Cornelia Speth

University of Innsbruck, Innsbruck, Tyrol, Austria

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Publications (95)319.67 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: In recent years, the view of platelets has changed from mere elements of hemostasis to immunological multitaskers. They are connected in manifold ways to other cellular and humoral components of the immune network, one of which is the complement system, a potent player in soluble innate immunity. Our article reviews the crucial and complex interplay between platelets and complement, focusing on mutual regulation of these two interaction partners by their respective molecular mechanisms. Furthermore, the putative relevance of these processes to infectious diseases, inflammatory conditions, and autoimmune disorders, as well as the treatment of patients with biomaterials is highlighted. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Molecular Immunology 04/2015; 67(1). DOI:10.1016/j.molimm.2015.03.244 · 3.00 Impact Factor
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    ABSTRACT: Background. Platelets were recently identified as a part of innate immunity. They are activated by contact with Aspergillus fumigatus; putative consequences include antifungal defense, but also thrombosis, excessive inflammation, and thrombocytopenia. We aimed to identify those fungal surface structures that mediate interaction with platelets. Methods. Human platelets were incubated with Aspergillus conidia and hyphae, isolated wall components, or fungal surface mutants. Interaction was visualized microscopically; activation was quantified by flow cytometry of specific markers. Results. The capacity of A. fumigatus conidia to activate platelets is at least partly due to melanin, since this effect can be mimicked with “melanin ghosts”; a mutant lacking melanin showed reduced platelet stimulating potency. In contrast, conidial hydrophobin masks relevant structures, since an A. fumigatus mutant lacking the hydrophobin protein induced stronger platelet activation than wild-type conidia. A. fumigatus hyphae also contain surface structures that interact with platelets. Neither wall proteins, nor galactomannan, chitin, nor β-glucan are the relevant hyphal components; instead, the recently identified fungal polysaccharide galactosaminogalactan potently triggered platelet activation. Conclusions. Conidial melanin and hydrophobin as well as hyphal galactosaminogalactan represent important pathogenicity factors that modulate platelet activity and thus might influence immune responses, inflammation, and thrombosis in infected patients.
    The Journal of Infectious Diseases 03/2015; DOI:10.1093/infdis/jiv191 · 5.78 Impact Factor
  • Cornelia Speth · Guenter Rambach · Cornelia Lass-Floerl
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    ABSTRACT: Up to date, perception of platelets has changed from key players in coagulation to multitaskers within the immune network, connecting its most diverse elements and crucially shaping their interplay with invading pathogens such as fungi. In addition, antimicrobial effector molecules and mechanisms in platelets enable a direct inhibitory effect on fungi, thus completing their immune capacity. To precisely assess the impact of platelets on the course of invasive fungal infections is complicated by some critical parameters. First, there is a fragile balance between protective antimicrobial effects and detrimental reactions that aggravate the fungal pathogenesis. Second, some platelet effects are exerted indirectly by other immune mediators and are thus difficult to quantify. Third, drugs such as antimycotics, antibiotics, or cytostatics, are commonly administered to the patients and might modulate the interplay between platelets and fungi. Our article highlights selected aspects of the complex interactions between platelets and fungi and the relevance of these processes for the pathogenesis of fungal infections.
    Thrombosis and Haemostasis 07/2014; 112(3). DOI:10.1160/TH14-01-0074 · 5.76 Impact Factor
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    ABSTRACT: Abstract As a result of fundamental changes in the International Code of Nomenclature on the use of separate names for sexual and asexual stages of fungi, generic names of many groups should be reconsidered. Members of the ECMM/ISHAM working group on Pseudallescheria/ Scedosporium infections herein advocate a novel nomenclature for genera and species in Pseudallescheria, Scedosporium and allied taxa. The generic names Parascedosporium, Lomentospora, Petriella, Petriellopsis, and Scedosporium are proposed for a lineage within Microascaceae with mostly Scedosporium anamorphs producing slimy, annellidic conidia. Considering that Scedosporium has priority over Pseudallescheria and that Scedosporium prolificans is phylogenetically distinct fromthe other Scedosporium species, some name changes are proposed. Pseudallescheria minutispora and Petriellidium desertorum are renamed as Scedosporium minutisporum and S. desertorum, respectively. Scedosporium prolificans is renamed as Lomentospora prolificans.
