The secreted Candida albicans protein Pra1 disrupts host defense by broadly targeting and blocking complement C3 and C3 activation fragments.

Abstract:

:Candida albicans the most frequently isolated clinical fungal pathogen can cause local as well as systemic and life-threatening infections particularly in immune-compromised individuals. A better and more detailed understanding how C. albicans evades human immune attack is therefore needed for identifying fungal immune-evasive proteins and develop new therapies. Here, we identified Pra1, the pH-regulated C. albicans antigen as a hierarchical complement inhibitor that targets C3, the central human complement component. Pra1 cleaved C3 at a unique site and further inhibited effector function of the activation fragments. The newly formed C3a-like peptide lacked the C-terminal arginine residue needed for C3a-receptor binding and activation. Moreover, Pra1 also blocked C3a-like antifungal activity as shown in survival assays, and the C3b-like molecule formed by Pra1 was degraded by the host protease Factor I. Pra1 also bound to C3a and C3b generated by human convertases and blocked their effector functions, like C3a antifungal activity shown by fungal survival, blocked C3a binding to human C3a receptor-expressing HEK cells, activation of Fura2-AM loaded cells, intracellular Ca2+ signaling, IL-8 release, C3b deposition, as well as opsonophagocytosis and killing by human neutrophils. Thus, upon infection C. albicans uses Pra1 to destroy C3 and to disrupt host complement attack. In conclusion, candida Pra1 represents the first fungal C3-cleaving protease identified and functions as a fungal master regulator of innate immunity and as a central fungal immune-escape protein.

journal_name

Mol Immunol

journal_title

Molecular immunology

authors

Luo S,Dasari P,Reiher N,Hartmann A,Jacksch S,Wende E,Barz D,Niemiec MJ,Jacobsen I,Beyersdorf N,Hünig T,Klos A,Skerka C,Zipfel PF

doi

10.1016/j.molimm.2017.07.010

subject

Has Abstract

pub_date

2018-01-01 00:00:00

pages

266-277

eissn

0161-5890

issn

1872-9142

pii

S0161-5890(17)30440-6

journal_volume

93

pub_type

杂志文章
  • The dual role of complement in the progression of renal disease in NZB/W F(1) mice and alternative pathway inhibition.

    abstract::Complement plays a dual role in the progression of systemic lupus erythematosus since it has important protective functions, such as the clearance of immune complexes and apoptotic cells, but is also a mediator of renal inflammation. To investigate this balance in a clinically relevant setting, we investigated how tar...

    journal_title:Molecular immunology

    pub_type: 杂志文章

    doi:10.1016/j.molimm.2011.09.015

    authors: Sekine H,Ruiz P,Gilkeson GS,Tomlinson S

    更新日期:2011-10-01 00:00:00

  • Structural, immunological and functional comparisons of factor H, rheumatoid arthritis protein (RHP), and its apparent normal counterpart (N-RHP).

    abstract::The isolation and characterization of two human serum proteins, RHP and N-RHP, are described. N-RHP appears to be the normal counterpart of RHP which is found at elevated levels in sera of patients with rheumatoid arthritis [Rosano et al. (1988b) Inflammation 12, 351 - 360]. Although both proteins crossreact with anti...

    journal_title:Molecular immunology

    pub_type: 杂志文章

    doi:10.1016/0161-5890(95)00068-2

    authors: Hurwitz C,Rosano CL,Hechemy KE,Weber P,Parhami N

    更新日期:1995-11-01 00:00:00

  • Quantitation of the immunogenic potential of protein antigens.

    abstract::A procedure to quantitate the immunogenic potential of protein antigens is presented. It is hypothesized that the intrinsic immunogenicity of an accessible region on the protein arises from the overall structural effect of the presence of the particular assemblage of amino acid residues in the given region. Structural...

    journal_title:Molecular immunology

    pub_type: 杂志文章

    doi:10.1016/0161-5890(85)90043-4

    authors: Padlan EA

    更新日期:1985-11-01 00:00:00

  • Differential expression profiles and gene structure of two tumor necrosis factor-alpha variants in Atlantic salmon (Salmo salar L.).

    abstract::Here we present the gene structure and expression data on two Atlantic salmon TNF-alpha genes. Both genes are approximately 2.0kb in length and organized into four exons and three introns. The open reading frame of both genes translates into 246 amino acid putative peptides, being 91.5% identical at the amino acid lev...

