Project C4

Modulation of monocyte and B cell functions by humoral immunity in response to Candida albicans

Protection from C. albicans infection is mainly based on innate cellular immunity that is fine-tuned by T cells. Project C4 aims at elucidating how C. albicans changes the humoral immune response to affect the cellular response, Monocytes/macrophages are an essential part of antifungal immunity, in part due to their regulatory role at the intersection of innate and adaptive immune responses. In the first funding period we characterized the reaction of monocytes to C. albicans and found that monocytes release extracellular DNA nets (ETs) that trap the fungal cells in a manner similar to neutrophilic granulocytes. These ETs contain substances like citrullinated histones and myeolperoxidase that attack the fungus. C. albicans is known to recruit human regulators like complement factor H to the surface to inhibit innate immune reactions like complement activation and opsonization. Recently we identified kallikrein, which is activated from prekallikrein in response to contact activation on the C. albicans surface as a complement activator that cleaves C3 and factor B. However, factor H on C. albicans also inhibits this pathway of complement activation. Further studies will include the detailed analysis of fungal proteins and recruited human complement regulatory proteins (FHR1) and their interaction with monocytes and B cells via distinct receptors. Furthermore, the analysis of B cell populations reacting to C. albicans in reporter mice infected or colonized with C. albicans will give insights into the in vivo immune response to C. albicans.

C. albicans (hyphae) trapped in extracellular nets derived from monocytes.
C. albicans (hyphae) trapped in extracellular nets derived from monocytes.
Principal Investigators
Prof. Dr. Christine Skerka
Prof. Dr. Christine Skerka

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
Ferreira-Gomes M, Wich M, Böde S, Hube B, Jacobsen ID, Jungnickel B 2021 B cell recognition of Candida albicans hyphae via TLR 2 promotes IgG1 and IL-6 Secretion for TH17 differentiation. Front Immunol 12: 698849 PubMed
Wich M, Greim S, Ferreira-Gomes M, Krüger T, Kniemeyer O, Brakhage AA, Jacobsen ID, Hube B, Jungnickel B 2021 Functionality of the human antibody response to Candida albicans. Virulence 12: 3137-48 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
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
Hirth G, Svensson CM, Böttcher K, Ullrich S, Figge MT, Jungnickel B 2019 Regulation of the germinal center reaction and somatic hypermutation dynamics by homologous recombination. J Immunol 203: 1493-1501 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
Klassert TE, Bräuer J, Hölzer M, Stock M, Riege K, Zubiría-Barrera C, Müller MM, Rummler S, Skerka C, Marz M, Slevogt H 2017 Differential effects of vitamins A and D on the transcriptional landscape of human monocytes during infection. Sci Rep 7: 40599 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
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
Kraibooj K, Park HR, Dahse HM, Skerka C, Voigt K, Figge MT 2014 Virulent strain of Lichtheimia corymbifera shows increased phagocytosis by macrophages as revealed by automated microscopy image analysis. Mycoses 57 Suppl 3: 56-66 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