Project C6

Secreted fungal proteins in immune evasion and pathogenicity

The fungal pathogens C. albicans and A. fumigatus secret immune evasion proteins to control the immune response of the human host. In project C6, we characterize the role of secreted fungal proteins in immune evasion. Both fungal pathogens use related proteins like Pra1 (C. albicans) and Aspf2 (the Pra1 homolog of A. fumigatus) to bind host regulators and plasminogen. Plasminogen attached to either the purified proteins or to the fungal pathogens is accessible for activators and can be converted to the active protease plasmin. Active plasmin then damages host endothelial and epithelial cells and induces cell retraction. Thus, the subcellular matrix is exposed and further degradation of matrix components is induced. Such local tissue damage ultimately helps the pathogenic microbe to cross host tissue barriers and to disseminate into deeper tissue layers.

Several of the secreted fungal proteins are fungal moonlighting proteins. Examples for such multifunctional fungal immune evasion proteins are Tef-1 (Translations elongation factor 1), and Pra1 (the pH regulated antigen1) that both contribute to fungal pathogenicity. Both C. albicans moonlighting proteins mediate fungal immune escape by inhibiting both innate and adaptive immune reaction of the human host. We have generated monoclonal antibodies (mAbs) against these immune evasion proteins. In the next funding period, we will continue the in vitro studies and extend the analyses to fungal immune escape in mice. Moreover, we will evaluate our anti-fungal mAbs in mouse models of C. albicans infections.

Human endothelial cells (HUVEC)

HUVEC cells + C. albicans with plasmin attached

C. albicans having the active protease plasmin attached to the surface damages human endothelial cells.
(A) Intact human endothelial cells (HUVEC) from a cell monolayer. (B) HUVEC cells challenged with C. albicans with the active protease on the surface are damaged. The cell retract and the sub endothelial matrix becomes exposed.
(C) C. albicans (arrow) attached to the surface of human cells.
(D) Enlarged view

