Factor H Family Proteins in Complement Evasion of Microorganisms

Józsi, Mihály

doi:10.3389/fimmu.2017.00571

Cited by 59 publications

(66 citation statements)

References 81 publications

(100 reference statements)

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“…EDTA presence also prevented fH binding to both viruses and SPIO nanoworms. Highly virulent human pathogens are known to acquire complement regulators such as fH, fH-related proteins and C4 binding protein for immune evasion (Stoiber et al, 1997; Zipfel et al, 2002; Józsi, 2017), but the lack of direct fH binding to SMV1 is in line with the notion that this virus is not a virulent human (or eukaryotic) pathogen.…”

Section: Resultsmentioning

confidence: 90%

“…Bearing in mind that SMV1 is as potent as zymosan in activating the human complement system (Fig. 2a and b), this higher level of fH deposition is presumably a reflection of the presence of more C3b on SMV1 surfaces (where fH may bind C3b through its complement control protein domains 1–4 and 19–20; Józsi, 2017) rather than direct fH binding to viruses (C3:fH density of 0.94 ± 0.26 and 3.5 ± 0.23 for SMV1 and SPIO nanoworms, respectively). Indeed, in 10 mM EDTA-treated serum (where complement activation is blocked), C3 deposition on both SMV1 and SPIO nanoworms corresponded to less than 15% of untreated serum.…”

Section: Resultsmentioning

confidence: 98%

“…Since SMV1 was directly capable of increasing the alternative pathway turnover, we further assessed the extent of both C3 and fH (a regulator of the alternative pathway and the amplification loop that binds to C3b and limits assembly of the C3bBb convertase deposition) (Józsi, 2017) deposition from serum on SMV1 and compared this with SPIO nanoworms (of similar size to SMV1). SPIO nanoworms were chosen as an established particulate model that predominantly triggers complement activation in human serum through the alternative pathway (Chen et al, 2017).…”

Section: Resultsmentioning

confidence: 99%

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Interaction of extremophilic archaeal viruses with human and mouse complement system and viral biodistribution in mice

Uldahl

Chen

et al. 2017

Molecular Immunology

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Archaeal viruses offer exceptional biophysical properties for modification and exploration of their potential in bionanotechnology, bioengineering and nanotherapeutic developments. However, the interaction of archaeal viruses with elements of the innate immune system has not been explored, which is a necessary prerequisite if their potential for biomedical applications to be realized. Here we show complement activation through lectin (via direct binding of MBL/MASPs) and alternative pathways by two extremophilic archaeal viruses (Sulfolobus monocaudavirus 1 and Sulfolobus spindle-shaped virus 2) in human serum. We further show some differences in initiation of complement activation pathways between these viruses. Since, Sulfolobus monocaudavirus 1 was capable of directly triggering the alternative pathway, we also demonstrate that the complement regulator factor H has no affinity for the viral surface, but factor H deposition is purely C3-dependent. This suggests that unlike some virulent pathogens Sulfolobus monocaudavirus 1 does not acquire factor H for protection. Complement activation with Sulfolobus monocaudavirus 1 also proceeds in murine sera through MBL-A/C as well as factor D-dependent manner, but C3 deficiency has no overall effect on viral clearance by organs of the reticuloendothelial system on intravenous injection. However, splenic deposition was significantly higher in C3 knockout animals compared with the corresponding wild type mice. We discuss the potential application of these viruses in biomedicine in relation to their complement activating properties.

