TY  - JOUR
A1  - Dühring, Sybille
A1  - Germerodt, Sebastian
A1  - Skerka, Christine
A1  - Zipfel, Peter F.
A1  - Dandekar, Thomas
A1  - Schuster, Stefan
T1  - Host-pathogen interactions between the human innate immune system and Candida albicans - understanding and modeling defense and evasion strategies
JF  - Frontiers in Microbiology
N2  - The diploid, polymorphic yeast Candida albicans is one of the most important human pathogenic fungi. C. albicans can grow, proliferate and coexist as a commensal on or within the human host for a long time. However, alterations in the host environment can render C. albicans virulent. In this review, we describe the immunological cross-talk between C. albicans and the human innate immune system. We give an overview in form of pairs of human defense strategies including immunological mechanisms as well as general stressors such as nutrient limitation, pH, fever etc. and the corresponding fungal response and evasion mechanisms. Furthermore, Computational Systems Biology approaches to model and investigate these complex interactions are highlighted with a special focus on game-theoretical methods and agent-based models. An outlook on interesting questions to be tackled by Systems Biology regarding entangled defense and evasion mechanisms is given.
KW  - agent-based model
KW  - antimicrobial peptides
KW  - fungal pathogens
KW  - Candida albicans
KW  - immunological cross-talk
KW  - beta-lactamase inhibition
KW  - in vitro
KW  - biomaterial surfaces
KW  - biofilm formation
KW  - dendritic cells
KW  - infection
KW  - resistance
KW  - human immune system
KW  - host-pathogen interaction
KW  - computational systems biology
KW  - defense and evasion strategies
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-151621
VL  - 6
IS  - 625
ER  - 
TY  - JOUR
A1  - Bergfeld, Arne
A1  - Dasari, Prasad
A1  - Werner, Sandra
A1  - Hughes, Timothy R.
A1  - Song, Wen-Chao
A1  - Hortschansky, Peter
A1  - Brakhage, Axel A.
A1  - Hünig, Thomas
A1  - Zipfel, Peter F.
A1  - Beyersdorf, Niklas
T1  - Direct binding of the pH-regulated Protein 1 (Pra1) from Candida albicans inhibits cytokine secretion by mouse CD4\(^{+}\) T cells
JF  - Frontiers in Microbiology
N2  - Opportunistic infections with the saprophytic yeast Candida albicans are a major cause of morbidity in immunocompromised patients. While the interaction of cells and molecules of innate immunity with C. albicans has been studied to great depth, comparatively little is known about the modulation of adaptive immunity by C. albicans. In particular, direct interaction of proteins secreted by C. albicans with CD4\(^{+}\) T cells has not been studied in detail. In a first screening approach, we identified the pH-regulated antigen 1 (Pra1) as a molecule capable of directly binding to mouse CD4\(^{+}\) T cells in vitro. Binding of Pra1 to the T cell surface was enhanced by extracellular Zn\(^{2+}\) ions which Pra1 is known to scavenge from the host in order to supply the fungus with Zn\(^{2+}\). In vitro stimulation assays using highly purified mouse CD4\(^{+}\) T cells showed that Pra1 increased proliferation of CD4\(^{+}\) T cells in the presence of plate-bound anti-CD3 monoclonal antibody. In contrast, secretion of effector cytokines such as IFNγ and TNF by CD4\(^{+}\) T cells upon anti-CD3/ anti-CD28 mAb as well as cognate antigen stimulation was reduced in the presence of Pra1. By secreting Pra1 C. albicans, thus, directly modulates and partially controls CD4\(^{+}\) T cell responses as shown in our in vitro assays.
KW  - Candida albicans
KW  - pH-regulated antigen 1 (Pra1)
KW  - CD4\(^{+}\) T cells
KW  - immune evasion
KW  - cytokine secretion
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-158274
VL  - 8
IS  - 844
ER  - 
TY  - JOUR
A1  - Halder, Luke D.
A1  - Abdelfatah, Mahmoud A.
A1  - Jo, Emeraldo A. H.
A1  - Jacobsen, Ilse D.
A1  - Westermann, Martin
A1  - Beyersdorf, Niklas
A1  - Lorkowski, Stefan
A1  - Zipfel, Peter F.
A1  - Skerka, Christine
T1  - Factor H binds to extracellular DNA traps released from human blood monocytes in response to Candida albicans
JF  - Frontiers in Immunology
N2  - Upon systemic infection with human pathogenic yeast Candida albicans (C. albicans), human monocytes and polymorph nuclear neutrophilic granulocytes are the first immune cells to respond and come into contact with C. albicans. Monocytes exert immediate candidacidal activity and inhibit germination, mediate phagocytosis, and kill fungal cells. Here, we show that human monocytes spontaneously respond to C. albicans cells via phagocytosis, decondensation of nuclear DNA, and release of this decondensed DNA in the form of extracellular traps (called monocytic extracellular traps: MoETs). Both subtypes of monocytes (CD14\(^{++}\)CD16\(^−\)/CD14\(^+\)CD16\(^+\)) formed MoETs within the first hours upon contact with C. albicans. MoETs were characterized by the presence of citrullinated histone, myeloperoxidase, lactoferrin, and elastase. MoETs were also formed in response to Staphylococcus aureus and Escherichia coli, indicating a general reaction of monocytes to infectious microbes. MoET induction differs from extracellular trap formation in macrophages as MoETs are not triggered by simvastatin, an inhibitor of cholesterol synthesis and inducer of extracellular traps in macrophages. Extracellular traps from both monocytes and neutrophils activate complement and C3b is deposited. However, factor H (FH) binds via C3b to the extracellular DNA, mediates cofactor activity, and inhibits the induction of the inflammatory cytokine interleukin-1 beta in monocytes. Altogether, the results show that human monocytes release extracellular DNA traps in response to C. albicans and that these traps finally bind FH via C3b to presumably support clearance without further inflammation.