Principal Investigators
Dr. Niklas Beyersdorf
PD Dr. Niklas Beyersdorf

Principal Investigator

Prof. Dr. Peter F. Zipfel
Prof. Dr. Peter F. Zipfel

Principal Investigator

Author Year Title Journal Links
Halder LD, Babych S, Palme DI, Mansouri-Ghahnavieh E, Ivanov L, Ashonibare V, Langenhorst D, Prusty B, Rambach G, Wich M, Trinks N, Blango MG, Kornitzer D, Terpitz U, Speth C, Jungnickel B, Beyersdorf N, Zipfel PF, Brakhage AA, Skerka C 2022 Candida albicans induces cross-kingdom miRNA trafficking in human monocytes to promote fungal growth. mBio 13(1): e0356321 mBio
Ickrath P, Sprügel L, Beyersdorf N, Scherzad A, Hagen R, Hackenberg S 2021 Detection of Candida albicans-specific CD4+ and CD8+ T cells in the blood and nasal mucosa of patients with chronic Rhinosinusitis. J Fungi (Basel) 7: 403 J Fungi
Shopova IA, Belyaev I, Dasari P, Jahreis S, Stroe MC, Cseresnyés Z, Zimmermann AK, Medyukhina A, Svensson CM, Krüger T, Szeifert V, Nietzsche S, Conrad T, Blango MG, Kniemeyer O, Lilienfeld-Toal Mv, Zipfel PF, Ligeti E, Figge MT, Brakhage AA 2020 Human neutrophils produce antifungal extracellular vesicles against Aspergillus fumigatus. mBio 11: e00596-20 PubMed
Halder LD, Jo EAH, Hasan MZ, Ferreira-Gomes M, Krüger T, Westermann M, Palme DI, Rambach G, Beyersdorf N, Speth C, Jacobsen ID, Kniemeyer O, Jungnickel B, Zipfel PF, Skerka C 2020 Immune modulation by complement receptor 3 dependent human monocyte TGF-β1-transporting vesicles. Nat Commun 11: 2331 PubMed
Tille A, Lehnert T, Zipfel PF, Figge MT 2020 Quantification of factor H mediated self versus non-self discrimination by mathematical modeling. Front Immunol 11: 1911 Frontiers
Haack S, Baiker S, Schlegel J, Sauer M, Sparwasser T, Langenhorst D, Beyersdorf N 2020 Superagonistic CD28 stimulation induces Interferon y release from mouse T Helper 1 cells in vitro and in vivo. Eur J Immunol [Epub ahead of print] PubMed
Irmscher S, Brix S, Zipfel SLH, Halder LD, Mutlutürk S, Wulf S, Girdauskasm E, Reichenspurner H, Stahl RAK, Jungnickel B, Wiech T, Zipfel PF, Skerka C 2019 Serum FHR1 binding to necrotic-type cells activates monocytic inflammasome and marks necrosic sites in vasculopathies. Nat Commun 10: 2961 PubMed
Breitenbach T, Liang C, Beyersdorf N, Dandekar T 2019 Analyzing pharmacological intervention points: A method to calculate external stimuli to switch between steady states in regulatory networks. PLoS Comput Biol 15: e1007075 PubMed
Klaile E, Müller MM, Brehme S, Zubiria-Barrera C, Klassert TE, Stock M, Durotin A, Nguyen TD, Feer S, Singer BB, Zipfel PF, Rudolphi S, Jacobsen ID, Slevogt H 2019 Unaltered fungal burden and lethality in human CEACAM1-transgenic mice during Candida albicans dissemination and systemic infection. Front Microbiol 10: 2703 PubMed
Dasari P, Koleci N, Shopova I, Wartenberg D, Beyersdorf N, Dietrich S, Sahagún-Ruiz A, Figge MT, Skerka C, Brakhage AA, Zipfel PF 2019 Enolase from Aspergillus fumigatus is a moonlighting and immune evasion protein that binds the human plasma complement protein factors H, FHL-1, C4BP, and Plasminogen. Front Immunol 10: 2573 PubMed
Lang SN, Germrodt S, Glock C, Skerka C, Zipfel PF, Schuster S 2019 Molecular crypsis by pathogenic fungi using human factor H. A numerical model. PLoS One 14: e0212187 PubMed
Yin C, Ackermann S, Ma Z, Mohanta SK, Zhang C, Li Y, Nietzsche S, Westermann M, Peng L, Hu D, Bontha SV, Srikakulapu P, Beer M, Megens RTA, Steffens S, Hildner M, Halder LD, Eckstein HH, Pelisek J, Herms J, Roeber S, Arzberger T, Borodovsky A, Habenicht L, Binder CJ, Weber C, Zipfel PF, Skerka C, Habenicht AJR 2019 ApoE attenuates unresolvable inflammation by complex formation with activated C1q. Nat Med 25: 496-506 PubMed
Meinel C, Spartà G, Dahse H-M, Hörhold F, König R, Westermann M, Cseresnyés Z, Coldewey SM, Figge MT, Hammerschmidt S, Skerka C, Zipfel PF 2018 Streptococcus pneumoniae from patients with hemolytic uremic syndrome binds human plasminogen via the surface protein PspC and uses plasmin to damage human endothelial cells. J Infect Dis 217: 358-70 PubMed
Irmscher S, Döring N, Halder LD, Jo EAH, Kopka I, Dunker C, Jacobsen ID, Luo S, Slevogt H, Lorkowski S, Beyersdorf N, Zipfel PF, Skerka C 2018 Kallikrein cleaves C3 and activates complement. J Innate Immun 10: 94-105 PubMed
Hummert S, Glock C, Lang SN, Hummert C, Skerka C, Zipfel PF, Germerodt S, Schuster S 2018 Playing ’hide-and-seek’ with factor H: game-theoretical analysis of a single nucleotide polymorphism. J R Soc Interface 15: 20170963 PubMed
Dasari P, Shopova IA, Stroe M, Wartenberg D, Dahse HM, Beyersdorf N, Hortschansky P, Dietrich S, Cseresnyés Z, Figge MT, Westermann M, Skerka C, Brakhage AA, Zipfel PF 2018 Aspf2 from Aspergillus fumigatus recruits human immune regulators for immune evasion and cell damage. Front Immunol 9: 1635 Frontiers
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 2018 The secreted Candida albicans protein Pra1 disrupts host defense by broadly targeting and blocking complement C3 and C3 activation fragments. Mol Immunol 93: 266-77 PubMed
Halder LD, Abdelfatah MA, Jo E, Jacobsen ID, Westermann M, Beyersdorf N, Lorkowski S, Zipfel PF, Skerka C 2017 Factor H binds to extracellular DNA traps released from human blood monocytes in response to Candida albicans. Front Immunol 7: 671 PubMed
Klaile E, Müller M, Schäfer MR, Feer S, Heyl K, Stock M, Klassert T, Zipfel P, Singer P 2017 Binding of Candida albicans to human CEACAM1 and CEACAM6 modulates the inflammatory response of intestinal epithelial cells. mBio 8: e02142-16 PubMed
Bergfeld A, Dasari P, Werner S, Hughes TR, Song WC, Hortschansky P, Brakhage AA, Hünig T, Zipfel PF, Beyersdorf N 2017 Direct binding of the pH-regulated protein 1 (Pra1) from Candida albicans inhibits cytokine secretion by mouse CD4+ T cells. Front Microbiol 8: 844 PubMed
Pollmächer J, Timme S, Schuster S, Brakhage AA, Zipfel PF, Figge MT 2016 Deciphering the counterplay of Aspergillus fumigatus infection and host inflammation by evolutionary games on graphs. Sci Rep 6: 27807 PubMed
Buhlmann D, Eberhardt HU, Medyukhina A, Prodinger WM, Figge MT, Zipfel PF, Skerka C 2016 Complement factor H related protein 3 (FHR3) blocks C3d-mediated co-activation of human B cells. J Immunol 197: 620-9 PubMed
Berges C, Kerkau T, Werner S, Wolf N, Winter N, Hünig T, Einsele H, Topp MS, Beyersdorf N 2016 Hsp90 inhibition ameliorates CD4+ T cell-mediated acute graft versus host disease in mice. Immun Inflamm Dis 4: 463-73 PubMed
Dühring S, Germerodt S, Skerka C, Zipfel PF, Dandekar T, Schuster S 2015 Host-pathogen interactions between the human innate immune system and Candida albicans - understanding and modeling defense and evasion strategies. Front Microbiol 6: 625 Frontiers
Luo S, Hipler UC, Münzberg C, Skerka C, Zipfel PF 2015 Sequence variations and protein expression levels of the two immune evasion proteins Gpm1 and Pra1 influence virulence of clinical Candida albicans isolates. PLoS One 10: e0113192 PubMed
Zipfel PF, Skerka C 2014 Staphylococcus aureus: the multi headed hydra resists and controls human complement response in multiple ways. Int J Med Microbio 304: 188-94 PubMed