    Fungal diversity 06/2014; DOI:10.1007/s13225-014-0295-4 · 6.94 Impact Factor
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    ABSTRACT: Shiga toxin 2 (Stx2) is believed to be a major virulence factor of enterohemorrhagic Escherichia coli (EHEC) contributing to hemolytic uremic syndrome (HUS). The complement system has recently been found to be involved in the pathogenesis of EHEC-associated HUS. Stx2 was shown to activate complement via the alternative pathway, to bind factor H (FH) at short consensus repeats (SCRs) 6-8 and 18-20 and to delay and reduce FH cofactor activity on the cell surface. We now show that complement factor H-related protein 1 (FHR-1) and factor H-like protein 1 (FHL-1), proteins of the FH protein family that show amino acid sequence and regulatory function similarities with FH, also bind to Stx2. The FHR-1 binding site for Stx2 was located at SCRs 3-5 and the binding capacity of FHR-1*A allotype was higher than that of FHR-1*B. FHR-1 and FHL-1 competed with FH for Stx2 binding, and in the case of FHR-1 this competition resulted in a reduction of FH cofactor activity. FHL-1 retained its cofactor activity in the fluid phase when bound to Stx2. In conclusion, multiple interactions of key complement inhibitors FH, FHR-1 and FHL-1 with Stx2 corroborate our hypothesis of a direct role of complement in EHEC-associated HUS.
    Molecular Immunology 12/2013; 58(1):77-84. DOI:10.1016/j.molimm.2013.11.009 · 3.00 Impact Factor
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    ABSTRACT: Platelets have been shown to cover a broad range of functions. Besides their role in hemostasis, they have immunological functions and thus participate in the interaction between pathogens and host defense. Platelets have a broad repertoire of receptor molecules that enable them to sense invading pathogens and infection-induced inflammation. Consequently, platelets exert antimicrobial effector mechanisms, but also initiate an intense crosstalk with other arms of the innate and adaptive immunity, including neutrophils, monocytes/macrophages, dendritic cells, B cells and T cells. There is a fragile balance between beneficial antimicrobial effects and detrimental reactions that contribute to the pathogenesis, and many pathogens have developed mechanisms to influence these two outcomes. This review aims to highlight aspects of the interaction strategies between platelets and pathogenic bacteria, viruses, fungi and parasites, in addition to the subsequent networking between platelets and other immune cells, and the relevance of these processes for the pathogenesis of infections.
    Future Microbiology 11/2013; 8(11):1431-51. DOI:10.2217/fmb.13.104 · 3.82 Impact Factor
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    ABSTRACT: As a consequence of innate immune activation granulocytes and macrophages produce hypochlorite/hypochlorous acid (HOCl) via secretion of myeloperoxidase (MPO) to the outside of the cells, where HOCl immediately reacts with proteins. Most proteins that become altered by this system do not belong to the invading microorganism but to the host. While there is no doubt that the myeloperoxidase system is capable of directly inactivating HIV-1, we hypothesized that it may have an additional indirect mode of action. We show in this article that HOCl is able to chemically alter proteins and thus turn them into Idea-Ps (Idea-P = immune defence-altered protein), potent amyloid-like and SH-groups capturing antiviral weapons against HIV-1. HOCl-altered plasma proteins (Idea-PP) have the capacity to bind efficiently and with high affinity to the HIV-1 envelope protein gp120, and to its receptor CD4 as well as to the protein disulfide isomerase (PDI). Idea-PP was able to inhibit viral infection and replication in a cell culture system as shown by reduced number of infected cells and of syncytia, resulting in reduction of viral capsid protein p24 in the culture supernatant. The unmodified plasma protein fraction had no effect. HOCl-altered isolated proteins antithrombin III and human serum albumin, taken as representative examples of the whole pool of plasma proteins, were both able to exert the same activity of binding to gp120 and inhibition of viral proliferation. These data offer an opportunity to improve the understanding of the intricacies of host-pathogen interactions and allow the generation of the following hypothetical scheme: natural immune defense mechanisms generate by posttranslational modification of plasma proteins a potent virucidal weapon that immobilizes the virus as well as inhibits viral fusion and thus entry into the host cells. Furthermore simulation of this mechanism in vitro might provide an interesting new therapeutic approach against microorganisms.
