Factor H family proteins: on complement, microbes and human diseases

Zipfel, Peter F.; Skerka, Christine; Hellwage, Jens; Jokiranta, Sakari; Meri, Seppo; Brade, Volker; Kraiczy, Peter; Noris, Marina; Remuzzi, Giuseppe

doi:10.1042/bst0300971

Cited by 231 publications

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“…FHL-1, which is derived from the Factor H gene by alternative splicing, is a 42-kDa plasma protein composed of 7 SCRs. The 7 SCRs of FHL-1 are identical to the Nterminal SCRs of Factor H, and, in addition, the FHL-1 protein has a C-terminal extension of four unique amino acids (7,8). Factor H and FHL-1 regulate the alternative pathway of complement by binding C3b, by accelerating the decay of the alternative pathway C3-convertase (C3bBb), and by acting as a cofactor for the Factor I-mediated cleavage of C3b (6)(7)(8).…”

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confidence: 99%

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Dihydrolipoamide Dehydrogenase of Pseudomonas aeruginosa Is a Surface-Exposed Immune Evasion Protein That Binds Three Members of the Factor H Family and Plasminogen

Hallström

Mörgelin

Barthel

et al. 2012

The Journal of Immunology

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The opportunistic human pathogen Pseudomonas aeruginosa causes a wide range of diseases. To cross host innate immune barriers, P. aeruginosa has developed efficient strategies to escape host complement attack. In this study, we identify the 57-kDa dihydrolipoamide dehydrogenase (Lpd) as a surface-exposed protein of P. aeruginosa that binds the four human plasma proteins, Factor H, Factor H-like protein-1 (FHL-1), complement Factor H-related protein 1 (CFHR1), and plasminogen. Factor H contacts Lpd via short consensus repeats 7 and 18–20. Factor H, FHL-1, and plasminogen when bound to Lpd were functionally active. Factor H and FHL-1 displayed complement-regulatory activity, and bound plasminogen, when converted to the active protease plasmin, cleaved the chromogenic substrate S-2251 and the natural substrate fibrinogen. The lpd of P. aeruginosa is a rather conserved gene; a total of 22 synonymous and 3 nonsynonymous mutations was identified in the lpd gene of the 5 laboratory strains and 13 clinical isolates. Lpd is surface exposed and contributes to survival of P. aeruginosa in human serum. Bacterial survival was reduced when Lpd was blocked on the surface prior to challenge with human serum. Similarly, bacterial survival was reduced up to 84% when the bacteria was challenged with complement active serum depleted of Factor H, FHL-1, and CFHR1, demonstrating a protective role of the attached human regulators from complement attack. In summary, Lpd is a novel surface-exposed virulence factor of P. aeruginosa that binds Factor H, FHL-1, CFHR1, and plasminogen, and the Lpd-attached regulators are relevant for innate immune escape and most likely contribute to tissue invasion.

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confidence: 99%

“…Factor H and Factor H-like protein 1 (FHL-1) are two central fluid-phase regulators of the alternative complement pathway (7). Factor H is a 150-kDa plasma protein composed of 20 short consensus repeats (SCRs).…”

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confidence: 99%

Dihydrolipoamide Dehydrogenase of Pseudomonas aeruginosa Is a Surface-Exposed Immune Evasion Protein That Binds Three Members of the Factor H Family and Plasminogen

Hallström

Mörgelin

Barthel

et al. 2012

The Journal of Immunology

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“…Another regulator of the alternative pathway is the FHL-1, which is a product of alternative splicing of the FH gene (21). FHL-1 is a 42-kDa protein composed of seven SCRs identical with the N-terminal SCRs of FH and includes an extension of 4 aa at its C-terminal end (16). The alternative pathway is regulated by FH and FHL-1 via a binding of C3b, accelerating the decay of the alternative pathway C3-convertase and acting as a cofactor for the factor I-mediated cleavage of C3b.…”

mentioning

confidence: 99%

“…To prevent nonspecific damage from excess complement activation, the complement cascade is tightly regulated. Important regulators of the complement system are factor H (FH) and factor H-like protein-1 (FHL-1) (alternative pathway) (16), C4BP (C4b-binding protein) (classical/lectin pathway) (17), and vitronectin (terminal pathway) (18).…”

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confidence: 99%

Haemophilus influenzae Interacts with the Human Complement Inhibitor Factor H

Hallström

Zipfel

Blom

et al. 2008

The Journal of Immunology

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Pathogenic microbes acquire human complement inhibitors to circumvent the innate immune system. In this study, we identify two novel host-pathogen interactions, factor H (FH) and factor H-like protein 1 (FHL-1), the inhibitors of the alternative pathway that binds to Hib. A collection of clinical Haemophilus influenzae isolates was tested and the majority of encapsulated and unencapsulated bound FH. The isolate Hib 541 with a particularly high FH-binding was selected for detailed analysis. An increased survival in normal human serum was observed with Hib 541 as compared with the low FH-binding Hib 568. Interestingly, two binding domains were identified within FH; one binding site common to both FH and FHL-1 was located in the N-terminal short consensus repeat domains 6–7, whereas the other, specific for FH, was located in the C-terminal short consensus repeat domains 18–20. Importantly, both FH and FHL-1, when bound to the surface of Hib 541, retained cofactor activity as determined by analysis of C3b degradation. Two H. influenzae outer membrane proteins of ∼32 and 40 kDa were detected with radiolabeled FH in Far Western blot. Taken together, in addition to interactions with the classical, lectin, and terminal pathways, H. influenzae interferes with the alternative complement activation pathway by binding FH and FHL-1, and thereby reducing the complement-mediated bactericidal activity resulting in an increased survival. In contrast to incubation with active complement, H. influenzae had a reduced survival in FH-depleted human serum, thus demonstrating that FH mediates a protective role at the bacterial surface.

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“…In addition, the complex promotes clearance of necrotic or apoptotic cells and inhibits the production of proinflammatory cytokines (Mihlan et al 2009). Many pathogens and spirochetes including T. denticola exploit the negative regulatory activity of FH by binding FH to the cell surface (reviewed in Zipfel et al 2002). The sole FH receptor produced by T. denticola is an 11.4 kD surface-exposed lipoprotein (FhbB) (McDowell et al 2005(McDowell et al , 2007.…”

Section: T Denticola and Immune Dysregulationmentioning

confidence: 99%

Gene Regulation, Two Component Regulatory Systems, and Adaptive Responses in Treponema Denticola

Marconi

2017

Current Topics in Microbiology and Immunology

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Factor H family proteins: on complement, microbes and human diseases

Cited by 231 publications

References 0 publications

Dihydrolipoamide Dehydrogenase of Pseudomonas aeruginosa Is a Surface-Exposed Immune Evasion Protein That Binds Three Members of the Factor H Family and Plasminogen

Dihydrolipoamide Dehydrogenase of Pseudomonas aeruginosa Is a Surface-Exposed Immune Evasion Protein That Binds Three Members of the Factor H Family and Plasminogen

Haemophilus influenzae Interacts with the Human Complement Inhibitor Factor H

Gene Regulation, Two Component Regulatory Systems, and Adaptive Responses in Treponema Denticola

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