    journal_title:Molecular immunology

    pub_type: 杂志文章

    doi:10.1016/j.molimm.2006.08.015

    authors: Haugland O,Mercy IS,Romøren K,Torgersen J,Evensen O

    更新日期:2007-03-01 00:00:00

  • Increased PD-1+CD154+ Tfh cells are possibly the most important functional subset of PD-1+ T follicular helper cells in adult patients with minimal change disease.

    abstract::T follicular helper (Tfh) cells, especially programmed cell death protein 1 (PD-1)+ Tfh cells, exert important functions in the normal immune response. The purpose of this study was to determine the frequency of different subsets of PD-1+ Tfh cells and their functional effects in adult patients with minimal change dis...

    journal_title:Molecular immunology

    pub_type: 杂志文章

    doi:10.1016/j.molimm.2017.12.020

    authors: Li T,Shi Y,Sun W,Wang H,Wang Q,Jiang Y

    更新日期:2018-02-01 00:00:00

  • TGF-beta 1 inhibition of IFN-gamma-induced signaling and Th1 gene expression in CD4+ T cells is Smad3 independent but MAP kinase dependent.

    abstract::In addition to classic Smad signaling pathways, the pleiotropic immunoregulatory cytokine TGF-beta1 can activate MAP kinases, but a role for TGF-beta1-MAP kinase pathways in T cells has not been defined heretofore. We have shown previously that TGF-beta1 inhibits Th1 development by inhibiting IFN-gamma's induction of ...

    journal_title:Molecular immunology

    pub_type: 杂志文章

    doi:10.1016/j.molimm.2007.02.024

    authors: Park IK,Letterio JJ,Gorham JD

    更新日期:2007-07-01 00:00:00

  • Tumor PD-L1 co-stimulates primary human CD8(+) cytotoxic T cells modified to express a PD1:CD28 chimeric receptor.

    abstract::Tumors exploit immunoregulatory checkpoints that serve to attenuate T cell responses as a means of circumventing immunologic rejection. Programmed death ligand 1 (PD-L1) is a negative regulator of T cell function and is frequently expressed by solid tumors. By engaging programmed death 1 (PD-1) on activated T cells, P...

    journal_title:Molecular immunology

    pub_type: 杂志文章

    doi:10.1016/j.molimm.2012.03.023

    authors: Prosser ME,Brown CE,Shami AF,Forman SJ,Jensen MC

    更新日期:2012-07-01 00:00:00

  • Binding of bivalent ligand to cell surface IgE: can one detect ring formation?

    abstract::It is well established that aggregation of cell surface immunoglobulin is involved in signal transduction by cells of the immune system. It is less well understood what special properties of these cell surface aggregates are important in initiating the signal cascade. Several authors have proposed that cells respond t...

    journal_title:Molecular immunology

    pub_type: 杂志文章

    doi:10.1016/0161-5890(94)90160-0

    authors: Posner RG,Dembo M

    更新日期:1994-12-01 00:00:00

  • The molecular weight of the endothelial cell IL-1 receptor is 78,000.

    abstract::Human endothelial cells have been shown to be distinctive from other IL-1 responsive cells (e.g. murine thymocytes), in the equal units of murine and human IL-1 do not have the same endothelial cell stimulatory effect, as measured by increased lymphocyte adherence. In this paper, the cell surface IL-1 receptors of hum...

    journal_title:Molecular immunology

    pub_type: 杂志文章

    doi:10.1016/0161-5890(89)90078-3

    authors: Thieme TR,Wagner CR

    更新日期:1989-03-01 00:00:00

  • IRF-1 and p65 mediate upregulation of constitutive HLA-A antigen expression by hepatocellular carcinoma cells.

    abstract::Malignant transformation of hepatocytes is frequently associated with upregulation of HLA-A expression. Currently there is no information available regarding the mechanisms underlying this phenotypic change. We investigated HLA-A expression in 165 paraffin embedded tissues and 21 fresh tissues from liver cancer patien...

    journal_title:Molecular immunology

    pub_type: 杂志文章

    doi:10.1016/j.molimm.2009.03.001

    authors: Shen Y,Xia M,Zhang J,Xu L,Yang J,Chen A,Miao F,Ferrone S,Xie W

    更新日期:2009-06-01 00:00:00

  • Solid-phase antigen binding by purified immunoproteins from antigen-specific monoclonal T cell hybridomas.