    PLoS ONE 06/2013; 8(6):e66073. DOI:10.1371/journal.pone.0066073 · 3.23 Impact Factor
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    ABSTRACT: Aspergillus terreus-induced invasive infections exhibit high lethality, partly due to the intrinsic resistance for amphotericin B (AmB). We compared the virulence and pathogenesis of an AmB-resistant isolate of A. terreus (ATR) with that of a rare variant showing enhanced sensitivity for AMB (ATS). The modifications that result in enhanced AmB sensitivity of isolates are not associated with reduced virulence in vivo; instead, the ATS-infected mice died even faster than the ATR-infected animals. Since A. terreus enters the blood stream in most patients and frequently induces thrombosis, we studied a putative correlation between virulence of the two A. terreus isolates and their effect on thrombocytes. Those mice infected with the more virulent ATS isolate had lower thrombocyte numbers and more phosphatidylserine exposure on platelets than ATR-infected mice. In vitro experiments confirmed that ATS and ATR differ in their effect on thrombocytes. Conidia, aleurioconidia and hyphae of ATS were more potent than ATR to trigger thrombocyte stimulation, and thrombocytes adhered better to ATS than to ATR fungal structures. Furthermore, ATS secreted more soluble factors that triggered platelet stimulation than ATR. Thus, it might be suggested that the capacity of a fungal isolate to modulate thrombocyte parameters contributes to its virulence in vivo.
    Medical Microbiology and Immunology 05/2013; 202(5). DOI:10.1007/s00430-013-0300-7 · 2.43 Impact Factor
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    ABSTRACT: Amphotericin B (AMB) is the predominant antifungal drug that acts fungicidal but the mechanism of resistance is not understood in detail.We compared in vivo virulence of AMB resistant (ATR) Aspergillus terreus (A. terreus) with a susceptible A. terreus (ATS) isolate using a murine model for disseminated aspergillosis. Furthermore we analyzed in vitro the molecular basis of intrinsic AMB resistance by comparing ergosterol content, cell associated AMB levels and AMB induced intracellular efflux and prooxidant effects between ATR and ATS. Infection of immunosuppressed mice with ATS or ATR showed that the ATS strain was even more lethal. However, AMB treatment improved the outcome of ATS infected mice while having no positive effect on animals infected with ATR. In vitro data displayed that ergosterol content is not the molecular basis for AMB resistance. ATR absorbed less AMB, discharged more intracellular compounds, and had better protection against oxidative damage than the susceptible strain.Our experiments showed that ergosterol content plays a minor role in intrinsic AMB resistance and is not directly associated with intracellular cell associated AMB content. AMB possibly exerts its antifungal activity rather by oxidative injury than by an increase of membrane permeation.
    Antimicrobial Agents and Chemotherapy 01/2013; 57(4). DOI:10.1128/AAC.01283-12 · 4.45 Impact Factor
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    ABSTRACT: In the course of invasive aspergillosis, platelets might be involved in immune defense, but also contribute to pathology of the disease. We tested the hypothesis that Aspergillus secretes factors that influence activity and functionality of thrombocytes. Platelets were incubated with medium wherein A. fumigatus was grown. This fungal culture supernatant potently stimulated thrombocytes time- and dose-dependently, inducing release of alpha and dense granules, membrane alterations, aggregation, and formation of microparticles. Fungus-induced platelet activation could be confirmed in vivo: thrombocytes from mice infected with A. fumigatus showed a higher activation level than platelets from non-infected animals. Two stimulating components in the fungal culture supernatant were identified: a fungal serine protease and the mycotoxin gliotoxin.Activation of platelets by fungal factors stimulates antifungal functions: platelets gain the capacity to interact with foreign particles, and they become able to inhibit fungal growth, thus supporting the host immune network. However, some consequences of platelet activation might also be harmful, including excessive inflammation and induction of thrombosis. These findings imply that measuring platelet activation in patients might be an interesting diagnostic parameter.
    The Journal of Infectious Diseases 12/2012; 207(5). DOI:10.1093/infdis/jis743 · 5.78 Impact Factor
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    Cornelia Speth · Günter Rambach
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    ABSTRACT: Invasive aspergillosis shows a high mortality rate particularly in immunocompromised patients. Perpetually increasing numbers of affected patients highlight the importance of a clearer understanding of interactions between innate immunity and fungi. Innate immunity is considered to be the most significant host defence against invasive fungal infections. Complement represents a crucial part of this first line defence and comprises direct effects against invading pathogens as well as bridging functions to other parts of the immune network. However, despite the potency of complement to attack foreign pathogens, the prevalence of invasive fungal infections is increasing. Two possible reasons may explain that phenomenon: First, complement activation might be insufficient for an effective antifungal defence in risk patients (due to, e.g., low complement levels, poor recognition of fungal surface, or missing interplay with other immune elements in immunocompromised patients). On the other hand, fungi may have developed evasion strategies to avoid recognition and/or eradication by complement. In this review, we summarize the most important interactions between Aspergillus and the complement system. We describe the various ways of complement activation by Aspergillus and the antifungal effects of the system, and also show proven and probable mechanisms of Aspergillus for complement evasion.
