Gpm1p Is a Factor H-, FHL-1-, and Plasminogen-binding Surface Protein of Candida albicans

SummaryThe acquisition of regulatory proteins is a means of blood‐borne pathogens to avoid destruction by the human complement. We recently showed that the gametes of the human malaria parasite Plasmodium falciparum bind factor H (FH) from the blood meal of the mosquito vector to assure successful sexual reproduction, which takes places in the mosquito midgut. While these findings provided a first glimpse of a complex mechanism used by Plasmodium to control the host immune attack, it is hitherto not known, how the pathogenic blood stages of the malaria parasite evade destruction by the human complement. We now show that the human complement system represents a severe threat for the replicating blood stages, particularly for the reinvading merozoites, with complement factor C3b accumulating on the surfaces of the intraerythrocytic schizonts as well as of free merozoites. C3b accumulation initiates terminal complement complex formation, in consequence resulting in blood stage lysis. To inactivate C3b, the parasites bind FH as well as related proteins FHL‐1 and CFHR‐1 to their surface, and FH binding is trypsin‐resistant. Schizonts acquire FH via two contact sites, which involve CCP modules 5 and 20. Blockage of FH‐mediated protection via anti‐FH antibodies results in significantly impaired blood stage replication, pointing to the plasmodial complement evasion machinery as a promising malaria vaccine target.

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“…meningitides for complement evasion (e.g. Poltermann et al , 2007; Malito et al , 2013; reviewed in Zipfel et al , 2007). …”

Section: Discussionmentioning

confidence: 99%

ThePlasmodium falciparumblood stages acquire factor H family proteins to evade destruction by human complement

Rosa

Flammersfeld

Ngwa

et al. 2015

Cellular Microbiology

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“…Therefore, it is unclear how Lpd and also the other microbial moonlighting proteins are exported to and anchored into the microbial membrane. In addition to Lpd, several other moonlighting proteins, including Tuf from P. aeruginosa, Gpm1 from C. albicans, and Tuf from Mycoplasma pneumoniae, bind complement regulators and other human plasma proteins (11,23,43). When Lpd was blocked at the surface of strain SG137 with specific antiserum and the bacteria were challenged with NHS, bacterial survival was reduced by 56%.…”

Section: Discussionmentioning

confidence: 99%

“…Factor H and FHL-1 are recruited by bacterial and fungal complement regulator-acquiring surface proteins and are attached via the same domains, that is, SCRs 6-7 and SCRs 18-20. Microbial proteins that bind Factor H and FHL-1 via these domains include Rck from Salmonella enterica and Gpm1 and Pra1 from C. albicans (23,35,44,45). A second group of microbial surface proteins binds the two human regulators either via SCRs 6-7 (e.g., M proteins and Fba from Streptococcus pyogenes, NspA from Neisseria meningitidis, CRASP-1 from B. burgdorferi) or via SCRs 18-20 (e.g., Scl1 from S. pyogenes and Por1B from Neisseria gonorrheae) of Factor H (30,(46)(47)(48).…”

Section: Discussionmentioning

confidence: 99%

“…When activated by endogenous activators like tissue-type plasminogen activator or urokinasetype plasminogen activator (uPA), the protease plasmin degrades ECM components like fibrinogen, fibronectin, vitronectin, and laminin and regulates cell migration, coagulation, fibrinolysis, inflammation, wound healing, and tissue remodeling (18,19). Plasminogen is acquired by several pathogens, including P. aeruginosa, Streptococcus pneumoniae, Borrelia burgdorferi, Staphylococcus aureus, Lactobacillus johnsonii, and Candida albicans for ECM interaction, and activated plasmin is then used for destruction of host basement membranes and ECM (11,(20)(21)(22)(23).…”

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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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“…However, the activation of complement can lead to opsonization of the fungal surface with C3b and C4b, and result in the generation of chemotactic and pro-inflammatory activation fragments, such as C3a and C5a Cheng et al, 2012), which together facilitate the elimination of the pathogen by attracting neutrophils and macrophages and enhancing opsonophagocytosis. In order to evade these complement-mediated defence processes, some fungi bind complement regulators, such as FH and C4b-binding protein, through a variety of surface-bound and secreted proteins (Poltermann et al, 2007;Vogl et al, 2008;Luo et al, 2009) and thus restrict complement activation in their environment. In addition, FH was reported to influence cellular adhesion and/or antifungal responses.…”

Section: Introductionmentioning

confidence: 99%

Secreted aspartic protease 2 of Candida albicans inactivates factor H and the macrophage factor H-receptors CR3 (CD11b/CD18) and CR4 (CD11c/CD18)

et al. 2015

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The opportunistic pathogenic yeast Candida albicans employs several mechanisms to interfere with the human complement system. This includes the acquisition of host complement regulators, the release of molecules that scavenge complement proteins or block cellular receptors, and the secretion of proteases that inactivate complement components. Furthermore, FH enhanced zymosan-induced production of these cytokines. C. albicans Sap2 cleaved FH, diminishing its complement regulatory activity, and Sap2-treatment resulted in less detectable CR3 and CR4 on macrophages. These data show that FH enhances the activation of human macrophages when bound on C. albicans. However, the fungus can inactivate both FH and its receptors on macrophages by secreting Sap2, which may represent an additional means for C. albicans to evade the host innate immune system.

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Gpm1p Is a Factor H-, FHL-1-, and Plasminogen-binding Surface Protein of Candida albicans

Cited by 118 publications

References 45 publications

ThePlasmodium falciparumblood stages acquire factor H family proteins to evade destruction by human complement

ThePlasmodium falciparumblood stages acquire factor H family proteins to evade destruction by human complement

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

Secreted aspartic protease 2 of Candida albicans inactivates factor H and the macrophage factor H-receptors CR3 (CD11b/CD18) and CR4 (CD11c/CD18)

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