    abstract::We have developed two distinct solid-phase immunoassays for the detection of antigen binding activity by products of antigen binding T cell hybridomas in the absence of MHC. Two suppressor T cell hybridomas studied (34s-18 and 34s-704) are specific for keyhole limpet hemocyanin, a protein antigen, and the other suppre...

    journal_title:Molecular immunology

    pub_type: 杂志文章

    doi:10.1016/0161-5890(89)90043-6

    authors: Bristow CL,Marchalonis JJ

    更新日期:1989-07-01 00:00:00

  • Identification of a linear B-cell epitope in the catalytic domain of bothropasin, a metalloproteinase from Bothrops jararaca snake venom.

    abstract::Bothropasin is a hemorrhagic snake venom metalloproteinase (SVMP) from Bothrops jararaca venom, the snake responsible for most bites in Southeastern Brazil. SVMPs, such as bothropasin, are involved in the main bothropic envenoming symptoms, which include hemorrhage, inflammation, necrosis and blood coagulation deficie...

    journal_title:Molecular immunology

    pub_type: 杂志文章

    doi:10.1016/j.molimm.2018.10.019

    authors: Molina Molina DA,Guerra-Duarte C,Naves de Souza DL,Costal-Oliveira F,Ávila GR,Soccol VT,Machado-de-Ávila RA,Chávez-Olórtegui C

    更新日期:2018-12-01 00:00:00

  • The regulation of the complement system: insights from genetically-engineered mice.

    abstract::The complement system is very tightly regulated by fluid-phase and membrane-bound factors that prevent injury to self-tissues. The study of genetically engineered animals with targeted deletion or gain of function mutations has highlighted the important role that many of the complement inhibitors play in vivo. The adv...

    journal_title:Molecular immunology

    pub_type: 杂志文章,评审

    doi:10.1016/s0161-5890(03)00110-x

    authors: Turnberg D,Botto M

    更新日期:2003-09-01 00:00:00

  • Analysis of immunoglobulin heavy chain delta transcription termination in the production of delta S or delta M mRNA.

    abstract::mRNA encoding secreted immunoglobulin is synthesized either by termination of transcription 3' to secreted terminus sequences and 5' to the membrane terminus sequences or by cleavage of a pre-mRNA transcript containing both secreted and membrane sequences at the appropriate polyadenylation site 5' to the membrane sequ...

    journal_title:Molecular immunology

    pub_type: 杂志文章

    doi:10.1016/0161-5890(91)90110-6

    authors: Weiss EA,Tucker PW,Finkelman FD,Yuan D

    更新日期:1991-07-01 00:00:00

  • Molecular characterization of interleukin-6 in the gilthead seabream (Sparus aurata).

    abstract::A cDNA clone, designated sbIL-6 (seabream interleukin-6), was obtained from a cDNA library of enriched immune-stimulated sequences from gilthead seabream. The deduced sbIL-6 protein corresponds to a 225-amino acid protein with a putative 24-amino acid signal peptide, four conserved alpha helices and one N-linked glyco...

    journal_title:Molecular immunology

    pub_type: 杂志文章

    doi:10.1016/j.molimm.2008.04.012

    authors: Castellana B,Iliev DB,Sepulcre MP,MacKenzie S,Goetz FW,Mulero V,Planas JV

    更新日期:2008-07-01 00:00:00

  • Characterizations of CD4-1, CD4-2 and CD8β T cell subpopulations in peripheral blood leucocytes, spleen and head kidney of Japanese flounder (Paralichthys olivaceus).

    abstract::In the previous study, antibodies against CD3 molecule have been produced and were used in labeling T cells in Japanese flounder (Paralichthys olivaceus). In this paper, CD4+ and CD8+ lymphocytes subpopulations in peripheral blood leucocytes (PBL), spleen and head kidney of flounder were investigated. The flounder CD4...

    journal_title:Molecular immunology

    pub_type: 杂志文章

    doi:10.1016/j.molimm.2017.02.015

    authors: Xing J,Ma J,Tang X,Sheng X,Zhan W

    更新日期:2017-05-01 00:00:00

  • Biased dA/dT somatic hypermutation as regulated by the heavy chain intronic iEmu enhancer and 3'Ealpha enhancers in human lymphoblastoid B cells.

    abstract::Somatic hypermutation (SHM) in immunoglobulin gene (Ig) variable (V) regions is critical for the maturation of the antibody response. It is dependent on the expression of activation-induced cytidine deaminase (AID) and translesion DNA polymerases in germinal center B cells as well as Ig V transcription, as regulated b...