    Interdisciplinary Perspectives on Infectious Diseases 08/2012; 2012(1):463794. DOI:10.1155/2012/463794
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    ABSTRACT: Representatives of the genus Pseudallescheria (anamorph: Scedosporium) are saprobes and the aetiologic agent of invasive mycosis in humans. After dissemination, the central nervous system (CNS) is one of the most affected organs. Prerequisites for the survival of Pseudallescheria/Scedosporium in the host are the ability to acquire nutrients and to evade the immune attack. The cleavage of complement compounds via the secretion of fungal proteases might meet both challenges since proteolytic degradation of proteins can provide nutrients and destroy the complement factors, a fast and effective immune weapon in the CNS. Therefore, we studied the capacity of different Pseudallescheria/Scedosporium species to degrade key elements of the complement cascade in the cerebrospinal fluid and investigated a correlation with the phylogenetic background. The majority of the Pseudallescheria apiosperma isolates tested were demonstrated to efficiently eliminate proteins like complement factors C3 and C1q, thus affecting two main components of a functional complement cascade, presumably by proteolytic degradation, and using them as nutrient source. In contrast, the tested strains of Pseudallescheria boydii have no or only weak capacity to eliminate these complement proteins. We hypothesise that the ability of Pseudallescheria/Scedosporium strains to acquire nutrients and to undermine the complement attack is at least partly phylogenetically determined.
    Mycoses 10/2011; 54 Suppl 3:48-55. DOI:10.1111/j.1439-0507.2011.02117.x · 1.81 Impact Factor
  • Mycoses 09/2011; 54(5):375-375. · 1.81 Impact Factor
  • Mycoses 09/2011; 54(5):380-380. · 1.81 Impact Factor
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    ABSTRACT: The complement system is tightly controlled by several regulators. Two of these, factor H (FH) and C4b-binding protein (C4BP), can be acquired by pathogens conveying resistance to complement attack. The aim of the study was to characterize the FH binding molecule of Candida albicans, a potentially life-threatening yeast. The gene coding for this molecule was identified by probing an expression library and homozygous deletion mutants of the respective gene were constructed. Binding and functional assays were undertaken to compare wild-type and knockout strains. The high-affinity glucose transporter 1 (CaHgt1p) was identified as an FH-binding molecule. Homozygous hgt1Δ/Δ deletion mutants, but not the restored strain in which HGT1 was reintegrated, showed a decreased binding of FH and even of C4BP, demonstrating its function as an FH- and C4BP-binding protein. This led to an enhanced terminal complement complex deposition after incubation with human serum; CaHgt1p thus functions as complement inhibitor. hgt1Δ/Δ mutants failed to form rosettes with complement-coated sheep erythrocytes, and show reduced binding to HIV-gp160, implying that a complement receptor 3 (CR3) moiety, known as fungal HIV binding molecule is lacking. CaHgt1p is a multifunctional evasion molecule, as complement inhibitor, CR3 analogue and HIV receptor.
    The Journal of Infectious Diseases 09/2011; 204(5):802-9. DOI:10.1093/infdis/jir455 · 5.78 Impact Factor
  • Mycoses 09/2011; 54(5):374-374. · 1.81 Impact Factor
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    ABSTRACT: The mycotoxin gliotoxin is an important metabolite produced by Aspergillus fumigatus, but its precise role in the pathogenesis of cerebral aspergillosis is not yet determined. We could demonstrate that growth in cerebrospinal fluid (CSF) induced the production and secretion of significant amounts of gliotoxin by A. fumigatus. These concentrations of 590-720nM were sufficient to reduce the viability of astrocytes and neurons, as well as of primary microglia, already after few hours of incubation. Annexin staining and electron microscopy revealed the induction of apoptosis rather than necrosis as the relevant mode of gliotoxin action in the brain. Furthermore, even a low gliotoxin concentration of 100nM, which was subtoxic for astrocytes, was able to significantly down-modulate the phagocytic capacity of astrocytes. In order to improve the current antimycotic therapy of cerebral aspergillosis by supporting innate immunity in the fight against Aspergillus, we aimed to neutralize the toxic potency of gliotoxin towards different brain cell types. Compounds such as dithiothreitol (DTT) or glutathione that reduce the internal disulfide bond of gliotoxin were shown here to be able to interfere with the gliotoxin-induced decrease of cell viability and to save the cells from induction of apoptosis. Thus, exploration of these substances may lead to novel approaches for adjunctive treatment of cerebral aspergillosis.