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Section: Resultsmentioning

confidence: 90%

Section: Resultsmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

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Interaction of extremophilic archaeal viruses with human and mouse complement system and viral biodistribution in mice

Uldahl

Chen

et al. 2017

Molecular Immunology

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“…The observed Sbi-III-IV mediated shift in the complement regulatory balance towards C3 activation could potentially be further enhanced by the formation of homo/heterodimeric forms of FHR-1 with itself and with other FHRs (FHR-2 and FHR-5) [12]. These data link to an ongoing evolutionary ‘arms race’ where FH was initially hijacked by S. aureus to protect it from complement [46] and then FHRs (devoid of intrinsic complement regulatory activity) were evolved/deployed by the host to compete with FH on that surface and restore complement opsonisation of the pathogen [22]. Perhaps the release/secretion of Sbi from S. aureus is a more recent event in this arms race with the host, which takes the C3b/C3 convertase binding potential away from the bacterial surface and leads to local rapid fluid phase consumption of complement, i.e.…”

Section: Discussionmentioning

confidence: 99%

Utilisation of staphylococcal immune evasion protein Sbi as a novel vaccine adjuvant

Yang

Back

Graewert³

et al. 2018

Preprint

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42Co--ligation of the B cell antigen receptor with complement receptor 2 on B--cells 43 via a C3d--opsonised antigen complex significantly lowers the threshold required 44 for B cell activation. Consequently, fusions of antigens with C3d polymers have 45 shown great potential in vaccine design. However, these linear arrays of C3d 46 multimers do not mimic the natural opsonisation of antigens with C3d. Here we 47 investigate the potential of using the unique complement activating 48 characteristics of Staphylococcal immune--evasion protein Sbi to develop a 49 pro--vaccine approach that spontaneously coats antigens with C3 degradation 50 products in a natural way. We show that Sbi rapidly triggers the alternative 51 complement pathway through recruitment of complement regulators, forming a 52 tripartite complex that acts as a competitive antagonist of factor H, resulting in 53 enhanced complement consumption. These functional results are corroborated 54 by the structure of this complement activating Sbi--III--IV:C3d:FHR--1 complex. 55Finally, we demonstrate that Sbi, fused with Mycobacterium tuberculosis antigen 56 Ag85b, causes efficient opsonisation with C3 fragments, thereby enhancing the 57 immune response significantly beyond that of Ag85b alone, providing proof of 58 concept for our pro--vaccine approach. 59 antigens by C3d at a molecular level and do not always enhance immune 82 responses [13]. After activation of C3, C3b attaches directly to the antigen 83 surface via the reactive thioester on the convex face of the protein's thioester 84 domain (TED). In the presence of complement regulators (factor I (FI) and its 85 co--factors, such as factor H (FH) and CR1) this is rapidly converted to iC3b and 86 then to C3d, exposing the concave CR2 binding site of the TED fragment away 87 from the antigen surface [14]. It is likely that multiple iC3b/C3d molecules attach 88 to complex antigens/pathogen surfaces during the initial activation phases of 89 complement, creating high--avidity binding site for complement fragment 90 receptors. 91In the last two decades, structural biology has helped to unveil many of the 92 molecular aspects that are crucial for the activation and regulation of the 93 complement system. Most notable are the crystal structures of the central 94 complement component activation states, native C3 [15], activated C3b and 95 inactive C3c [16]. The structure of C3b in complex with factors B and D [17] 96 subsequently revealed a detailed view of the alternative pathway C3 convertase 97 assembly and its activation, leading to the amplified cleavage of C3 molecules 98 that result in opsonisation and clearance of microbial pathogens and host debris. 99 The covalent attachment of C3b to surfaces does not discriminate between self 100 or non--self surfaces and requires tight regulation to protect host surfaces. 101 Structures of C3b in complex with FH domains 1--4 [18] and domains 19--20 [19, 102 20] provided insights into protection of host cells [21] and demonstrated how 103 5 factor H--related prote...

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“…This capacity lies mainly in the conserved domains homologous to the main ligand binding sites for host and non-host molecules in FH ( Figure 1A (8, 13)). Results obtained in the past years raise the possibility that the evolution of the CFH gene cluster and the appearance of the CFHR genes are microorganism-driven, due to coevolution with microbes, and the FHRs function as decoys to prevent FH binding by pathogens, thus blocking one of their escape mechanisms (42). At the same time, FHRs can compete with FH for self-ligands such as pentraxins, too [ Figure 5A and (23, 24)].…”

Section: Discussionmentioning

confidence: 99%