    journal_title:Molecular immunology

    pub_type: 杂志文章

    doi:10.1016/j.molimm.2005.10.018

    authors: Komori A,Xu Z,Wu X,Zan H,Casali P

    更新日期:2006-04-01 00:00:00

  • Orexin A prevents degradation of the articular matrixes in human primary chondrocyte culture.

    abstract::Excessive production of pro-inflammatory cytokines such as interleukin-1β (IL-1β) plays a key role in the pathophysiological development of osteoarthritis (OA). Orexin A is an important peptide of hypothalamic origin, which has displayed its multiple biological functions in several chronic diseases via activation of i...

    journal_title:Molecular immunology

    pub_type: 杂志文章

    doi:10.1016/j.molimm.2018.05.012

    authors: Wang D,Ren H,Li C,Liu F,Wang G,Shi F,Sun Y

    更新日期:2018-09-01 00:00:00

  • Intracellular co-localization of SPLUNC1 protein with nanobacteria in nasopharyngeal carcinoma epithelia HNE1 cells depended on the bactericidal permeability increasing protein domain.

    abstract::Epithelial surfaces constitute natural immunobarriers against environmental threats. These barriers are brimming with fluids that bind, transport, cleave or degrade bacterial cells and their endotoxic by-products. Saliva and the airway surface-lining fluid (ASL) comprise the important fluid constituents. Short palate,...

    journal_title:Molecular immunology

    pub_type: 杂志文章

    doi:10.1016/j.molimm.2005.10.021

    authors: Zhou HD,Li GY,Yang YX,Li XL,Sheng SR,Zhang WL,Zhao J

    更新日期:2006-04-01 00:00:00

  • SOCS3-deficient lung epithelial cells uptaking neutrophil-derived SOCS3 worsens lung influenza infection.

    abstract::Suppressor of cytokine signaling 3 (SOCS3) is a negative regulator of TBK1 and interferon pathway and the expression of SOCS3 is closely correlated with symptoms of influenza patients. However, whether deletion of Socs3 in the lung epithelial cells would affect influenza lung replication and inflammation in vivo is un...

    journal_title:Molecular immunology

    pub_type: 杂志文章

    doi:10.1016/j.molimm.2020.06.022

    authors: Li L,Wu H,Li Q,Chen J,Xu K,Xu J,Su X

    更新日期:2020-09-01 00:00:00

  • The N-linked oligosaccharides of the Fc epsilon receptors of rat basophilic leukemia cells.

    abstract::This study was undertaken to investigate the nature and microheterogeneity of the carbohydrate moiety of the Fc epsilon receptors of RBL-CA10 and RBL-CA10.7 cells. Treatment using the glycosylation processing inhibitors, castanospermine (CN), 1-deoxymannojirimycin (DMJ), and swainsonine (SW) resulted in a decrease of ...

    journal_title:Molecular immunology

    pub_type: 杂志文章

    doi:10.1016/0161-5890(93)90060-o

    authors: LaCroix EL,Froese A

    更新日期:1993-02-01 00:00:00

  • Discerning the kinetics of autoimmune manifestations in a model of Sjögren's syndrome.

    abstract::Ectopic follicles are non-encapsulated organized lymphoid structures that form at sites of inflammation and presumably contribute to the activation and differentiation of cells with autoreactive potential within target tissues. As such, directed targeting of ectopic follicles in settings of autoimmunity may provide a ...

    journal_title:Molecular immunology

    pub_type: 杂志文章

    doi:10.1016/j.molimm.2014.05.006

    authors: Karnell JL,Mahmoud TI,Herbst R,Ettinger R

    更新日期:2014-12-01 00:00:00

  • Selection of human antibodies against cell surface-associated oligomeric anthrax protective antigen.

    abstract::The protective antigen (PA(83)) of Bacillus anthracis is the dominant antigen in natural and vaccine-induced immunity to anthrax infection. Three human single-chain variable fragments (scFvs) against cell bound PA were isolated from an antibody phage display library. Specifically, the antibodies were evaluated for the...

    journal_title:Molecular immunology

    pub_type: 杂志文章

    doi:10.1016/j.molimm.2006.11.011

    authors: Steiniger SC,Altobell LJ 3rd,Zhou B,Janda KD

    更新日期:2007-04-01 00:00:00

  • Analysis and characterization of the expression of the secretory and membrane forms of IgM heavy chains in the pufferfish, Takifugu rubripes.