KW  - Candida
KW  - monocytes
KW  - DNA traps
KW  - MPO
KW  - factor H
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-181127
VL  - 7
ER  - 
TY  - JOUR
A1  - Dasari, Prasad
A1  - Shopova, Iordana A.
A1  - Stroe, Maria
A1  - Wartenberg, Dirk
A1  - Martin-Dahse, Hans
A1  - Beyersdorf, Niklas
A1  - Hortschansky, Peter
A1  - Dietrich, Stefanie
A1  - Cseresnyés, Zoltán
A1  - Figge, Marc Thilo
A1  - Westermann, Martin
A1  - Skerka, Christine
A1  - Brakhage, Axel A.
A1  - Zipfel, Peter F.
T1  - Aspf2 From Aspergillus fumigatus Recruits Human Immune Regulators for Immune Evasion and Cell Damage
JF  - Frontiers in Immunology
N2  - The opportunistic fungal pathogen Aspergillus fumigatus can cause life-threatening infections, particularly in immunocompromised patients. Most pathogenic microbes control host innate immune responses at the earliest time, already before infiltrating host immune cells arrive at the site of infection. Here, we identify Aspf2 as the first A. fumigatus Factor H-binding protein. Aspf2 recruits several human plasma regulators, Factor H, factor-H-like protein 1 (FHL-1), FHR1, and plasminogen. Factor H contacts Aspf2 via two regions located in SCRs6–7 and SCR20. FHL-1 binds via SCRs6–7, and FHR1 via SCRs3–5. Factor H and FHL-1 attached to Aspf2-maintained cofactor activity and assisted in C3b inactivation. A Δaspf2 knockout strain was generated which bound Factor H with 28% and FHL-1 with 42% lower intensity. In agreement with less immune regulator acquisition, when challenged with complement-active normal human serum, Δaspf2 conidia had substantially more C3b (>57%) deposited on their surface. Consequently, Δaspf2 conidia were more efficiently phagocytosed (>20%) and killed (44%) by human neutrophils as wild-type conidia. Furthermore, Aspf2 recruited human plasminogen and, when activated by tissue-type plasminogen activator, newly generated plasmin cleaved the chromogenic substrate S2251 and degraded fibrinogen. Furthermore, plasmin attached to conidia damaged human lung epithelial cells, induced cell retraction, and caused matrix exposure. Thus, Aspf2 is a central immune evasion protein and plasminogen ligand of A. fumigatus. By blocking host innate immune attack and by disrupting human lung epithelial cell layers, Aspf2 assists in early steps of fungal infection and likely allows tissue penetration.
KW  - complement
KW  - blocking opsonization
KW  - phagocytosis
KW  - acquisition of host regulators
KW  - immune evasion
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-197013
SN  - 1664-3224
VL  - 9
IS  - 1635
ER  - 
TY  - JOUR
A1  - Dasari, Prasad
A1  - Koleci, Naile
A1  - Shopova, Iordana A.
A1  - Wartenberg, Dirk
A1  - Beyersdorf, Niklas
A1  - Dietrich, Stefanie
A1  - Sahagún-Ruiz, Alfredo
A1  - Figge, Marc Thilo
A1  - Skerka, Christine
A1  - Brakhage, Axel A.
A1  - Zipfel, Peter F.
T1  - Enolase from Aspergillus fumigatus is a moonlighting protein that binds the human plasma complement proteins factor H, FHL-1, C4BP, and plasminogen
JF  - Frontiers in Immunology
N2  - The opportunistic fungal pathogen Aspergillus fumigatus can cause severe infections, particularly in immunocompromised individuals. Upon infection, A. fumigatus faces the powerful and directly acting immune defense of the human host. The mechanisms on how A. fumigatus evades innate immune attack and complement are still poorly understood. Here, we identify A. fumigatus enolase, AfEno1, which was also characterized as fungal allergen, as a surface ligand for human plasma complement regulators. AfEno1 binds factor H, factor-H-like protein 1 (FHL-1), C4b binding protein (C4BP), and plasminogen. Factor H attaches to AfEno1 via two regions, via short conserved repeats (SCRs) 6–7 and 19–20, and FHL-1 contacts AfEno1 via SCRs 6–7. Both regulators when bound to AfEno1 retain cofactor activity and assist in C3b inactivation. Similarly, the classical pathway regulator C4BP binds to AfEno1 and bound to AfEno1; C4BP assists in C4b inactivation. Plasminogen which binds to AfEno1 via lysine residues is accessible for the tissue-type plasminogen activator (tPA), and active plasmin cleaves the chromogenic substrate S2251, degrades fibrinogen, and inactivates C3 and C3b. Plasmin attached to swollen A. fumigatus conidia damages human A549 lung epithelial cells, reduces the cellular metabolic activity, and induces cell retraction, which results in exposure of the extracellular matrix. Thus, A. fumigatus AfEno1 is a moonlighting protein and virulence factor which recruits several human regulators. The attached human regulators allow the fungal pathogen to control complement at the level of C3 and to damage endothelial cell layers and tissue components.
KW  - complement factor H
KW  - moonlighting
KW  - immune evasion
KW  - plasminogen
KW  - blocking phagocytosis
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-195612
SN  - 1664-3224
VL  - 10
ER  -