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

Institute for Virology and Immunobiology and Research Center for Infectious Diseases (ZINF)
 
Julius Maximilians University Würzburg

niklas.beyersdorf@vim.uni-wuerzburg.de

 

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

Department of Infection Biology 

Leibniz Institute for Natural Product Research and Infection Biology – Hans Knöll Institute  

peter.zipfel@leibniz-hki.de

Publications
Author Year Title Journal Links
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 Royal Society Publishing
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
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(2) pii: 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 Front Microbiol
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