    abstract::We investigated the structure and expression of immunoglobulin genes in the pufferfish, Takifugu rubripes, a highly prized and economically important fish species. The cDNA fragment that partially encodes the constant region of the IgM heavy chain was isolated in these animals by RACE using degenerate primers after wh...

    journal_title:Molecular immunology

    pub_type: 杂志文章

    doi:10.1016/j.molimm.2004.06.034

    authors: Saha NR,Suetake H,Suzuki Y

    更新日期:2005-01-01 00:00:00

  • Generation, ex vivo expansion and safety of engineered PD1-knockout primary T cells from cynomolgus macaques.

    abstract::Programmed cell death protein 1 (PD1) is a cell-surface receptor that plays a vital regulatory role in suppressing inflammatory T cell activity; therefore, it is an ideal target for T cell-redirecting therapies. Here, we describe a cynomolgus macaque model for studying the transfer of PD1-modified T cells. We develope...

    journal_title:Molecular immunology

    pub_type: 杂志文章

    doi:10.1016/j.molimm.2020.05.007

    authors: Gao CE,Song Q,Zhang M,Li J,Miao Y,Li Z,Dong J

    更新日期:2020-08-01 00:00:00

  • The function of MITF and associated proteins in mast cells.

    abstract::Mutation of microphthalmia transcription factor (MITF) results in deafness, bone loss, small eyes, and poorly pigmented eyes and skin. The primary cell types affected in MITF-deficient mice are melanocytes, osteoclasts and mast cells. A search for MITF-associated proteins, using a mast cell library that was screened w...

    journal_title:Molecular immunology

    pub_type: 杂志文章,评审

    doi:10.1016/s0161-5890(02)00059-7

    authors: Nechushtan H,Razin E

    更新日期:2002-09-01 00:00:00

  • ANCA associated vasculitis: The journey to complement-targeted therapies.

    abstract::ANCA associated vasculitis is a serious, very often recurrent disease that despite the current standard treatment with high-dose glucocorticoids and either cyclophosphamide or rituximab, patients have a nine-fold increased mortality risk in the first year compared with healthy controls, attributed to infections, vascu...

    journal_title:Molecular immunology

    pub_type: 杂志文章,评审

    doi:10.1016/j.molimm.2019.06.018

    authors: Quintana LF,Kronbichler A,Blasco M,Zhao MH,Jayne D

    更新日期:2019-08-01 00:00:00

  • Molecular analysis of induced idiotypes associated with autoanti-thyroglobulin.

    abstract::Idiotype (Id) and autoanti-thyroglobulin were induced in different strains of mice by priming with anti-Id to monoclonal anti-thyroglobulins (D8 and G4) and challenged with a subimmunogenic dose of thyroglobulin (Tg). Both D8.Id and G4.Id were induced in CBA mice by priming with the appropriate anti-Id, but only primi...

    journal_title:Molecular immunology

    pub_type: 杂志文章

    doi:10.1016/0161-5890(85)90159-2

    authors: Male D,Pryce G,Roitt I

    更新日期:1985-03-01 00:00:00

  • Cardamonin inhibits COX and iNOS expression via inhibition of p65NF-kappaB nuclear translocation and Ikappa-B phosphorylation in RAW 264.7 macrophage cells.

    abstract::Cardamonin, a chalcone isolated from the fruits of a local plant Alpinia rafflesiana, has demonstrated anti-inflammatory activity in cellular models of inflammation. In this report, we evaluated the ability of cardamonin to suppress both NO and PGE2 synthesis, iNOS and COX-2 expression and enzymatic activity, and key ...

    journal_title:Molecular immunology

    pub_type: 杂志文章

    doi:10.1016/j.molimm.2006.04.025

    authors: Israf DA,Khaizurin TA,Syahida A,Lajis NH,Khozirah S

    更新日期:2007-02-01 00:00:00

  • Activation of p38 MAP kinase in T cells facilitates the immune response to the influenza virus.

    abstract::Activation of p38 MAP kinase in T cells leads to increased interferon-gamma production in CD4+ and CD8+ T cells, and the selective cell death of CD8+ T cells. To address the role of p38 MAP kinase activation in T cells during an in vivo immune response, we examined the response against the influenza virus in transgeni...

    journal_title:Molecular immunology

    pub_type: 杂志文章

    doi:10.1016/s0161-5890(00)00078-x

    authors: Conze D,Lumsden J,Enslen H,Davis RJ,Le Gros G,Rincón M

    更新日期:2000-06-01 00:00:00