result in the loss of the ability to induce significant angiogenic lesions in infected patients, suggesting that VirB/VirD4-T4SS is dispensable for angiogenesis in at least some species of Bartonella . Substantiating this notion is the evidence that the GroEL chaperone of B. bacilliformis exhibits mitotic activity in HUVECs, implying its key role in Bartonella -induced angiogenesis [ 81 , and 145 ]. Additionally, BafA, a pro-angiogenic autotransporter identified in both B. henselae and B. quintana , exhibits affinity for VEGF receptor-2 (VEGFR2), exerting biological effects similar to those of VEGF [ 82 ].…”

Section: Induction Of Vascular Endothelial Growth Factor (Vegf) and H...mentioning

confidence: 99%

Sneaky tactics: Ingenious immune evasion mechanisms of Bartonella

Xi,

Li,

Liu

et al. 2024

Virulence

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Gram-negative Bartonella species are facultative intracellular bacteria that can survive in the harsh intracellular milieu of host cells. They have evolved strategies to evade detection and degradation by the host immune system, which ensures their proliferation in the host. Following infection, Bartonella alters the initial immunogenic surface-exposed proteins to evade immune recognition via antigen or phase variation. The diverse lipopolysaccharide structures of certain Bartonella species allow them to escape recognition by the host pattern recognition receptors. Additionally, the survival of mature erythrocytes and their resistance to lysosomal fusion further complicate the immune clearance of this species. Certain Bartonella species also evade immune attacks by producing biofilms and anti-inflammatory cytokines and decreasing endothelial cell apoptosis. Overall, these factors create a challenging landscape for the host immune system to rapidly and effectively eradicate the Bartonella species, thereby facilitating the persistence of Bartonella infections and creating a substantial obstacle for therapeutic interventions. This review focuses on the effects of three human-specific Bartonella species, particularly their mechanisms of host invasion and immune escape, to gain new perspectives in the development of effective diagnostic tools, prophylactic measures, and treatment options for Bartonella infections.

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“…B. henselae strains were transformed by electroporation following a previously described protocol [126,128]. B. henselae strains were cultivated on CBA plates and collected via cotton swabs in BALI medium.…”

Section: Electroporation Of B Henselaementioning

confidence: 99%

Characterisation of the fibronectin binding domains and genomic variation of the Bartonella adhesin A of Bartonella henselae

Thibau¹

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Adhesion to host cells is the first and most crucial step in infections with pathogenic Gram negative bacteria and is often mediated by trimeric autotransporter adhesins (TAAs). TAA-producing bacteria are the causative agent of many human diseases and TAA targeted anti-adhesive compounds might counteract such bacterial infections. The modularly structured Bartonella adhesin A (BadA) is one of the best characterised TAAs and serves as an attractive adhesin to study the domain-function relationship of TAAs during infection. BadA is a major virulence factor of B. henselae and is essential for the initial attachment to host cells via adhesion to extracellular matrix proteins. B. henselae is the causative agent of cat scratch disease and adheres to fibronectin using its long BadA fibres. The life cycle of this pathogen, with alternating host conditions, drives evolutionary and host-specific adaptations. Human, feline, and laboratory adapted B. henselae isolates display genomic and phenotypic differences. By analysing the genomes of eight B. henselae strains using long-read sequencing, a variable genomic badA island with a diversified and highly repetitive badA gene flanked by badA pseudogenes was identified. Moreover, numerous conserved flanking genes were characterised, however, their influence on the regulation of badA expression and modification remains to be explored. It seems that B. henselae G 5436 is the evolutionary ancestor of the other B. henselae strains analysed in this work. The diversity of the badA island among the B. henselae strains indicates that the downstream badA-like domain region might be used as a ‘toolbox’ for rearrangements in the badA gene. Overall, it is suggested that badA-domain duplications, insertions, and/or deletions are the result of active phase variation via site-specific recombination and contribute to rapid host adaptation in the scope of pathogenicity, immune evasion, and/or enhanced long-term colonisation. The model strain B. henselae Marseille expresses a badA gene that includes 30 repetitive neck/stalk domains, each consisting of several predicted structural motifs. To further elucidate the motif sequences that mediate fibronectin binding, various modified badA constructs were generated. Their ability to bind fibronectin was assessed via whole-cell ELISA and fluorescence microscopy. In conclusion, it is suggested that BadA adheres to fibronectin in a cumulative fashion with quick saturation via unpaired β-strands appearing in structural motifs present in BadA neck/stalk domains 19, 27, and other homologous domains. Furthermore, antibodies targeting a 15-mer amino acid sequence in the DALL motif of BadA neck/stalk domain 27 were able to reduce fibronectin binding of the B. henselae mutant strain S27. Moreover, this DALL motif sequence is conserved in the genome of all analysed B. henselae strains. The identification of common binding motifs between BadA and fibronectin supports the development of new anti-adhesive compounds that might inhibit the initial adherence of B. henselae and other TAA-producing pathogens during infection.

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Adhesion of Bartonella henselae to Fibronectin Is Mediated via Repetitive Motifs Present in the Stalk of Bartonella Adhesin A

Cited by 6 publications

References 50 publications

The role of Bartonella adhesin A and fibronectin in adherence of Bartonella henselae to endothelial cells

The role of Bartonella adhesin A and fibronectin in adherence of Bartonella henselae to endothelial cells

Sneaky tactics: Ingenious immune evasion mechanisms of Bartonella

Characterisation of the fibronectin binding domains and genomic variation of the Bartonella adhesin A of Bartonella henselae

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