    Molecular Immunology 07/2011; 48(15-16):2122-9. DOI:10.1016/j.molimm.2011.07.005 · 3.00 Impact Factor
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    ABSTRACT: A collection of 2,834 isolates of Candida spp. and 1,079 isolates of Aspergillus spp. and other moulds that were recovered between 2000 and 2007 in Tyrol, Austria, were examined for their susceptibility to antifungal drugs. The susceptibility of Candida spp. to amphotericin B (AMB), caspofungin (CPF), fluconazole (FLC), and voriconazole (VRC) were studied, while filamentous fungi were tested against AMB, CPF, VRC, itraconazole (ITC), and posaconazole (POS). As EUCAST and CLSI are currently revising their breakpoints for several antifungal agents, epidemiological cutoff values (ECVs) of these two guidelines were used to examine trends in susceptibility. For Candida spp. we noted increases in the percentage of non-wild type isolates which were resistant to CPF, FLC, and VRC. Most noticeably, we observed a change in: C. tropicalis (from 0.9-3.8%) and C. parapsilosis (from 4.0-6.0%) relative to CPF; C. parapsilosis (from 0.8-3.4%) and C. glabrata (from 11.0-20%) against FLC; and C. glabrata (from 3.0-12.0%) for VRC. Among the moulds, most Aspergillus spp. isolates were found to be susceptible to VRC, ITC, and POS, while AMB and POS were confirmed to be the most effective agents against zygomycetes. EUCAST and CLSI should continue their efforts to harmonize their methods of antimicrobial susceptibility testing (AST) and to define additional and shareable epidemiological cutoff values and clinical breakpoints.
    Medical mycology: official publication of the International Society for Human and Animal Mycology 05/2011; 49(8):856-63. DOI:10.3109/13693786.2011.583943 · 2.26 Impact Factor
  • Mycoses 09/2010; 53(5):382-383. · 1.81 Impact Factor
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    ABSTRACT: Complement represents a central immune weapon in the brain, but the high lethality of cerebral aspergillosis indicates a low efficacy of the antifungal complement attack. Studies with cerebrospinal fluid (CSF) samples derived from a patient with cerebral aspergillosis showed a degradation of complement proteins, implying that Aspergillus might produce proteases to evade their antimicrobial potency. Further investigations of this hypothesis showed that Aspergillus, when cultured in CSF to simulate growth conditions in the brain, secreted a protease that can cleave various complement proteins. Aspergillus fumigatus, the most frequent cause of cerebral aspergillosis, destroyed complement activity more efficiently than other Aspergillus species. The degradation of complement in CSF resulted in a drastic reduction of the capacity to opsonize fungal hyphae. Furthermore, the Aspergillus-derived protease could diminish the amount of complement receptor CR3, a surface molecule to mediate eradication of opsonized pathogens, on granulocytes and microglia. The lack of these prerequisites caused a significant decrease in phagocytosis of primary microglia. Additional studies implied that the complement-degrading activity shares many characteristics with the previously described alkaline protease Alp1. To improve the current therapy for cerebral aspergillosis, we tried to regain the antifungal effects of complement by repressing the secretion of this degrading activity. Supplementation of CSF with nitrogen sources rescued the complement proteins and abolished any cleavage. Glutamine or arginine are of special interest for this purpose since they represent endogenous substances in the CNS and might be included in a future supportive therapy to reduce the high lethality of cerebral aspergillosis.
    Molecular Immunology 03/2010; 47(7-8):1438-49. DOI:10.1016/j.molimm.2010.02.010 · 3.00 Impact Factor

Publication Stats

1k Citations
319.67 Total Impact Points

Institutions

  • 1997–2015
    • University of Innsbruck
      • Institute of Biochemistry
      Innsbruck, Tyrol, Austria
    • IST Austria
      Klosterneuberg, Lower Austria, Austria
  • 2007
    • Lund University
      Lund, Skåne, Sweden
    • Medizinische Universität Innsbruck
      • Sektion für Hygiene und Medizinische Mikrobiologie
      Innsbruck, Tyrol, Austria